Alzheimer's disease is a progressive neurodegenerative disorder characterized by accumulation of amyloid-beta plaques and neurofibrillary tau tangles, leading to irreversible cognitive decline and dementia.

Exam domain	One-glance essentials
Definition / diagnosis	*Alzheimer disease is biologically defined by amyloid-β and tau pathology; symptoms are not required for biological diagnosis* ^[1] *It is the commonest dementia cause, accounting for about 50–60%* ^[2] Dementia requires cognitive decline that interferes with independent daily function
Epidemiology / risks	Age is strongest; family history, female sex, APOE ε4, Down syndrome and head trauma increase risk ^[2]^[3] Vascular risks, low education, hearing loss, inactivity and social isolation are modifiable contributors
Core mechanism	APP β/γ-secretase cleavage → Aβ42 oligomers/plaques → tau hyperphosphorylation → intracellular tangles and synaptic loss ^[3] Pathology spreads entorhinal cortex → hippocampus → parietal association cortex → neocortex Nucleus basalis cholinergic loss explains the symptomatic response to cholinesterase inhibitors
Clinical picture	Insidious, steadily progressive anterograde amnesia is typical; remote memory is relatively spared early ^[2]^[3] Progression produces the 4 As: amnesia, aphasia, apraxia, agnosia plus visuospatial/executive decline Early neurological examination is usually normal; behavioural symptoms emerge with progression
Investigations	Collateral history + MoCA and functional assessment; exclude delirium and depression Mandatory screen: CBC, B12/folate, TFT, RFT, calcium, glucose and CT/MRI brain ^[3] MRI: medial temporal/hippocampal atrophy; biological signature: Aβ42/40 low + p-tau high ^[1]
Management	Mild–moderate: donepezil, rivastigmine or galantamine; moderate–severe: memantine ± cholinesterase inhibitor ^[3] BPSD: identify triggers and use non-pharmacological care first; antipsychotics only for danger/distress Exercise, cognitive stimulation, carer support, safety review and early advance care planning
Complications	Dysphagia → aspiration pneumonia, the commonest cause of death Falls, malnutrition, wandering, incontinence, pressure injury, seizures and delirium superimposed on dementia Cholinesterase inhibitors may cause GI upset, weight loss, bradycardia and syncope
Prevention / follow-up	Control hypertension, diabetes, lipids and smoking; maintain physical, cognitive and social activity Optimise hearing/vision and reduce anticholinergic burden Home safety, driving assessment, medication supervision and carer respite prevent downstream harm
Exam traps	Acute fluctuating inattention = delirium until proven otherwise, even in established AD Step-change after a fall → exclude chronic subdural haematoma DLB clues (early visual hallucinations, RBD, parkinsonism) demand caution: antipsychotic sensitivity APOE ε4 is a risk allele, not a stand-alone diagnosis

References

^[1] Lecture slides: GC 241. Reference (1) - Alzheimers Dementia - Revised criteria for diagnosis and staging of Alzheimer s disease.pdf ^[2] Lecture slides: GC 169. My grandmother keeps forgetting things Geriatric psychiatry, Dementia.pdf ^[3] Senior notes: Ryan Ho Neurology.pdf (pp. 128–131); Ryan Ho Psychiatry.pdf (pp. 90–92)

Alzheimer's Disease

Alzheimer's disease (AD) is a chronic, progressive neurodegenerative disease defined by its unique neuropathology — specifically, the accumulation of amyloid-beta (Aβ) plaques and neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau protein in the brain. It is the commonest cause of dementia, accounting for 50–60% of all dementia cases ^[1].

The name "Alzheimer's" comes from Dr. Alois Alzheimer, the German psychiatrist who first described the clinical and neuropathological features in 1906.

Biology vs Syndrome: A Critical Distinction (2024 NIA-AA Revised Criteria)

AD is now defined by its biology, not by its symptoms. ^[3] The 2024 revised NIA-AA criteria emphasise that:

AD is defined by its unique neuropathologic findings; therefore, detection of AD neuropathologic change by biomarkers is equivalent to diagnosing the disease. ^[3]
Symptoms are a result of the disease process and are not necessary to diagnose AD. ^[3]
Clinical syndromes commonly seen with AD may also be caused by disorders other than AD, and therefore clinical presentation alone is not diagnostic of AD. ^[3]
AD exists on a continuum. The disease is first evident in vivo with the appearance of disease-specific Core biomarkers while people are asymptomatic. ^[3]

This is analogous to oncology: you can have a cancer (disease) before you have symptoms (illness). An unimpaired person with abnormal Aβ/tau biomarkers is not "at risk" for AD — they already have it. ^[3]

DSM-5 Diagnostic Criteria for Major Neurocognitive Disorder (Dementia) — the syndromic framework within which AD is the most common cause ^[5]:

Evidence of significant cognitive decline from a previous level of performance in ≥1 cognitive domain: learning and memory, language, executive function, complex attention, perceptual-motor, social cognition
The cognitive deficits interfere with independence in everyday activities (at minimum, assistance required with complex instrumental ADLs such as paying bills or managing medications)
Not fully explained by delirium or another mental disorder

2. Epidemiology

Prevalence increases with age: ~10% at age 65; ~25% at age 85 ^[1]
Worldwide: ~55 million people living with dementia (WHO 2023), projected to exceed 150 million by 2050
Duration from diagnosis to death: approximately 8–10 years ^[1]
Prevalence approximately doubles every 5 years after age 65 ^[5]

Hong Kong has one of the world's most rapidly ageing populations (~20% aged ≥65 in 2024)
Estimated > 100,000 people with dementia in Hong Kong; prevalence in those ≥70 is ~10%
Late-onset AD (≥65 years) predominates; early-onset AD (< 65 years) accounts for < 1% of cases but is important to recognise ^[5]
High prevalence of cardiovascular risk factors (hypertension, T2DM, dyslipidaemia) in Hong Kong amplifies AD risk through vascular pathways

Female sex is a risk factor ^[1] — women have approximately 1.5–2× higher lifetime risk, partly due to longer life expectancy, but also biological factors (e.g., post-menopausal oestrogen loss, differential APOE ε4 effects)

3. Risk Factors

Understanding risk factors is crucial for both prevention and for constructing differential diagnoses.

Factor	Mechanism/Explanation
Age (strongest RF)	Prevalence doubles every 5 years after 65. Ageing → ↓Aβ clearance, ↑oxidative stress, ↓synaptic plasticity, ↑tau phosphorylation
Family history ^[1]	10–30% ↑ risk; up to 30% of AD is familial ^[5]. 1st-degree relative with AD ≈ 2–4× risk
Genetics ^[1] (see §4.3)	PSEN1, PSEN2, APP (early-onset); APOE ε4 (late-onset)
Female sex ^[1]	As above
Down syndrome (Trisomy 21)	APP gene is on chromosome 21 → overexpression of APP → virtually all individuals with DS have sufficient AD neuropathology by mid-40s ^[3]

Factor	Mechanism
Low education ^[1]	↓ cognitive reserve → brain less able to compensate for neuronal loss
Cardiovascular dysfunction ^[1] / Vascular RFs (HTN, dyslipidaemia, T2DM, obesity, physical inactivity, prior stroke, peripheral atherosclerosis) ^[5]	Vascular RFs → cerebral small vessel disease, BBB dysfunction, neuroinflammation; cerebrovascular disease and AD frequently co-exist as "mixed dementia"
Head trauma ^[1]	Traumatic brain injury → diffuse axonal injury, ↑Aβ deposition, neuroinflammation
Smoking	↑ oxidative stress, vascular damage
Hearing loss (mid-life)	↓ cognitive stimulation, social isolation → ↓ cognitive reserve
Depression	Chronic cortisol elevation → hippocampal atrophy; also shares neuroinflammatory pathways
Social isolation	↓ cognitive stimulation
Excessive alcohol	Direct neurotoxicity (thiamine deficiency, Wernicke-Korsakoff), ↑ vascular risk
Air pollution	Systemic inflammation, microglial activation
Untreated vision loss	Similar to hearing loss — sensory deprivation reduces cognitive stimulation

Higher education and cognitive activity ^[5] — builds "cognitive reserve"
Physical activity — ↑ BDNF, ↑ cerebral blood flow, ↓ neuroinflammation
Social engagement
Mediterranean diet
NSAIDs, HRT, statins have been associated with ↓ risk in observational studies, but RCTs have not demonstrated efficacy ^[5]

High Yield: Risk Factor Mnemonic — 'OLD AGE FACTS'

O — Old age (strongest RF) L — Low education D — Down syndrome / Diabetes

A — APOE ε4 / APP / Autosomal dominant genes G — Gender (female) E — Environment (pollution, toxins)

F — Family history A — Atherosclerotic risk factors (HTN, dyslipidaemia, obesity) C — Cardiovascular disease / Cerebrovascular disease T — Traumatic brain injury S — Sedentary lifestyle / Smoking / Social isolation

4. Anatomy and Function

4.1 Key Neuroanatomical Structures in AD

To understand AD's clinical features, you need to understand the anatomy it destroys — and in what order.

The entorhinal cortex (medial temporal lobe) is the gateway to the hippocampus — it acts as a relay between neocortex and hippocampal formation
The hippocampus is the critical structure for encoding new episodic memories (declarative/explicit memory)
AD neuropathology first starts in the entorhinal cortex → then spreads to hippocampus ^[5] — this is why anterograde amnesia (inability to form new memories) is the earliest and most characteristic symptom

Why does hippocampal damage cause memory loss? The hippocampus binds together distributed cortical representations into a unified memory trace. Without the hippocampus, new information cannot be consolidated from short-term to long-term storage. Old, remote memories (already consolidated into neocortex) are relatively preserved early on.

Involved in visuospatial processing, navigation, calculation, attention
Pathology then spreads to parietal association areas ^[5] → causes visuospatial disorientation, dyscalculia, apraxia

Semantic memory, object naming, language comprehension (dominant hemisphere)
Damage → anomia (word-finding difficulty), semantic paraphasias

Executive function (planning, judgment, abstract thinking, working memory)
Behaviour regulation, social cognition
Involved in later stages → personality changes, disinhibition, apathy

Major source of cholinergic projections to the entire neocortex and hippocampus
Severely affected in AD → profound cholinergic deficit → rationale for cholinesterase inhibitor therapy
Acetylcholine (ACh) is critical for attention, learning, and memory consolidation

Pathology also involves subcortical nuclei ^[5] — locus coeruleus (noradrenergic), raphe nuclei (serotonergic) → contributes to behavioural/psychiatric symptoms (depression, agitation, sleep disturbance)

The cholinergic hypothesis is one of the oldest and most therapeutically relevant models of AD:

AD selectively destroys cholinergic neurons, particularly those originating from the nucleus basalis of Meynert
This results in a cortical acetylcholine deficit proportional to degree of dementia
ACh is essential for attention, encoding of new memories, and cortical modulation
This deficit forms the basis for cholinesterase inhibitor (ChEI) therapy (donepezil, rivastigmine, galantamine) — these drugs inhibit acetylcholinesterase → ↑ synaptic ACh availability

Feature	Posterior (Temporal-Parietal) Dementia	Anterior (Frontal) Dementia
Predominant deficits	Memory, language, visuospatial	Behaviour, personality, executive function
Classic example	Alzheimer's disease	Frontotemporal dementia (FTD), NPH, Huntington's
Preserved features	Personality relatively preserved early	Memory relatively preserved early
Key signs	Amnesia, anomia, apraxia, agnosia	Disinhibition, apathy, antisocial behaviour

AD is a posterior (temporal-parietal) dementia in its typical presentation ^[5].

5. Aetiology and Pathophysiology

AD has two cardinal neuropathological hallmarks ^[5]:

Neuritic (senile) plaques: extracellular deposits of amyloid-beta (Aβ) peptides surrounded by degenerated axons and synaptic structures ^[5]
Neurofibrillary tangles (NFTs): intracellular paired helical filaments composed of hyperphosphorylated tau protein (MAPT) ^[5]

Plus:

Synaptic loss (best correlate of cognitive decline)
Neuronal loss and cortical atrophy
Neuroinflammation (microglial activation)
Cerebral amyloid angiopathy (Aβ deposition in blood vessel walls)

The Central Hypothesis of AD Pathogenesis

The amyloid cascade hypothesis is the most influential hypothesis ^[5]: it proposes that ↑ amyloid-beta formation/deposition (especially the 42-amino acid variant, Aβ42) is the central core pathology ^[5] that triggers a cascade of downstream events leading to neurodegeneration.

However, it is likely more complex with other factors involved ^[5].

Step-by-step breakdown:

Step 1: Amyloid Precursor Protein (APP) Processing

APP (Amyloid Precursor Protein) is a transmembrane protein encoded on chromosome 21 ^[5]
APP is normally expressed in neurons and has roles in synaptic function
APP can be cleaved by two competing pathways:

Non-amyloidogenic (normal) pathway: APP → cleaved by α-secretase → soluble APPα + C83 fragment → no Aβ production

Amyloidogenic (pathological) pathway: APP → cleaved first by β-secretase (BACE1) → then by γ-secretase → produces Aβ peptides of varying lengths

Aβ40: most abundant form, less toxic
Aβ42: less common but much more prone to aggregation and much more neurotoxic — this is the key pathogenic species ^[5]

Step 2: Aβ Aggregation

Aβ42 monomers → oligomers (soluble, highly toxic) → protofibrils → insoluble fibrils → neuritic plaques
Soluble Aβ oligomers are now thought to be the most neurotoxic species (more than plaques themselves)

Step 3: Downstream Cascade

Aβ oligomers → synaptic dysfunction, disruption of long-term potentiation (LTP), glutamate excitotoxicity
Aβ → triggers hyperphosphorylation of tau protein → tau detaches from microtubules → aggregates into paired helical filaments → NFTs
Loss of tau function → microtubule instability → impaired axonal transport → neuronal death
Neuroinflammation: Aβ activates microglia and astrocytes → chronic inflammatory state → further neuronal damage
Oxidative stress and mitochondrial dysfunction
Ultimately → widespread neuronal loss, synaptic loss, and cortical atrophy

The progression of tau pathology follows a stereotypical pattern described by the Braak staging system ^[5]:

Braak Stage	Region Involved	Clinical Correlation
I–II (Transentorhinal)	Entorhinal cortex	Preclinical / very mild memory complaints
III–IV (Limbic)	Hippocampus, limbic structures	Mild cognitive impairment → early dementia
V–VI (Neocortical)	Widespread neocortex (parietal → frontal)	Moderate to severe dementia

Onset of neuropathology long precedes signs and symptoms of dementia ^[5] — neuropathological changes may begin 15–20 years before clinical symptoms appear. This is the "preclinical AD" phase.

5.4 Genetics of AD

Autosomal dominant inheritance pattern ^[5], associated with three highly penetrant genes:

Gene	Chromosome	Protein/Function	Mechanism
APP	Ch 21	Amyloid precursor protein	Mutations → ↑ Aβ42 production or ↑ aggregation propensity ^[5]
PSEN1	Ch 14	Presenilin-1: catalytic subunit of γ-secretase	Accounts for > 70% of early-onset familial AD cases; mutations → altered γ-secretase cleavage → ↑ Aβ42/Aβ40 ratio ^[5]
PSEN2	Ch 1	Presenilin-2: regulator of γ-secretase	Similar mechanism to PSEN1 but less common ^[5]

Why Down syndrome → AD: Trisomy 21 → 3 copies of the APP gene on chromosome 21 → lifelong overproduction of Aβ → virtually all individuals with DS develop sufficient AD neuropathology by mid-40s ^[3].

Genetic basis is more complex, involving multiple susceptibility genes of lower penetrance ^[5]:

Gene	Effect
APOE (Ch 19)	APOE ε4 allele is the single strongest genetic risk factor for late-onset AD. Accounts for ~50% of vulnerability to late-onset AD ^[5]. Heterozygous ε4 carrier → 3× risk; homozygous ε4/ε4 → 12× risk. APOE ε2 is protective.
~20+ other loci	TREM2, BIN1, CLU, PICALM, CR1, CD33, etc. — involved in immune function, lipid metabolism, endocytosis, Aβ clearance

How does APOE ε4 increase risk?

APOE is an apolipoprotein involved in cholesterol transport and Aβ clearance
The ε4 isoform is less efficient at clearing Aβ from the brain compared to ε3 or ε2
ε4 also promotes Aβ aggregation, neuroinflammation, and BBB dysfunction
ε4 may also directly impair synaptic function and promote tau pathology

Vascular risk factors (HTN, dyslipidaemia, T2DM, obesity, inactivity, prior stroke, peripheral atherosclerosis) are well-established risk factors for AD ^[5]:

Pathogenic mechanisms linking vascular RFs to AD are unclear ^[5]
May involve brain cholesterol metabolism ^[5]
Cerebrovascular disease and AD frequently co-exist in the form of mixed dementia ^[5]
Vascular disease → BBB breakdown → impaired Aβ clearance, neuroinflammation
Chronic cerebral hypoperfusion → ↑ β-secretase activity → ↑ Aβ production

Microglia (brain's resident macrophages) become chronically activated in AD
Initially attempt to clear Aβ (phagocytosis)
Chronic activation → release pro-inflammatory cytokines (TNF-α, IL-1β, IL-6) → bystander neuronal damage
TREM2 gene (triggering receptor expressed on myeloid cells 2) — key regulator of microglial function; variants associated with ↑ AD risk

Gross features of AD ^[5]:

↓ Hippocampal volume (earliest and most sensitive structural change)
Medial temporal lobe atrophy
→ Generalised cortical atrophy (progressive)
Widened sulci, enlarged ventricles (hydrocephalus ex vacuo)
Relative sparing of primary motor and sensory cortex until late stages

6. Classification

Type	Age	Proportion	Genetics	Features
Early-onset AD	< 65 years ^[1]	< 1–5%	Often autosomal dominant (APP, PSEN1, PSEN2)	More aggressive course, may present with atypical features (posterior cortical atrophy, logopenic aphasia)
Late-onset AD	≥ 65 years ^[1]	> 95%	Complex polygenic (APOE ε4 major)	"Classic" amnestic presentation

Phenotype	Key Features	Predominant Atrophy
Typical/Amnestic AD (most common)	Progressive episodic memory loss → other domains	Medial temporal → parietal → generalised
Posterior Cortical Atrophy (PCA)	Visual/visuospatial deficits (simultanagnosia, visual agnosia); relatively preserved memory early	Occipito-parietal
Logopenic Primary Progressive Aphasia	Word-finding pauses, impaired sentence repetition	Left temporo-parietal junction
Frontal/Behavioural variant AD	Executive dysfunction, behavioural changes; mimics FTD	Frontal

AD exists on a continuum ^[3]:

Stage	Biomarker Status	Symptoms
Preclinical AD	Core biomarkers positive (A+T+)	Cognitively normal
MCI due to AD	Core biomarkers positive	Mild cognitive impairment, functionally independent
Dementia due to AD	Core biomarkers positive	Meets dementia criteria, functionally dependent

7. Clinical Features

A useful mnemonic for the core cognitive deficits:

Amnesia (memory loss)
Aphasia (language impairment)
Apraxia (inability to perform learned motor tasks)
Agnosia (inability to recognise objects/people)

All of these flow logically from the pattern of cortical atrophy described above.

7.2 Symptoms (What the Patient/Carer Reports)

A. Memory Impairment (Earliest and Most Prominent)

Anterograde amnesia (inability to learn and retain new information) is the hallmark early symptom
- Pathophysiological basis: Earliest NFT and plaque deposition occurs in the entorhinal cortex → hippocampus ^[5] — these structures are essential for encoding new episodic memories
- Presents as: repeating questions, forgetting recent conversations, misplacing objects, forgetting appointments
- Remote (long-term) memories are relatively preserved early — because these have already been consolidated into neocortical stores independent of hippocampus (Ribot's law: "last in, first out")
Progressive: eventually retrograde amnesia also develops as pathology spreads to neocortex

B. Language Impairment (Aphasia)

Word-finding difficulty (anomia) is often an early symptom
- Pathophysiological basis: Temporal neocortex (particularly left hemisphere) stores semantic representations; as pathology spreads from medial temporal to lateral temporal cortex, word retrieval becomes impaired
Circumlocution: using roundabout descriptions when unable to find the correct word (e.g., "the thing you write with" instead of "pen")
Progression: naming → comprehension → fluency → eventually mutism in late stages
Semantic paraphasias (substituting a related word, e.g., "fork" for "knife")

C. Visuospatial Dysfunction

Getting lost in familiar places (topographical disorientation)
- Pathophysiological basis: Parietal association cortex involvement → impaired spatial navigation and mental mapping
Difficulty judging distances, parking, navigating stairs
Difficulty with dressing (putting clothes on correctly requires spatial processing)

D. Executive Dysfunction

Poor judgment, impaired problem-solving, difficulty with planning and multitasking
- Pathophysiological basis: Prefrontal and parietal cortex involvement (later in disease)
Difficulty managing finances, medications, following recipes
Loss of abstract thinking ability

E. Dyscalculia

Difficulty with numbers and arithmetic
- Pathophysiological basis: Parietal cortex (angular gyrus) involvement

F. Temporal Disorientation → Spatial Disorientation → Personal Disorientation

Disorientation progresses characteristically: first loses track of time (dates, day of week) → then place (where they are) → finally person (who they are, who family members are)
This follows the spread of pathology from medial temporal → parietal → widespread cortex

BPSD are extremely common (affecting up to 90% of AD patients at some point) and are a major cause of carer distress and institutionalisation ^[5]:

Symptom	Pathophysiological Basis
Apathy (most common BPSD)	Frontal lobe and anterior cingulate involvement → ↓ motivation circuitry
Depression	Raphe nuclei (serotonergic) and locus coeruleus (noradrenergic) degeneration; also reactive to insight about decline
Anxiety/agitation	Amygdala involvement; disrupted serotonergic/noradrenergic systems; environmental overstimulation
Irritability/aggression	Orbitofrontal cortex damage → impaired impulse control; frustration from cognitive deficits
Psychosis: delusions	Typically referential/persecutory (e.g., "someone is stealing from me") — frontal/temporal dysfunction; also paranoid ideation from memory gaps
Psychosis: hallucinations	Visual hallucinations more common than auditory (contrast with schizophrenia); temporal-occipital dysfunction
Wandering/pacing	Frontal-subcortical circuit dysfunction; spatial disorientation
Disinhibition	Orbitofrontal cortex damage
Sleep disturbance	Suprachiasmatic nucleus and brainstem nuclei degeneration → disrupted circadian rhythm
Sundowning	Worsening of confusion/agitation in late afternoon/evening — multifactorial: circadian disruption, fatigue, reduced environmental cues

This is required for a diagnosis of dementia (vs MCI) ^[5]
Progresses from complex instrumental ADLs (iADLs) → basic ADLs (bADLs)

Stage	iADL Impairment	bADL Impairment
Early/Mild	Managing finances, medications, cooking, driving, shopping	Preserved
Moderate	Most iADLs lost	Begins: bathing, dressing (visuospatial component)
Severe	All iADLs lost	All bADLs lost: feeding, toileting, transferring

7.3 Signs (What You Find on Examination)

A. Mini-Mental State Examination (MMSE) / Montreal Cognitive Assessment (MoCA)

Typical pattern in AD:

Memory: Impaired delayed recall (3-word recall) — most sensitive early sign (hippocampal encoding failure)
Orientation: Impaired time orientation first → then place → person
Language: Impaired naming; later impaired repetition and comprehension
Visuospatial: Impaired clock drawing, impaired copying of intersecting pentagons
Executive function: Impaired trail-making, impaired verbal fluency (categorical and phonemic)

B. Specific Neuropsychological Signs

Sign	Definition	Pathophysiological Basis
Anomia	Inability to name objects	Left temporal cortex degeneration → disrupted semantic access
Apraxia	Inability to perform learned motor tasks despite intact motor function	Parietal cortex (dominant hemisphere) — stores motor programmes (praxis)
Agnosia	Inability to recognise objects/faces despite intact sensory function	Temporo-parietal/occipital association cortex — higher-order sensory processing
Acalculia	Inability to perform calculations	Left parietal (angular gyrus)
Agraphia	Inability to write	Parietal/frontal involvement
Constructional apraxia	Inability to copy figures or construct shapes	Parietal cortex (non-dominant hemisphere)
Prosopagnosia (late)	Inability to recognise familiar faces	Fusiform gyrus (temporal) involvement

C. Gerstmann Syndrome (parietal lobe localisation sign — not specific to AD but occurs when dominant parietal involved):

Finger agnosia + agraphia + acalculia + left-right disorientation

In early AD, neurological examination is typically remarkably normal — this is a key distinguishing feature from other dementias:

Stage	Neurological Signs
Early	Usually no motor or sensory deficits; no extrapyramidal signs; reflexes normal; gait normal
Moderate	May develop: paratonic rigidity (gegenhalten), primitive reflexes (grasp, palmomental, snout, glabellar)
Late/Advanced	Pyramidal and extrapyramidal signs ^[5], myoclonus, seizures (10–20%), incontinence, dysphagia, akinetic mutism

Why is the neurological exam normal early? Because AD preferentially affects association cortex and limbic structures. Primary motor cortex (precentral gyrus) and primary sensory cortex (postcentral gyrus) are relatively spared until late stages.

Primitive (frontal release) reflexes (e.g., grasp, palmomental, snout, glabellar tap) — these are normally suppressed by frontal lobe inhibition; frontal atrophy → loss of inhibition → reflexes re-emerge.

Early AD: Physical exam is typically normal — patients appear well and may be socially intact ("pleasant demented patient" who maintains social graces)
Weight loss: Common in moderate-advanced AD — multifactorial: forgetting to eat, altered appetite regulation (hypothalamic involvement), increased energy expenditure from wandering
Late AD: Cachexia, contractures, bedsores (from immobility), aspiration pneumonia (from dysphagia)

Stage	Cognitive	Behavioural	Functional	Neurological
Preclinical (biomarker+ only)	Normal or subtle	Normal	Normal	Normal
MCI due to AD	Isolated memory impairment (amnestic MCI) or mild multi-domain impairment	Mild anxiety/depression	Independent (by definition)	Normal
Mild Dementia	Impaired new learning, anomia, early visuospatial deficits	Apathy, depression, anxiety; early delusions	iADL impairment (finances, medications)	Normal
Moderate Dementia	Severe amnesia, aphasia, apraxia, agnosia	Agitation, wandering, psychosis, sundowning	bADL impairment begins	Paratonic rigidity, primitive reflexes
Severe Dementia	Minimal cognition, mutism	Possible apathy, agitation	Totally dependent, bedbound	Myoclonus, seizures, incontinence, dysphagia
Terminal	Unresponsive	—	—	Flexion contractures, akinetic mutism

Feature	AD	Vascular Dementia	DLB	FTD
Onset	Insidious	Stepwise / sudden	Insidious	Insidious
Course	Gradually progressive	Stepwise deterioration	Fluctuating cognition	Progressive
Earliest deficit	Memory	Executive function, processing speed	Attention, visuospatial, executive	Behaviour/personality OR language
Motor signs	Late	Focal neurological signs	Parkinsonism (early), RBD	Usually absent early
Hallucinations	Late (if present)	Uncommon	Recurrent detailed visual hallucinations (early core feature)	Uncommon
Neurological exam (early)	Normal	Upper motor neuron signs, gait abnormality	Parkinsonism, autonomic dysfunction	Usually normal
Imaging	Medial temporal atrophy	Infarcts, white matter disease	Relative preservation of medial temporal lobe; occipital atrophy	Frontal / temporal atrophy (often asymmetric)

High Yield: Differentiating AD from Delirium

Feature	Alzheimer's Disease	Delirium
Onset	Insidious (months-years)	Acute (hours-days)
Course	Progressive, stable day-to-day	Fluctuating with diurnal variation (worse at night)
Consciousness	Preserved (until very late)	Impaired (hallmark of delirium)
Attention	Relatively preserved early	Impaired (hallmark)
Hallucinations	Late, less prominent	Common (especially visual)
Reversibility	Irreversible (progressive)	Often reversible if cause treated
Key point	Dementia is a major risk factor for delirium — 2/3 of delirium occurs in dementia patients ^[6]

Clinical Pearl — 'The Socially Intact Patient'

A common exam scenario: a well-dressed, polite elderly patient is brought in by family who report significant memory problems. The patient chats pleasantly with the doctor and seems "fine." But when formally tested, delayed recall is 0/3 and clock drawing is grossly abnormal. This is classic early AD — social behaviour is a highly overlearned, procedural skill (frontal-subcortical) that is preserved even when declarative memory (hippocampal) is severely impaired. Never rely on casual conversation to assess cognition.

The approach to a patient with suspected AD should follow this logical sequence:

Suspect dementia when carer/patient reports progressive cognitive decline affecting daily function
Confirm cognitive impairment with formal cognitive testing (MMSE, MoCA)
Characterise the pattern — is it amnestic (typical AD)? Is it non-amnestic? What domains are affected?
Assess functional impact — does it meet criteria for dementia (vs MCI)?
Exclude delirium — acute onset? Fluctuating consciousness? Look for precipitants
Exclude reversible causes — the "reversible dementias" (10–15%) ^[5]: hypothyroidism, B12 deficiency, NPH, chronic SDH, depression (pseudodementia), neurosyphilis, HIV, drugs
Characterise the dementia subtype — clinical features + imaging + biomarkers
Stage severity — mild/moderate/severe

High Yield Summary

AD is defined by biology (Aβ plaques + tau tangles), not symptoms — 2024 NIA-AA criteria ^[3]
Most common cause of dementia (50–60%); prevalence doubles every 5 years after 65 ^[1]
Risk factors: Age (strongest), female sex, family history, APOE ε4, low education, cardiovascular RFs, head trauma ^[1]^[5]
Genetics: Early-onset (< 1%): APP (Ch21), PSEN1 (Ch14, > 70%), PSEN2 (Ch1) — autosomal dominant. Late-onset: APOE ε4 (~50% of genetic vulnerability), polygenic ^[5]
Amyloid cascade hypothesis: ↑Aβ42 → oligomer toxicity → tau hyperphosphorylation → NFTs → neuronal death ^[5]
Braak staging: Entorhinal cortex → hippocampus → parietal association → generalised neocortex ^[5]
Neuropathology precedes symptoms by 15–20 years ^[5]
Clinical hallmarks: Insidious onset, gradually progressive amnestic syndrome → aphasia, apraxia, agnosia, visuospatial/executive dysfunction; BPSD in 90%; normal neurological exam early
Key distinguishing feature from delirium: Preserved consciousness in AD
Cholinergic deficit (nucleus basalis of Meynert) → basis for cholinesterase inhibitor therapy
10–15% of dementia has reversible causes — always exclude ^[5]

Active Recall - Alzheimer's Disease (Definition to Clinical Features)

^[1] Lecture slides: GC 169. My grandmother keeps forgetting things Geriatric psychiatry, Dementia.pdf ^[2] Senior notes: Ryan Ho Fundamentals.pdf, p325 (Delirium) ^[3] Lecture slides: GC 241. Reference (1) - Alzheimers Dementia - Revised criteria for diagnosis and staging of Alzheimer s disease.pdf ^[4] Lecture slides: GC 241. Reference (3) - Patel dementia with lewy bodies.pdf ^[5] Senior notes: Ryan Ho Neurology.pdf, pp128–130; Ryan Ho Psychiatry.pdf, pp90–91 ^[6] Senior notes: Ryan Ho Fundamentals.pdf, p325

Differential Diagnosis of Alzheimer's Disease

The differential diagnosis (DDx) of AD is, in practice, the differential diagnosis of progressive cognitive decline / dementia. You are not just asking "does this patient have AD?" — you are asking "what is causing this patient's dementia, and is any of it reversible?"

The key clinical reasoning framework follows three tiers:

Is this really dementia? → Rule out mimics (delirium, depression, amnestic syndromes, neurodevelopmental disorders)
Is this a reversible cause? → The "must-not-miss" category (10–15% of dementia can be reversed ^[5])
Which neurodegenerative or irreversible dementia is it? → Pattern recognition using clinical features, course, imaging, and biomarkers

1. Conditions That Mimic Dementia ("Is This Really Dementia?")

These are not true dementias but can present with cognitive impairment and be confused with AD.

Depression is the most important mimic of dementia, accounting for ~10% of presumed dementia ^[7].

Feature	Depression (Pseudodementia)	Alzheimer's Disease
Onset	More well-defined, more rapid decline ^[7]	Insidious over months–years
Self-awareness	Tends to complain/worry about poor memory and present by themselves ^[7]	Poor insight; brought by family
Effort on testing	Tends to give less effort; frequent "I don't know" answers ^[7]	Tries hard but gives incorrect answers
Attention	More impaired concentration and attention ^[7]	Relatively preserved early
Language/motor	Slow but not impaired ^[7]	Truly impaired (anomia, apraxia)
Mood features	Morning dysphoria, psychomotor retardation, anhedonia, guilt ^[7]	Mood symptoms may occur but not the dominant picture
Biological features	Early morning waking, appetite loss, diurnal variation	Sleep disturbance is more fragmented; appetite loss later

Pathophysiological basis of why depression mimics dementia: Depression causes functional impairment of prefrontal-hippocampal circuits (via chronic hypercortisolaemia and monoamine depletion) → poor concentration, slowed processing speed, and impaired memory encoding. However, the neural hardware is intact — it's a "functional" rather than "structural" deficit, hence potentially reversible.

High Yield Exam Tip

As differentiation between depression and dementia may be difficult, it may be prudent to treat depressive symptoms if present before concluding on a diagnosis of dementia. ^[7] In practice, a therapeutic trial of antidepressants can be both diagnostic and therapeutic. If cognition improves → pseudodementia. Note: depression and AD frequently coexist, so resolution of depression may unmask underlying dementia.

Delirium is commonly confused with dementia ^[7]^[8]. The hallmark differentiator is acute onset with fluctuating consciousness.

Feature	Delirium	Alzheimer's Disease
Onset	Acute (hours–days) ^[9]	Insidious (months–years)
Consciousness	Impaired/clouded (hallmark) ^[7]	Preserved until very late stages
Attention	Characteristically impaired (hallmark) ^[7]	Relatively preserved early
Course	Fluctuating with diurnal variation	Gradual progressive decline
Hallucinations	Common (especially visual)	Late feature
Reversibility	Usually reversible if cause treated	Irreversible
Precipitant	Usually precipitated by acute medical illness / new drug use ^[7]	No acute precipitant

Critical point: Dementia is the leading risk factor for delirium — 2/3 of delirium occurs in dementia patients ^[2]. So in practice, you often see delirium superimposed on dementia. The key is to determine whether there has been an acute change from baseline (→ delirium) versus the patient's usual level of cognitive impairment.

AOS High Yield: In a patient with known AD who acutely deteriorates, the feature most consistent with delirium rather than exacerbation of dementia is "acute onset and fluctuating course of symptoms" ^[9]. Poor delayed recall, disorientation, and sundowning can occur in both conditions and are not specific ^[9].

Pathophysiological basis: Delirium represents acute, global brain dysfunction from a systemic insult (infection, metabolic derangement, drugs, etc.) → disrupted neurotransmitter balance (↓ACh, ↑dopamine, ↑glutamate, neuroinflammation) → widespread cortical and subcortical dysfunction including arousal circuits (reticular activating system). AD has chronic, progressive neuronal loss with preserved arousal until terminal stages.

By definition, amnestic syndrome involves severe disruption of memory with minimal involvement of other domains ^[7].

Confabulation may be prominent, especially in diencephalic amnesias ^[7]
Look for: history of alcoholism, risk factors for nutritional deficiencies (Wernicke-Korsakoff), evidence of brain disease (diencephalic, medial temporal lesions) ^[7]
Key distinction from AD: memory is severely impaired but other cognitive domains (language, visuospatial, executive) are preserved → does not meet criteria for "dementia" (which requires multi-domain impairment)

Many non-degenerative neurological diseases result in one-off insults to the brain and can impair cognition. Most importantly, there is no progressive deterioration (or even improvement), and often an identifiable cause. ^[7]

Examples: post-stroke cognitive impairment (single event, stable), post-TBI, post-encephalitis.

Oligophrenia: longstanding poverty of intellect ^[5] — the key is that cognitive function has been low since childhood, not a decline from a previous higher level. History is essential.

Isolated disorder of higher function, e.g., dysphasia, visual agnosia ^[5] — a focal lesion (e.g., stroke affecting Wernicke's area) can impair a single cognitive domain. This is not dementia because it does not involve multiple domains.

Critical Clinical Principle

10–15% of dementia can be reversed ^[5]. Every patient presenting with cognitive decline must be screened for these causes. Missing a reversible cause is a serious clinical error because the patient could be cured.

The mnemonic "DEMENTIA" helps recall reversible causes:

Letter	Cause	Mechanism / Why It Causes Cognitive Decline	Key Investigation
D	Drugs (polypharmacy, anticholinergics, benzodiazepines, opioids)	Anticholinergic drugs directly antagonise the cholinergic system essential for memory; sedatives suppress cortical function globally	Drug history review
E	Emotional (Depression)	As above (§1.1)	GDS, PHQ-9
M	Metabolic: Hypothyroidism, B12/folate deficiency, hypercalcaemia	Hypothyroidism → ↓neuronal metabolic rate; B12 deficiency → impaired myelin synthesis + direct neurotoxicity; hypercalcaemia → neuronal membrane dysfunction	TFT, serum B12 and folate, RFT, Ca, glucose ^[5]^[7]
E	Eyes/Ears (sensory deprivation)	↓ sensory input → ↓ cognitive stimulation → apparent cognitive decline	Hearing/vision assessment
N	Normal pressure hydrocephalus (NPH)	Classical triad: frontal dementia, apraxic gait, urinary incontinence ^[7]. Enlarged ventricles compress periventricular white matter → disrupts frontal-subcortical circuits	CT/MRI: ALL ventricles enlarged disproportionate to sulcal effacement; periventricular lucency on FLAIR ^[7]
T	Tumours (frontal, corpus callosum, 3rd ventricle) / chronic SDH	Mass effect → compression of adjacent cortex/white matter; frontal tumours particularly mimic dementia	CT/MRI brain
I	Infections: Neurosyphilis, HIV, chronic meningitis	Chronic neuroinflammation → neuronal damage. Neurosyphilis → meningovascular and parenchymal forms; HIV → direct viral neurotoxicity	VDRL, HIV test, LP ^[5]
A	Alcohol (Wernicke-Korsakoff) / other toxins (heavy metals)	Thiamine (B1) deficiency → mamillary body and medial thalamic damage; chronic alcohol → direct cortical neurotoxicity	History, thiamine levels, heavy metal screen

Minimum Investigations for Reversible Causes (NICE Guidelines)

Included in NICE 2010 guidelines as minimum investigations ^[5]^[7]:

CBC, serum B12 and folate (for nutritional deficiency)
TFT (for hypothyroidism)
RFT, Ca, and glucose (for hypercalcaemia, Cushing's, Addison's)
CT/MRI brain (for structural lesions: SDH, tumours, NPH)

Additional targeted tests: Vasculitic screen, ESR; LFT for hepatic encephalopathy; VDRL for neurosyphilis; LP for chronic meningitis/neurosyphilis; EEG for CJD and metabolic encephalopathy; copper studies for Wilson's disease ^[5]

Wilson's disease deserves special mention in younger patients with cognitive decline:

Can mimic Parkinson's disease — extrapyramidal deposition of copper ^[10]
Autosomal recessive; ATP7B gene
Look for: Kayser-Fleischer rings, low caeruloplasmin, hepatic dysfunction
Important because it is treatable with copper chelation (penicillamine, trientine)

3. Other Neurodegenerative / Irreversible Dementias

Once mimics and reversible causes are excluded, the differential narrows to the major dementia subtypes. The clinical challenge is distinguishing AD from its neurodegenerative "neighbours."

Feature	Alzheimer's Disease	Vascular Dementia
Onset	Insidious	Acute onset ^[8]
Course	Gradual progressive decline	Stepwise decline (each step = new vascular event) ^[8]
Earliest deficit	Memory (episodic)	Executive function ^[8]; processing speed
Neurological signs	Absent early	Focal neurological signs (UMN signs, pseudobulbar palsy, gait abnormality)
Vascular RFs	May be present (but not required)	Prominent: HTN, DM, AF, smoking, prior stroke
Imaging	Medial temporal lobe atrophy	Infarcts, white matter hyperintensities
Subtypes	—	Multi-infarct VaD, subcortical VaD (Binswanger's disease), strategic infarct dementia, cerebral amyloid angiopathy (CAA) ^[8]
Associated with ICH	No	Deep ICH (CV RFs), lobar ICH (CAA) ^[8]

Pathophysiology: Cerebrovascular disease (large vessel infarcts, small vessel disease, microhaemorrhages) → destruction of cortical/subcortical tissue → cognitive impairment. The "stepwise" pattern occurs because each new stroke causes an abrupt decline, followed by a plateau.

Mixed dementia (AD + VaD) is extremely common, especially in the elderly — cerebrovascular disease and AD frequently co-exist ^[5]. In practice, many patients have elements of both.

DLB is the commonest degenerative dementia after AD ^[5]. It is a critical differential because of its unique management considerations (antipsychotic sensitivity).

Core clinical features of DLB (must have ≥2 core features for probable DLB, or 1 core + 1 indicative biomarker) ^[4]^[5]:

Core Feature	Frequency	Pathophysiological Basis
Fluctuating cognition ^[4] (60–80%)	Episodes of "blanking out," daytime drowsiness, bizarre behaviour interspersed with near-normal function	Disrupted thalamocortical circuits by Lewy body pathology → variable cortical activation
Recurrent well-formed visual hallucinations ^[4] (67%)	Complex, detailed (people, animals); occur early	Occipital/visual association cortex Lewy body deposition → aberrant visual processing
REM sleep behaviour disorder (RBD) ^[4] (85%)	Dream enactment behaviour (vocalisation, complex motor behaviour during REM sleep)	Loss of normal REM atonia from brainstem Lewy bodies (sublaterodorsal nucleus)
Parkinsonism ^[4] (70–90%)	Usually more bilaterally symmetric and milder than idiopathic PD	Nigrostriatal dopaminergic neuron loss from α-synuclein deposition

Supportive features of DLB ^[4]^[5]:

Antipsychotic sensitivity (30–50%): acute irreversible parkinsonism, loss of consciousness ± neuroleptic malignant syndrome towards antipsychotics ^[5]
Repeated falls, syncope, transient loss of consciousness
Autonomic dysfunction (postural hypotension, constipation, urinary symptoms)
Hallucinations in other modalities, systematized delusions, apathy/anxiety/depression ^[4]

Key distinguishing features from AD:

Early prominent visual hallucinations (vs late in AD) ^[5]
Cognitive fluctuations (vs steady decline in AD)
Parkinsonism early (vs no motor signs early in AD)
Imaging: Relative preservation of medial temporal lobe structures (contrast with hippocampal atrophy in AD) ^[5]; reduced occipital activity on FDG-PET ^[4]; reduced dopamine transporter uptake on SPECT (DaTscan) ^[4]

"Dopamine transporter imaging is most helpful in distinguishing DLB from Alzheimer disease" ^[4]

The 1-year rule ^[4]: If dementia occurs before or within 1 year of motor symptoms → DLB. If dementia occurs > 1 year after established motor PD → PD-dementia (PDD). This is somewhat arbitrary but clinically useful.

Copathology with AD occurs in more than 50% of patients with DLB — individuals with this mix experience more memory changes and faster disease progression ^[4].

High Yield: DLB is Frequently Misdiagnosed

Two of every three cases of DLB are missed or misdiagnosed as Alzheimer disease ^[4]. It may take an average of 18 months for patients to receive a correct DLB diagnosis. This matters clinically because:

Antipsychotics (commonly prescribed for BPSD in AD) can be catastrophically dangerous in DLB
DLB responds particularly well to cholinesterase inhibitors (especially rivastigmine) ^[8]
AChEI for cognition; quetiapine/clozapine only if absolutely necessary for psychosis; levodopa for parkinsonism; melatonin/clonazepam for RBD ^[8]

Feature	Alzheimer's Disease	Frontotemporal Dementia
Age of onset	Usually ≥ 65	Often younger onset (45–65 years); in those < 65, FTD accounts for ~12% of dementias ^[8]
Earliest deficit	Memory	Behaviour/personality (bvFTD) or language (PPA)
Personality change	Late	Early and prominent: disinhibition, apathy, loss of empathy, compulsive/repetitive behaviours, dietary changes (sweet craving)
Memory	Impaired early	Relatively preserved early
Insight	Poor (but gradual loss)	Strikingly poor from onset (often unaware/unconcerned)
Social conduct	Preserved early	Early breakdown: antisocial behaviour, irresponsibility ^[5]
Neurological signs	Absent early	May develop motor neuron disease features (FTD-MND overlap)
Imaging	Medial temporal atrophy	Frontal and/or anterior temporal atrophy (often asymmetric)
Perfusion (SPECT/PET)	Bilateral posterior temporal + parietal hypoperfusion ^[11]	Bilateral frontal + temporal hypoperfusion ^[11]

FTD is classified as an anterior dementia (frontal, motor cortex involvement) ^[5], whereas AD is a posterior dementia (temporal-parietal).

Subtypes of FTD:

Behavioural variant FTD (bvFTD): personality/behavioural changes predominate
Primary progressive aphasias (PPA): language variants
- Semantic variant (fluent but empty speech, loss of word meaning)
- Non-fluent/agrammatic variant (effortful, halting speech)
- Logopenic variant (actually more often AD pathology)

Genetics: ~30–50% familial; associated genes include MAPT (tau), GRN (progranulin), C9orf72 (hexanucleotide repeat expansion — also causes ALS).

Rapidly progressive dementia (in months) ^[7] — this is the key red flag.

Feature	AD	CJD
Course	Years	Months (typically < 1 year to death in sporadic CJD)
Motor signs	Late	Early: myoclonic jerks, seizures, cerebellar ataxia ^[7]
Imaging	Medial temporal atrophy	MRI: cortical ribboning on DWI/FLAIR ^[7]
EEG	Usually non-specific	Periodic sharp-wave complexes (in sporadic CJD)
CSF	Aβ42 ↓, tau ↑	14-3-3 protein, RT-QuIC (prion seeding assay)

Variant CJD (linked to BSE/mad cow disease): Young onset with early psychiatric symptoms; pulvinar sign (bilateral hyperintensity at pulvinar nucleus on MRI) ^[7].

Pathophysiology: Misfolded prion protein (PrPSc) acts as a template to convert normal PrPC → spongiform change, neuronal loss, astrocytic gliosis. Rapidly fatal.

Classical triad: frontal dementia, apraxic gait, and urinary incontinence ^[7].

Feature	Detail
Gait	Magnetic/apraxic gait (wide-based, shuffling, "glued to the floor") — often the first symptom
Dementia	Mental slowing, apathy, inattention ^[7] — subcortical/frontal pattern
Incontinence	Urge incontinence → later complete incontinence
Age group	Commonest in 50–70 years ^[7]
Imaging	ALL ventricles enlarged disproportionate to sulcal effacement; periventricular lucency on FLAIR ^[7]
Key feature	No psychiatric symptoms, sleep disorder, or dysautonomic features ^[5] (helps distinguish from DLB)
Treatment	Ventriculoperitoneal shunt — one of the truly reversible dementias (gait responds best; cognition response variable)

Why NPH is different from AD on imaging: In AD, ventricles enlarge because brain atrophies (hydrocephalus ex vacuo) → sulci are also widened proportionately. In NPH, ventricles enlarge disproportionately to the degree of sulcal widening, indicating that CSF pressure (not atrophy) is driving the ventricular enlargement.

Diagnosis of motor PD > 1 year before dementia ^[8] (contrast with DLB: dementia before or within 1 year of motor symptoms)
Similar clinical features to DLB: cognitive fluctuations, visual hallucinations, executive/attentional deficits
Pathology: Lewy bodies progressing from brainstem → cortex

Autosomal dominant; CAG trinucleotide repeat expansion on chromosome 4p16.3 ^[12]
Triad: chorea, psychiatric symptoms (depression, psychosis), and progressive dementia ^[12]
Atrophy of caudate and putamen ^[12]
Subcortical dementia pattern (executive dysfunction, slowed processing, personality change)
Juvenile onset (inherited from fathers) tends to be more severe due to anticipation ^[12]

Diagnosis	Onset	Course	Key Cognitive Domain	Key Distinguishing Feature	Imaging
AD	Insidious	Gradual progressive	Memory first	Amnestic syndrome; normal neuro exam early	Medial temporal atrophy
VaD	Acute/subacute	Stepwise	Executive function	Vascular RFs; focal neuro signs; stepwise course	Infarcts, WMH
DLB	Insidious	Fluctuating	Attention, visuospatial, executive	Visual hallucinations, RBD, parkinsonism, fluctuation	Preserved MTL; ↓ occipital metabolism; DaTscan+
FTD	Insidious	Progressive	Behaviour or language	Early personality/behavioural change; young onset	Frontal/temporal atrophy
CJD	Subacute	Rapid (months)	Global	Rapid course; myoclonus; ataxia	Cortical ribboning (DWI)
NPH	Insidious	Progressive	Frontal/executive	Triad: gait-dementia-incontinence	Ventriculomegaly out of proportion to atrophy
Depression	Defined onset	Variable	Attention, concentration	Subjective complaints > objective deficits; treatable	Normal
Delirium	Acute	Fluctuating	Attention (hallmark)	Acute onset; impaired consciousness; precipitant	Depends on cause

The distribution of dementia types varies by age ^[8]:

Age Group	AD	FTD	VaD	DLB
≥ 65 years	~2/3 of cases ^[8]	Very few ^[8]	Significant minority	~10%
< 65 years	~1/3 of cases ^[8]	~12% ^[8]	Less common	Less common

This has practical implications: in a young patient with dementia (< 65), you must especially consider early-onset AD (familial/genetic), FTD, Huntington's disease, Wilson's disease, HIV, and substance misuse — not just "assume AD."

In Hong Kong specifically:

High burden of vascular risk factors (HTN, DM) → mixed AD/VaD is very common
Relatively low prevalence of CJD
Wilson's disease, though rare globally, should be considered in any young Chinese patient with cognitive/psychiatric symptoms + liver disease or movement disorder

High Yield Summary — Differential Diagnosis of AD

Depression ("pseudodementia") accounts for ~10% of presumed dementia — always screen; consider therapeutic trial of antidepressants ^[7]
Delirium: differentiate by acute onset, fluctuating consciousness, identifiable precipitant — remember 2/3 of delirium occurs in dementia patients ^[2]
10–15% of dementia is reversible ^[5] — mandatory minimum screen: CBC, B12/folate, TFT, RFT, Ca, glucose, CT/MRI brain ^[5]
VaD: stepwise course, focal neuro signs, vascular RFs, infarcts on imaging
DLB: visual hallucinations, fluctuating cognition, RBD, parkinsonism; antipsychotic sensitivity; preserved medial temporal lobe on MRI; DaTscan most helpful to distinguish from AD ^[4]^[5]
FTD: young onset, early behaviour/personality change or language deficit, frontal/temporal atrophy
CJD: rapidly progressive (months), myoclonus, cortical ribboning on MRI
NPH: gait-dementia-incontinence triad, ventriculomegaly disproportionate to atrophy — treatable with shunt
AD copathology with DLB occurs in > 50% of DLB cases ^[4]; mixed AD/VaD is also extremely common
In those < 65, FTD accounts for ~12% and AD only ~1/3 ^[8] — broaden differential in young patients

Active Recall - Differential Diagnosis of Alzheimer's Disease

References

^[2] Senior notes: Ryan Ho Fundamentals.pdf, p325 ^[4] Lecture slides: GC 241. Reference (3) - Patel dementia with lewy bodies.pdf ^[5] Senior notes: Ryan Ho Neurology.pdf, pp128–131 ^[7] Senior notes: Ryan Ho Psychiatry.pdf, pp82, 88 ^[8] Senior notes: Maksim Medicine Notes.pdf, pp113, 253 ^[9] AOS material: AOS - Geriatrics.pdf, pp3–4; Geriatrics AOS.pdf, p4 ^[10] Senior notes: Block A - Patients with non-viral chronic liver diseases.pdf, p2 ^[11] Senior notes: Ryan Ho Diagnostic Radiology.pdf, p69 ^[12] Senior notes: learning_points_output.txt (Neurology - Two Cases of Movement Disorders)

Diagnostic Criteria, Algorithm, and Investigations for Alzheimer's Disease

1. Diagnostic Criteria

The diagnosis of AD operates at two levels: first you establish dementia (the syndrome), then you attribute it to AD (the aetiology). Understanding both sets of criteria is essential.

Two classification systems are used. Both require the same core elements: cognitive decline + functional impairment + preserved consciousness.

ICD-10 (Dementia, F00–03)	DSM-5 (Major Neurocognitive Disorder)
Evidence of decline in both memory and thinking sufficient to impair personal ADL ^[7]	Evidence of significant cognitive decline from a previous level of performance in ≥1 of 6 cognitive domains ^[7]
Impairment of memory affects registration, storage, and retrieval of new information; previously learned material may also be lost in later stages ^[7]	Based on: (1) clinical evidence of decline in cognitive function; and (2) impairment in cognitive performance, preferably documented by standardised assessment ^[7]
Impairment of thinking: impairment of reasoning capacity, reduction of flow of ideas, impairment of processing incoming information, difficulty attending to ≥1 stimulus ^[7]	The cognitive deficits interfere with independence in everyday activities (at minimum, require assistance with complex iADLs) ^[7]
Evidence of clear consciousness is required (unless double diagnosis of delirium superimposed on dementia) ^[7]	The cognitive deficits do not occur exclusively in the context of a delirium ^[7]
Symptoms and impairments should have been evident for at least 6 months ^[7]	Not better explained by another mental disorder (e.g., MDD, schizophrenia) ^[7]

DSM-5 cognitive domains (6 domains): Learning and memory, Language, Executive function, Complex attention, Perceptual-motor function, Social cognition.

Why do we need ≥6 months in ICD-10? To ensure chronicity and distinguish from transient causes like delirium or acute confusional states. DSM-5 does not specify a time threshold but implies chronicity through the requirement for a progressive or established decline.

What about MCI (Minor NCD)? — Same cognitive decline but functionally independent (no interference with ADLs). This is the prodromal stage where the patient has measurable deficits (typically 1–1.5 SD below age-matched norms) but compensates adequately in daily life.

1.2 Step 2 — Attributing the Syndrome to AD

Once dementia is established, you need to determine which type. Two major frameworks exist for attributing dementia specifically to AD.

These are the traditional criteria used in everyday clinical practice.

ICD-10 (Dementia in AD, F00) — All are required ^[7]:

(a) Presence of dementia as described above ^[7]

(b) Insidious onset with slow deterioration. While the onset usually seems difficult to pinpoint in time, realisation by others that the defects exist may come suddenly. An apparent plateau may occur in the progression. ^[7]

(c) Absence of clinical evidence or findings from special investigations to suggest that the mental state may be due to other systemic or brain disease which can induce a dementia ^[7]

(d) Absence of a sudden, apoplectic onset or of neurological signs of focal damage occurring early in the illness ^[7]

The ICD-10 approach is essentially one of exclusion — you diagnose AD by ruling out everything else. There is no biomarker requirement.

DSM-5 (Major or Mild NCD due to AD) ^[7]:

A. Criteria are met for major or mild neurocognitive disorder. ^[7]

B. There is insidious onset and gradual progression in ≥1 cognitive domains (≥2 domains must be impaired for major NCD due to AD). ^[7]

C. Criteria are met for probable or possible AD:

For major NCD: probable AD is diagnosed when ≥1 of the following is present, otherwise possible AD ^[7]:

(1) Evidence of causative mutation from FHx or genetic tests ^[7]

(2) All three of: ^[7]

a. Clear evidence of decline in memory and learning (and in major NCD, ≥1 other cognitive domain) ^[7]

b. Steadily progressive gradual decline in cognition, without extended plateaus ^[7]

c. No evidence of mixed aetiology ^[7]

D. Not better explained by cerebrovascular disease, another neurodegenerative disease, effects of a substance, or another mental, neurological or systemic disorder. ^[7]

Key Exam Point: Probable vs Possible AD (DSM-5)

Probable AD = typical clinical presentation (amnestic, progressive, no mixed cause) OR confirmed genetic mutation
Possible AD = atypical features (e.g., plateau in progression, mixed aetiology, non-amnestic presentation) but no better alternative explanation
In clinical practice, a "probable AD" diagnosis made by experienced clinicians has ~85–90% accuracy at autopsy

This represents the paradigm shift: AD is defined by its biology, not by its symptoms ^[3]. These criteria are increasingly used in research and are beginning to enter clinical practice, particularly with the advent of disease-modifying therapies (anti-amyloid antibodies).

Core Biomarker Classification ^[3]:

The 2024 criteria update the AT(N) biomarker classification:

Category	Biomarker	What It Detects	Modality
A (Amyloid)	Aβ42/40 ratio ↓, Amyloid PET+	Amyloid plaque deposition	CSF, blood, PET
T1 (Core AD tau)	p-tau 181, p-tau 217 ↑	Tau phosphorylation (AD-specific)	CSF, blood
T2 (Tau PET)	Tau PET+	Tau tangle deposition (regional)	PET
N (Neurodegeneration)	Total tau, NfL, hippocampal volume ↓, FDG-PET ↓	Neuronal injury/death (non-specific)	CSF, blood, MRI, PET

Core 1 biomarkers ^[3]: A + T1 — An abnormality on Core 1 biomarkers (A+ and T1+) is now sufficient to define AD in vivo ^[3]. You do not need symptoms.

AD exists on a continuum ^[3]:

Biological Stage	Core Biomarker Status	Clinical Status
Stage 1 (Initial/Preclinical)	A+ only	Cognitively unimpaired
Stage 2 (Early)	A+ T1+	Cognitively unimpaired
Stage 3 (Intermediate)	A+ T1+ T2+ (limited regions)	May have MCI or mild dementia
Stage 4 (Advanced)	A+ T1+ T2+ (widespread)	Usually dementia

High Yield: Why This Matters Clinically

Three major developments prompted this update ^[3]:

Treatments targeting core disease pathology (anti-amyloid immunotherapies) have received regulatory approval for the first time
Development of blood-based markers (BBM) with accurate diagnostic performance — makes biological diagnosis accessible without PET or LP
Recognition that AD neuropathology precedes symptoms by 15–20 years — a purely syndromic definition misses the preclinical disease

The field is now in a transition phase during which BBM are being integrated with traditional CSF and PET biomarkers ^[3].

The clinical approach to a patient with suspected AD follows a systematic sequence. The key principles are: confirm cognitive decline → establish dementia → exclude reversible causes → characterise the dementia subtype → stage severity.

3. Investigation Modalities

Investigations for AD serve three purposes:

Exclude reversible causes (mandatory in every patient)
Support the clinical diagnosis of AD vs other dementia subtypes
Confirm biological diagnosis of AD (biomarkers — increasingly important)

Tool	Description	Key Features	Interpretation
MMSE (Mini-Mental State Examination)	30-point screening tool	Tests: orientation (10), registration (3), attention/calculation (5), recall (3), language (8), construction (1)	≤ 24 suggests dementia; 20–24 mild, 10–19 moderate, < 10 severe. Ceiling effect — may miss MCI
MoCA (Montreal Cognitive Assessment)	30-point screening tool; preferred for AD evaluation ^[5]	More sensitive for MCI; tests: visuospatial/executive (5), naming (3), attention (6), language (3), abstraction (2), delayed recall (5), orientation (6)	≤ 25 suggests cognitive impairment. Better at detecting executive and visuospatial deficits
CDR (Clinical Dementia Rating)	Clinician-rated global staging	Assesses 6 domains via patient + informant interview	0 = normal, 0.5 = MCI, 1 = mild, 2 = moderate, 3 = severe dementia
ADAS-Cog (Alzheimer's Disease Assessment Scale–Cognitive)	Research/trial outcome measure	70-point scale; tests memory, language, praxis, orientation	Higher score = worse cognition; used to measure treatment response in drug trials
ACE-III (Addenbrooke's Cognitive Examination)	100-point detailed assessment	Covers attention, memory, fluency, language, visuospatial	More granular than MMSE/MoCA; useful for subtype differentiation

Typical cognitive profile in AD:

Delayed recall is the most impaired domain early (hippocampal encoding failure)
Clock drawing test abnormal (visuospatial + executive)
Category fluency (e.g., "name as many animals as possible in 1 minute") impaired before letter fluency
Orientation to time impaired before place before person

MoCA vs MMSE

MoCA is preferred ^[5] because:

More sensitive for MCI (MMSE has ceiling effect — patients with MCI can score 26–28)
Better testing of executive function and visuospatial ability (domains affected early in AD)
+1 point for ≤12 years education (corrects for education bias)
MMSE is copyrighted; MoCA is freely available

Minimum investigations (NICE guidelines) ^[5]^[7]:

Test	Target Condition	Rationale
CBC	Anaemia, infection, haematological malignancy	Anaemia → cerebral hypoxia; macrocytic anaemia → B12/folate deficiency
Serum B12 and folate	B12/folate deficiency	B12 deficiency → subacute combined degeneration, dementia; folate deficiency → homocysteinaemia
TFT	Hypothyroidism	Hypothyroidism → ↓ neuronal metabolism → reversible cognitive impairment
RFT (urea, creatinine)	Renal failure	Uraemic encephalopathy
Calcium	Hypercalcaemia	Hypercalcaemia → neuronal membrane dysfunction ("stones, bones, moans, groans, psychic overtones")
Glucose	Diabetes, hypoglycaemia, Cushing's, Addison's	Chronic hyper-/hypoglycaemia → neuronal damage

Additional targeted tests (as clinically indicated) ^[5]:

Test	When to Order	Target Condition
LFT	Liver disease suspected	Hepatic encephalopathy
VDRL / RPR	Risk factors for syphilis	Neurosyphilis (tertiary syphilis → general paresis of the insane)
HIV test	Risk factors present	HIV-associated neurocognitive disorder
ESR, vasculitic screen (ANA, anti-dsDNA, ANCA)	Young patient, systemic features	Cerebral vasculitis, SLE
Copper studies (caeruloplasmin, 24h urinary copper)	Young patient, liver disease, movement disorder	Wilson's disease
Cortisol	Features of Cushing's/Addison's	Adrenal disease

3.3 Structural Neuroimaging — CT and MRI Brain

CT/MRI brain is included in NICE minimum investigations ^[5]^[7].

Primary purpose: Exclude structural/reversible causes (chronic SDH, tumours, NPH) and support pattern recognition for dementia subtype.

Widely available, fast, low cost
Can identify: chronic SDH, tumours, NPH (ventriculomegaly), large infarcts, gross atrophy
Limited sensitivity for early AD changes (hippocampal atrophy)

Sequence	What It Shows	Key Findings in AD
T1-weighted (structural)	Grey/white matter anatomy	Hippocampal atrophy (earliest structural change); medial temporal lobe atrophy (MTA); generalised cortical atrophy with widened sulci and dilated ventricles ^[7]
T2/FLAIR	White matter lesions, oedema	White matter hyperintensities (if vascular co-pathology); periventricular lucency (NPH)
DWI	Acute ischaemia, CJD	Cortical ribboning in CJD; acute infarcts in VaD
SWI/T2*	Microhaemorrhages	Cerebral amyloid angiopathy (lobar microbleeds); hypertensive microbleeds (deep)
Volumetric MRI	Quantitative atrophy measurement	Hippocampal volumetry can be quantified; serial scans show rate of atrophy

Medial Temporal Atrophy (MTA) Scale (Scheltens scale, 0–4):

Visual rating of hippocampal/entorhinal atrophy on coronal T1 MRI
Score ≥2 in patients < 75 years, or ≥3 in patients ≥75 years is considered abnormal
Sensitivity ~85%, specificity ~85% for AD vs normal ageing

Key imaging findings by dementia subtype ^[5]^[7]^[11]:

Dementia Type	Structural Imaging Pattern
AD	Unilateral/bilateral perihippocampal atrophy (early) → generalised cerebral atrophy with widened sulci and dilated ventricles (late) ^[7]
VaD	Multiple infarcts (cortical/subcortical), confluent white matter hyperintensities, strategic infarcts (thalamus, angular gyrus)
DLB	Relative preservation of medial temporal lobe structures (cf AD) ^[5]
FTD	Frontal and/or anterior temporal atrophy (often asymmetric; "knife-edge" atrophy)
CJD	Cortical ribboning on DWI/FLAIR ^[7]; caudate/putamen signal change
NPH	ALL ventricles enlarged disproportionate to sulcal effacement; periventricular lucency on FLAIR ^[7]

High Yield: How to Tell NPH from AD on Imaging

Both can show enlarged ventricles. The key distinction:

AD: Ventricles enlarge because brain atrophies → sulci are also widened proportionately (hydrocephalus ex vacuo)
NPH: Ventricles enlarge disproportionate to sulcal widening → CSF dynamics problem, not atrophy. Evans index (max ventricular width / max cranial width) > 0.3 supports NPH

3.4 Functional Neuroimaging — PET and SPECT

These demonstrate metabolic activity or perfusion of specific brain areas and are extremely useful for differentiating dementia subtypes.

Measures cerebral glucose metabolism (a proxy for neuronal activity)
Neurons that are dying/dysfunctional have ↓ glucose uptake → hypometabolism

Dementia	FDG-PET Pattern
AD	↓ metabolism in parietotemporal and hippocampal regions ^[7]; posterior cingulate and precuneus hypometabolism (very early); frontal involvement in advanced disease
FTD	Bilateral frontal + temporal hypometabolism ^[11]
DLB	Generalised ↓ with reduced occipital activity ^[4]; posterior cingulate island sign (relative preservation of posterior cingulate metabolism compared to occipital — helps distinguish DLB from AD) ^[4]

Why parietotemporal in AD? Because AD pathology (plaques and tangles) preferentially affects the temporal and parietal association cortices, hippocampus, and posterior cingulate. Primary motor and sensory cortex are relatively spared → these regions maintain normal glucose metabolism.

Demonstrates cerebral perfusion using 99mTc-HMPAO ^[11]
Less expensive and more widely available than PET, but lower spatial resolution
Different types of dementia typically present with different patterns of perfusion changes ^[11]

Dementia	SPECT Pattern
AD	Bilateral posterior temporal + parietal hypoperfusion ^[11]
FTD	Bilateral frontal + temporal hypoperfusion ^[11]
DLB	Generalised ↓ with reduced occipital perfusion

Uses radioligands (e.g., ¹¹C-PiB, ¹⁸F-florbetapir, ¹⁸F-florbetaben, ¹⁸F-flutemetamol) that bind to fibrillar Aβ plaques
Positive = diffuse cortical Aβ binding → supports AD diagnosis
Negative = essentially rules out AD as the cause of dementia (very high negative predictive value)
Limitations: expensive, limited availability; amyloid positivity increases with age (20–40% of cognitively normal elderly are amyloid+)
CSF Aβ / Aβ-PET is the earliest biomarker to become abnormal in AD ^[8]

Uses ¹⁸F-flortaucipir (or newer tracers) to visualise tau tangle deposition
Shows regional distribution of tau pathology — correlates better with clinical symptoms than amyloid PET
Most useful for staging AD severity and tracking disease progression
Helps confirm T2+ status in 2024 NIA-AA criteria

Uses ¹²³I-FP-CIT to visualise presynaptic dopamine transporters in the striatum
Normal in AD; abnormal (reduced uptake) in DLB and PD/PDD
"Dopamine transporter imaging is most helpful in distinguishing DLB from Alzheimer disease" ^[4]
This is an indicative biomarker for DLB

Obtained via lumbar puncture. CSF is in direct contact with brain interstitial fluid, so it reflects brain pathology directly.

Biomarker	Change in AD	What It Reflects	Explanation
Aβ42	↓	Amyloid plaque deposition	Aβ42 is sequestered into plaques in the brain → less available in CSF
Aβ42/Aβ40 ratio	↓	More specific than Aβ42 alone	Aβ40 acts as a normalisation factor for individual variation in total Aβ production
Total tau (t-tau)	↑	Neuronal injury/death (non-specific)	Dying neurons release tau into CSF
Phosphorylated tau (p-tau 181, p-tau 217)	↑	AD-specific tau pathology	Hyperphosphorylated tau is the building block of NFTs — highly specific for AD

CSF biomarker profile in AD: ↓ Aβ42 (or ↓ Aβ42/40 ratio) + ↑ p-tau + ↑ t-tau = "AD signature"

CSF biomarker profile in CJD: ↑ 14-3-3 protein, ↑ t-tau (often markedly elevated), RT-QuIC assay positive

When to order CSF biomarkers?

Diagnostic uncertainty between AD and other dementias
Young-onset dementia (< 65)
Atypical clinical presentation
Suspected CJD (rapidly progressive)
When considering eligibility for anti-amyloid immunotherapy

The most significant advance in AD diagnostics in recent years has been the development of blood-based markers ^[3]. The 2025 Alzheimer's Association Clinical Practice Guideline provides formal recommendations on BBM use ^[13].

Blood Biomarker	What It Measures	Performance
Plasma p-tau 217	AD-specific tau phosphorylation	Best single blood biomarker; AUC 0.93–0.97 for predicting amyloid PET positivity
Plasma p-tau 181	AD-specific tau phosphorylation	Slightly lower accuracy than p-tau 217
Plasma Aβ42/Aβ40 ratio	Amyloid pathology	Moderate accuracy alone; improves when combined with p-tau
Plasma NfL (neurofilament light)	Neurodegeneration (non-specific)	Elevated in many neurodegenerative diseases; useful for prognosis
Plasma GFAP	Astrocytic activation	Reflects neuroinflammation; may ↑ early in AD

Current recommendations ^[13]:

Blood-based biomarkers should be used in specialised care settings as part of a comprehensive diagnostic process by providers with training and experience in diagnosing memory disorders ^[13]
Best use: as a screening/triage tool — if blood biomarkers suggest AD, confirmatory testing (amyloid PET or CSF) may follow, particularly if treatment decisions depend on it
Plasma p-tau 217 has emerged as the leading candidate for clinical implementation

Why Blood Biomarkers Matter — The Access Revolution

Previously, confirming AD biology required PET scans (expensive, limited availability, radiation) or lumbar puncture (invasive, patient reluctance). Blood-based biomarkers now make the biological diagnosis of AD more generally accessible ^[3] — a simple blood draw could replace or triage these invasive/expensive tests. This is projected to revolutionise clinical care and research ^[3].

AD: Non-specific changes; generalised slowing of background rhythm (↓ alpha, ↑ theta/delta) in later stages; relatively normal early
CJD: Periodic sharp-wave complexes (triphasic waves at 1–2 Hz) — classic but not always present; most useful in sporadic CJD
DLB: Posterior slow-wave EEG activity with frequencies slower than 8 Hz ^[4] — observed in ~90% of DLB vs ~10% of AD
Delirium: Generalised slowing (helps confirm delirium when suspected)
Non-convulsive status epilepticus: EEG is the only way to diagnose this mimic of confusion/delirium

When to Consider	What to Test	Interpretation
Early-onset AD (< 65) with positive FHx	APP, PSEN1, PSEN2	If mutation found → autosomal dominant AD; high penetrance; implications for family counselling
Late-onset AD	APOE genotyping	ε4/ε4 → highest risk (~12× population risk); ε4 heterozygosity → ~3× risk; ε2 → protective. NB: APOE genotyping is NOT diagnostic — it is a risk factor, not a deterministic test
Suspected FTD	MAPT, GRN, C9orf72	Autosomal dominant FTD
Suspected Huntington's	HTT gene (CAG repeats)	Diagnostic if ≥36 repeats

Important: APOE Testing is Risk Stratification, Not Diagnosis

Many students confuse this: having APOE ε4 does not diagnose AD. Many ε4 carriers never develop AD, and many AD patients are ε4 negative. It is a susceptibility gene, not a deterministic one. However, APOE ε4 homozygosity is now considered by some to be treated as a genetic form of AD (2024 debate) — but this remains controversial and is not standard clinical practice.

Investigation	Purpose	Key AD Finding	When to Use
Cognitive testing (MoCA)	Confirm and profile cognitive impairment	↓ delayed recall, clock drawing, orientation	Every patient
Blood tests (CBC, B12, TFT, Ca...)	Exclude reversible causes	Normal in AD	Every patient (mandatory minimum)
CT brain	Exclude structural lesions	Generalised atrophy (non-specific)	Every patient (minimum)
MRI brain	Better characterisation	Hippocampal/MTA, generalised atrophy	Preferred over CT when available
FDG-PET	Functional: metabolism	Parietotemporal + posterior cingulate hypometabolism	Diagnostic uncertainty
SPECT	Functional: perfusion	Bilateral posterior temporal + parietal ↓	More available than PET
Amyloid PET	Confirm amyloid pathology	Diffuse cortical Aβ binding	Diagnostic uncertainty; pre-treatment
Tau PET	Confirm tau pathology, staging	Regional tau deposition (temporal → widespread)	Research; staging; pre-treatment
CSF biomarkers	Biological confirmation	↓ Aβ42, ↑ p-tau, ↑ t-tau	Diagnostic uncertainty; young-onset
Blood biomarkers	Screening/triage	↑ plasma p-tau 217	Emerging; specialist settings
DaTscan	Distinguish AD from DLB	Normal in AD; reduced in DLB	Suspected DLB vs AD
EEG	Exclude CJD, seizures; support DLB	Non-specific slowing (late AD)	Rapid progression; suspected CJD
Genetic testing	Familial/early-onset cases	APP, PSEN1, PSEN2 mutations	Early-onset AD with FHx

Level	Basis	Notes
Definite AD	Neuropathological confirmation (autopsy/biopsy)	Neuritic plaques + NFTs meeting NIA-AA neuropathological criteria; this was historically the only "definitive" diagnosis
Biologically confirmed AD	Core 1 biomarkers positive (A+ T1+) ^[3]	The 2024 NIA-AA criteria now consider this equivalent to diagnosing the disease in vivo
Probable AD (clinical)	Typical clinical syndrome + exclusion of alternatives (ICD-10/DSM-5) ^[7]	The standard in current clinical practice; ~85–90% accuracy vs autopsy
Possible AD (clinical)	Atypical features, mixed aetiology, or incomplete workup ^[7]	Lower certainty; warrants further investigation

High Yield Summary — Diagnostics

Dementia diagnosis requires: cognitive decline in ≥1 domain + functional impairment + preserved consciousness + exclusion of delirium ^[7]
AD clinical diagnosis (ICD-10/DSM-5): insidious onset, gradual progression, exclusion of other causes, absence of sudden/apoplectic onset or early focal neurological signs ^[7]
2024 NIA-AA: AD defined biologically — Core 1 biomarkers (A+ T1+) = AD, even without symptoms ^[3]
MoCA preferred over MMSE for cognitive assessment (more sensitive for MCI) ^[5]
Mandatory minimum investigations: CBC, B12/folate, TFT, RFT, Ca, glucose + CT/MRI brain ^[5]^[7]
MRI AD pattern: hippocampal/medial temporal atrophy (early) → generalised atrophy (late) ^[7]
FDG-PET/SPECT AD pattern: bilateral posterior temporal + parietal hypometabolism/hypoperfusion ^[7]^[11]
CSF AD signature: ↓ Aβ42 (or ↓ Aβ42/40 ratio) + ↑ p-tau + ↑ t-tau
Plasma p-tau 217 is the leading blood-based biomarker — set to revolutionise AD diagnosis ^[3]^[13]
DaTscan distinguishes DLB (abnormal) from AD (normal) ^[4]
Amyloid PET is earliest biomarker to become abnormal; negative amyloid PET essentially rules out AD ^[8]

Active Recall - Diagnostic Criteria, Algorithm and Investigations for AD

References

^[3] Lecture slides: GC 241. Reference (1) - Alzheimers Dementia - Revised criteria for diagnosis and staging of Alzheimer s disease.pdf ^[4] Lecture slides: GC 241. Reference (3) - Patel dementia with lewy bodies.pdf ^[5] Senior notes: Ryan Ho Neurology.pdf, pp128–131 ^[7] Senior notes: Ryan Ho Psychiatry.pdf, pp77, 81, 88, 92 ^[8] Senior notes: Maksim Medicine Notes.pdf, p113 ^[11] Senior notes: Ryan Ho Diagnostic Radiology.pdf, p69 ^[13] Lecture slides: Alzheimers Dementia - Palmqvist - Alzheimer s Association Clinical Practice Guideline on the use of blood-based.pdf

Management of Alzheimer's Disease

The management of AD is multimodal and must be understood through the lens of a disease that is currently not curable — but for which we can slow cognitive decline, manage symptoms, reduce carer burden, and maintain quality of life for as long as possible. The approach integrates pharmacological, non-pharmacological, psychosocial, and (in the latest era) disease-modifying strategies.

Before diving into specifics, understand the overarching framework:

Treat any reversible/contributing causes (always first)
Pharmacological therapy for cognition (symptomatic — cholinesterase inhibitors, memantine)
Disease-modifying therapy (anti-amyloid immunotherapy — new era, 2023+)
Management of BPSD (non-pharmacological first, then judicious pharmacotherapy)
Non-pharmacological / psychosocial interventions (for patient and carer)
Advance care planning and end-of-life care
Vascular risk factor management (especially in mixed dementia)

Key Principle

Pharmacotherapy does not modify the course of disease ^[8] — this statement applies to traditional symptomatic treatments (ChEIs, memantine). The new anti-amyloid antibodies (lecanemab, donanemab) do target the underlying biology, but their clinical impact is modest and they carry significant risks. The mainstay of management remains supportive and symptomatic.

3. Pharmacological Management for Cognition

3.1 Cholinesterase Inhibitors (ChEIs)

"Cholinesterase" = choline + esterase — the enzyme that breaks down acetylcholine. An "inhibitor" blocks this enzyme → more ACh stays in the synapse.

Rationale (Cholinergic Hypothesis): AD selectively destroys cholinergic neurons (especially from the nucleus basalis of Meynert) → profound cortical ACh deficit → memory and attention impairment. ChEIs ↓ ACh breakdown at synapses → ↑ cholinergic transmission ^[7].

Drug	Brand	Dose	Specifics
Donepezil	Aricept	5 mg OD → 10 mg OD after 4–6 weeks ^[7]	Selective AChE inhibitor; once-daily dosing (long t½); most widely used
Rivastigmine	Exelon	Oral: 1.5 mg BD → titrate to 6 mg BD; Patch: 4.6 mg/24h → 9.5 mg/24h → 13.3 mg/24h	Dual inhibitor (AChE + BuChE); rivastigmine patch: ↓ S/E, ↑ concentration, ↑ compliance ^[8]
Galantamine	Reminyl	4 mg BD → 8 mg BD → 12 mg BD (or ER formulation OD) ^[7]	AChE inhibitor + allosteric modulator of nicotinic ACh receptors (enhances pre-synaptic ACh release)

Mild-to-moderate AD ^[7]^[8]

Less evidence when advanced, e.g., MMSE < 12 ^[7]

In practice, many clinicians continue ChEIs into moderate-severe stages if they were started earlier and the patient/carer perceives benefit. NICE guidelines (2018) recommend ChEIs across all AD severities.

Modest improvement in cognition: MMSE ~1.37 points improvement, ADAS-Cog ~2.7 points improvement at 6–12 months ^[7]. These are symptomatic effects — they do not alter disease trajectory. Think of it as "raising the curve but not changing the slope." Clinically, this translates to a delay of ~6–12 months in functional decline, which is meaningful for patients and carers.

S/E: nausea/vomiting, diarrhoea, anorexia, bradycardia ^[8]

The side effects are predictable from the mechanism — all are due to excess cholinergic stimulation:

Side Effect	Mechanism
Nausea, vomiting, diarrhoea	↑ ACh at muscarinic receptors in GI tract → ↑ gut motility, ↑ secretions
Anorexia / weight loss	Central cholinergic stimulation of satiety centres + GI upset
Bradycardia	↑ ACh at cardiac vagal (muscarinic M2) receptors → ↑ vagal tone → ↓ heart rate
Muscle cramps	↑ ACh at neuromuscular junction → sustained muscle activation
Insomnia / vivid dreams	Central cholinergic activation (especially if taken at night — advise morning dosing for donepezil)
Urinary incontinence	↑ ACh at detrusor muscle M3 receptors → bladder contraction

Contraindication / Caution	Reason
COPD / Asthma ^[8]	↑ ACh → bronchoconstriction (muscarinic M3 receptors on bronchial smooth muscle)
Peptic ulcer disease (PUD) ^[8]	↑ ACh → ↑ gastric acid secretion (M1/M3 receptors on parietal cells) → ulcer exacerbation
Sick sinus syndrome / Significant bradycardia	↑ vagal tone → dangerous bradycardia, syncope
Heart block (2nd/3rd degree)	Risk of complete heart block from excessive vagotonic effect
Active GI bleeding	↑ GI secretions and motility may worsen bleeding
Concomitant anticholinergic drugs	Pharmacological antagonism — the anticholinergic drug cancels out the ChEI effect (surprisingly common prescribing error in elderly patients)

Common Exam Trap: Prescribing Contradictions in Elderly Patients

A classic error: prescribing donepezil for AD while simultaneously prescribing oxybutynin (anticholinergic) for urinary incontinence. These drugs directly oppose each other pharmacologically. Oxybutynin blocks muscarinic receptors → ↓ ACh effect; donepezil ↑ ACh. Always review the full drug list and avoid anticholinergic drugs in dementia patients. Use the STOPP/START criteria to guide prescribing in older adults ^[14].

Start low, go slow — titrate up gradually to minimise GI side effects
Take with food to reduce nausea
Donepezil: take in the morning (if insomnia) or evening (if daytime drowsiness)
Rivastigmine patch is preferred when oral tolerance is poor — ↓ side effects, ↑ steady-state drug concentration, ↑ compliance ^[8]
Monitor: heart rate, weight, GI symptoms; consider baseline ECG if cardiac history

"Memantine" — think of "membrane" — it works at the NMDA receptor on the neuronal membrane.

Rationale (Glutamate Excitotoxicity Hypothesis): In AD, there is chronic low-level activation of NMDA receptors by excess glutamate → tonic Ca²⁺ influx → neuronal damage ("excitotoxicity") + interference with normal synaptic signalling (the constant "noise" drowns out the "signal"). Memantine is an uncompetitive, moderate-affinity NMDA receptor antagonist — it blocks this chronic pathological activation while still allowing normal phasic (burst) activation during learning. It essentially reduces the background noise so that true signals can be detected.

Feature	Detail
Drug name	Memantine ^[8]
Indication	Moderate-to-severe AD ^[8] (MMSE ~3–14; some guidelines extend to moderate AD, MMSE 10–20)
Dose	5 mg OD → titrate weekly by 5 mg → maintenance 10 mg BD (20 mg/day)
Efficacy	Modest benefit in cognition, ADL function, behaviour, and global impression; often combined with ChEI
S/E	Constipation, headache, somnolence ^[8]; also dizziness, hypertension (uncommon)
Caution	Seizure history ^[8] (lowers seizure threshold — NMDA blockade can be pro-convulsant at high doses); also caution in severe renal impairment (renally excreted)

Can ChEI and memantine be used together? Yes — combination therapy (e.g., donepezil + memantine) is common in moderate-to-severe AD and is supported by evidence showing additional benefit vs monotherapy. They work on different neurotransmitter systems (cholinergic vs glutamatergic) and are not pharmacologically contradictory.

	ChEIs (Donepezil, Rivastigmine, Galantamine)	Memantine
Target	Cholinergic deficit	Glutamate excitotoxicity
MoA	↓ ACh breakdown → ↑ synaptic ACh	Uncompetitive NMDA antagonist → ↓ excitotoxicity
Indication	Mild-to-moderate AD ^[8]	Moderate-to-severe AD ^[8]
Key S/E	N/V, diarrhoea, anorexia, bradycardia ^[8]	Constipation, headache, somnolence ^[8]
Caution	COPD/asthma, PUD ^[8]	Seizures ^[8], renal impairment
Combination	Can combine with memantine	Can combine with ChEI
Disease-modifying?	No ^[8]	No

4. Disease-Modifying Therapy — Anti-Amyloid Immunotherapy (New Era)

These are the first treatments that target the underlying biology of AD, specifically amyloid-beta plaque removal.

Feature	Detail
Class	Humanised monoclonal antibody targeting soluble Aβ protofibrils
Mechanism	Binds Aβ protofibrils (the most toxic soluble species) → promotes microglial phagocytosis → clears amyloid plaques
Approval	FDA full approval (2023); EMA conditional approval
Indication	Early AD (MCI due to AD or mild AD dementia) with confirmed amyloid pathology (amyloid PET+ or CSF biomarker+)
Efficacy	CLARITY-AD trial: 27% slowing of cognitive decline (CDR-SB) at 18 months vs placebo; significant amyloid PET clearance
Administration	IV infusion every 2 weeks
Key adverse effect	ARIA (Amyloid-Related Imaging Abnormalities): ARIA-E (oedema/effusion, ~13%) and ARIA-H (haemorrhage/hemosiderin, ~17%). Mostly asymptomatic but can cause headache, confusion, visual disturbance. Rarely fatal
Monitoring	Serial MRI brain before and during treatment (baseline, weeks 5, 9, 14, then periodically) to detect ARIA
Contraindications / High risk	APOE ε4 homozygotes (much higher ARIA risk — ~35%); anticoagulant use (↑ haemorrhage risk); significant cerebral amyloid angiopathy or prior macrohemorrhage

Feature	Detail
Class	Humanised monoclonal antibody targeting N-terminal truncated Aβ (pyroglutamate Aβ) — targets deposited plaques
Approval	FDA approved (2024)
Indication	Early AD with confirmed amyloid and intermediate tau pathology
Efficacy	TRAILBLAZER-ALZ 2: 35% slowing of decline (iADRS) in low/medium tau group at 18 months
Unique feature	Time-limited treatment — can stop once amyloid is cleared (unlike lecanemab which is continuous)
Key AE	Similar ARIA risk; higher in APOE ε4 homozygotes

Anti-Amyloid Therapy: The Reality Check

These drugs represent a genuine breakthrough — they prove that removing amyloid does slow decline. However, be clear-eyed about the limitations:

Effect size is modest (~27–35% slowing — patients still decline, just more slowly)
ARIA can be serious (oedema, microhaemorrhages)
Require biomarker confirmation of amyloid (PET or CSF) — cannot be given empirically
Require regular MRI monitoring
Only applicable to early-stage AD — not moderate/severe
Extremely expensive (~$26,500/year for lecanemab in the US)
Not yet widely available in Hong Kong (2025–2026 status: limited access, not HA standard formulary)

5. Management of BPSD (Behavioural and Psychological Symptoms of Dementia)

BPSD affects up to 90% of AD patients and is the leading cause of carer burnout and institutionalisation. The approach is always non-pharmacological first.

Strategy	Examples	Rationale
Identify and address triggers	Pain (often unrecognised), constipation, urinary retention, infection, hunger/thirst, environmental overstimulation	BPSD is often a communication of unmet needs in a patient who can no longer verbalise them
Environmental modification	Calm, well-lit environment; reduce noise; maintain consistent routine; familiar objects	↓ confusion and agitation from sensory overload; predictability ↓ anxiety
Person-centred care	Understand the patient's life history, preferences, personality	Behaviours have meaning — tailor approach to the individual
Carer education and support	Teach de-escalation techniques, distraction, validation therapy	Carers who understand BPSD cope better and resort to less pharmacotherapy
Cognitive stimulation therapy	Group activities, reminiscence therapy, music/art therapy	Maintains engagement, ↓ apathy and depression
Physical exercise	Walking programmes, supervised exercise	↑ BDNF, ↑ endorphins, ↑ sleep quality, ↓ agitation
Music therapy	Familiar music from the patient's era	Procedural memory for music is preserved even in advanced AD (stored in basal ganglia/cerebellum, not hippocampus)

Symptomatic management, e.g., neuroleptics for confusion, aggressive behaviour and paranoia ^[5]

Symptom	Drug Class	Specific Agents	Key Considerations
Depression	SSRIs (1st line)	Sertraline, escitalopram, citalopram	Preferred over TCAs (TCAs have anticholinergic effects → worsen cognition). Citalopram shown to ↓ agitation (CitAD trial) but watch QTc prolongation at higher doses
Agitation / Aggression	Atypical antipsychotics (2nd line, after non-pharm fails)	Risperidone (best evidence), olanzapine, quetiapine ^[15]	Only for patients at risk of harming others or own safety ^[15]. Black box warning: ↑ mortality (1.6–1.7× vs placebo) and ↑ cerebrovascular events in elderly with dementia. Use lowest dose, shortest duration. Review within 6–12 weeks
Psychosis (delusions, hallucinations)	Atypical antipsychotics	Risperidone (0.25–1 mg), quetiapine (12.5–50 mg)	Only if psychosis causes significant distress or danger. Quetiapine preferred if parkinsonism co-exists (lower EPS risk)
Anxiety	SSRIs, buspirone	Sertraline, buspirone	Avoid benzodiazepines if possible (paradoxical disinhibition, falls, sedation, dependence)
Sleep disturbance	Melatonin, trazodone	Melatonin 2–5 mg; trazodone 25–50 mg	Melatonin for circadian dysregulation; trazodone (sedating antidepressant) for insomnia without hangover effect. Avoid "Z-drugs" (falls risk)
Agitation (newer)	Brexpiprazole (atypical antipsychotic)	Brexpiprazole 2–3 mg	FDA-approved (2023) specifically for agitation in AD dementia — first drug with this specific indication

High Yield: Antipsychotic Use in Dementia — Critical Safety Points

Black box warning: All antipsychotics carry a ~1.6–1.7× increased risk of death (mainly from cardiovascular events and infections) in elderly patients with dementia
Pronounced sensitivity to antipsychotic EPSE in DLB ^[8] — always consider DLB before prescribing. If DLB is possible, avoid typical antipsychotics entirely; use only quetiapine or clozapine if absolutely necessary
Anticholinergic burden: Some antipsychotics (olanzapine) have significant anticholinergic effects → can worsen cognition
Metabolic effects: Weight gain, hyperglycaemia, dyslipidaemia (especially olanzapine, clozapine)
Always try non-pharmacological measures first; always use lowest dose for shortest duration; always set a review date

These are often underemphasised in exam revision but are core management and frequently tested.

Intervention	Evidence/Rationale	Stage
Cognitive stimulation therapy (CST)	NICE-recommended; group-based; improves cognition comparable to ChEI effect	Mild-moderate
Physical exercise	Regular aerobic exercise (30 min × 5/week) → ↑ cerebral perfusion, ↑ BDNF, ↓ neuroinflammation	All stages
Occupational therapy	Home safety assessment, assistive devices, ADL training	All stages
Speech and language therapy	Communication strategies, swallowing assessment (late stage)	Moderate-severe
Structured daily routine	Regular wake/sleep times, meals, activities	All stages
Reminiscence therapy	Discussion of past events using prompts (photos, music)	Mild-moderate
Caregiver education and support	Psychoeducation, support groups, respite care	All stages
Advance care planning	Enduring Power of Attorney, advance directives, discussion of goals of care	All stages (earlier = better)

Given the strong association between vascular risk factors and AD (and the high prevalence of mixed AD/VaD), aggressive vascular risk factor management is part of AD care:

Hypertension: Target BP < 130/80 if tolerated (avoid excessive lowering causing falls/hypoperfusion)
Diabetes: Good glycaemic control (avoiding hypoglycaemia — dangerous in dementia patients who cannot recognise or communicate symptoms)
Dyslipidaemia: Statin therapy if indicated for cardiovascular risk (but not specifically for AD)
Smoking cessation
Physical activity
Mediterranean diet

The STOPP/START criteria ^[14] are essential for managing polypharmacy in elderly patients with dementia:

STOPP (Screening Tool of Older Persons' Potentially Inappropriate Prescriptions):

Stop anticholinergics (bladder antimuscarinics, TCAs, first-generation antihistamines) — worsen cognition
Stop benzodiazepines long-term — falls, sedation, paradoxical agitation, dependence
Stop typical antipsychotics long-term — mortality risk, EPS
Stop drugs with no ongoing indication — simplify regimen

START (Screening Tool to Alert to Right Treatment):

Where a drug is clearly indicated and considered appropriate in the particular clinical context and there is no clear contraindication, that drug should be initiated ^[14]
Ensure ChEI is prescribed for mild-moderate AD if no contraindications
Ensure appropriate cardiovascular prevention is not omitted

This is a critical and frequently neglected aspect of AD management:

Element	Detail
Psychoeducation	Explain diagnosis, expected progression, BPSD, communication strategies
Carer training	Practical skills: bathing, feeding, de-escalation, handling wandering
Respite care	Day centres, in-home respite, short-term institutional respite
Support groups	Alzheimer's Disease International, JCCPA (Hong Kong), HKADA
Mental health screening for carers	Carers have ↑↑ rates of depression, anxiety, burnout
Financial and legal guidance	Enduring Power of Attorney (EPA), guardianship (Mental Health Ordinance Cap. 136 in HK)

When AD progresses to severe/end-stage (bedbound, unable to communicate, recurrent infections):

Focus on comfort measures and provide palliative care, respecting dignity and preferences ^[9]:

Goals of care discussion with family: shift from curative/life-prolonging to comfort-focused
Symptom management: pain (often unrecognised — use observational pain scales like PAINAD), dyspnoea, secretions
Feeding: Consider hand-feeding over PEG tube (evidence shows PEG does NOT improve survival or comfort in advanced dementia and ↑ aspiration, restraint use, pressure ulcers)
Infections: Consider antibiotics for comfort (e.g., treating UTI symptoms) but avoid aggressive IV antibiotics for pneumonia if goals are comfort-focused
Avoid unnecessary investigations and interventions
Advance directives: Document patient's known wishes; involve family

Frailty-Guided Management in End-Stage AD

Frailty-guided clinical management ^[9]:

Preserve physiologic reserve
Prevent avoidable stressors
Consider trade-off between disease and treatment burden

For end-stage frailty (CFS 7–9), aggressive diagnostics and treatments are inappropriate as they may cause stress and discomfort without meaningful benefit ^[9]. The appropriate approach is palliative care — prioritising symptom control, comfort, dignity, and respecting the patient's and family's wishes ^[9].

Stage	Pharmacological	Non-Pharmacological	Key Priorities
MCI due to AD	No proven pharmacotherapy (ChEIs not recommended); consider anti-amyloid Rx if biomarker+ (research/specialist)	Exercise, cognitive activity, vascular RF management	Monitoring for conversion; risk reduction
Mild AD	ChEI (donepezil/rivastigmine/galantamine) ^[8]	CST, exercise, OT, structured routine, carer education	Maintain independence; advance care planning
Moderate AD	ChEI ± Memantine ^[8]; manage BPSD	As above + day care, respite	Safety (driving, cooking, wandering); BPSD management
Severe AD	Memantine ± ChEI ^[8]; manage BPSD cautiously	Comfort care, sensory stimulation, music therapy	Dysphagia management; fall prevention; carer support
End-stage AD	Palliative symptom management only	Comfort measures, dignity-preserving care	Goals of care; avoid futile interventions; support family

High Yield Summary — Management of AD

Pharmacotherapy does not modify the course of disease (for traditional Rx) ^[8]
ChEIs (donepezil, rivastigmine, galantamine): mild-to-moderate AD; MoA: ↓ ACh breakdown → ↑ cholinergic transmission ^[7]; S/E: N/V, diarrhoea, anorexia, bradycardia; caution in COPD/asthma, PUD ^[8]
Rivastigmine patch: ↓ S/E, ↑ concentration, ↑ compliance ^[8]
Memantine: moderate-to-severe AD; NMDA antagonist; S/E: constipation, headache, somnolence; caution in seizures ^[8]
ChEI + memantine combination is appropriate in moderate-severe AD
Anti-amyloid immunotherapy (lecanemab, donanemab): early AD with biomarker confirmation; 27–35% slowing; ARIA is the key risk; APOE ε4 homozygotes at highest risk
BPSD: non-pharmacological first always; antipsychotics only for safety; black box warning for ↑ mortality in elderly; pronounced antipsychotic sensitivity in DLB ^[8]
Avoid anticholinergic drugs in dementia patients (pharmacological contradiction with ChEIs)
Vascular risk factor management is integral
End-stage: palliative approach — comfort measures, respecting dignity and preferences ^[9]

Active Recall - Management of Alzheimer's Disease

References

^[5] Senior notes: Ryan Ho Neurology.pdf, p130 ^[7] Senior notes: Ryan Ho Psychiatry.pdf, p92 ^[8] Senior notes: Maksim Medicine Notes.pdf, p113 ^[9] AOS material: AOS - Geriatrics.pdf, pp28–29, 31; Geriatrics AOS.pdf, p31 ^[14] Lecture slides: GC 079 (supp-2) STOPP-START-V3.pdf, p11 ^[15] Senior notes: Ryan Ho Neurology.pdf, p96; Ryan Ho Fundamentals.pdf, p326

Complications of Alzheimer's Disease

Complications in AD are logical consequences of progressive cortical destruction. If you understand which brain structures are lost and in what order, every complication makes sense from first principles. Think of it this way: AD progressively strips away the neural infrastructure for memory → language → spatial awareness → judgment → motor planning → swallowing → autonomic function. Each lost function creates a cascade of clinical problems.

The complications can be organised into:

Direct neurological complications (from disease progression itself)
Behavioural and psychological complications (BPSD — covered in clinical features/management; focus here on consequences)
Functional decline and its downstream consequences (falls, immobility, malnutrition, institutionalisation)
Medical complications (aspiration pneumonia, infections, seizures)
Iatrogenic complications (treatment-related)
Caregiver burden (a complication of the disease on the family system)
End-of-life complications

1. Direct Neurological Complications

These arise from progressive neurodegeneration spreading through the brain.

Occur in 10–20% of AD patients, typically in moderate-to-advanced stages
Early-onset (familial) AD has higher seizure rates (~30%) — possibly because the total amyloid burden is greater and accumulates faster
Pathophysiological basis: Aβ oligomers cause neuronal hyperexcitability → aberrant neuronal network activity → cortical epileptiform discharges. Progressive neuronal loss also disrupts the balance between excitatory (glutamate) and inhibitory (GABA) neurotransmission
Types: generalised tonic-clonic most common; myoclonic jerks (especially in advanced disease); subtle partial seizures may be unrecognised (mistaken for fluctuations in cognition or "spells")
Clinical significance: Seizures can precipitate acute confusion (postictal state) → easily mistaken for worsening dementia or delirium. Always consider non-convulsive status epilepticus (NCSE) in any sudden unexplained decline — requires EEG for diagnosis

Brief, involuntary, shock-like muscle jerks
Common in advanced AD (up to 10–15%)
Pathophysiological basis: Cortical and subcortical neuronal loss → aberrant motor circuit activity. Also seen in CJD (where it is earlier and more prominent — important DDx point)
Can interfere with feeding, dressing, and comfort

Pyramidal and extrapyramidal signs ^[5] emerge in late-stage AD as neurodegeneration extends beyond association cortex into motor-related structures
Extrapyramidal features: rigidity (paratonic/gegenhalten type — resistance that increases proportionally to the speed of passive movement), bradykinesia, shuffling gait
Pyramidal features: hyperreflexia, extensor plantar responses (Babinski sign)
Primitive reflexes: grasp, palmomental, snout, glabellar — these re-emerge because frontal lobe degeneration releases them from cortical inhibition
Ultimately → akinetic mutism (terminal state): the patient is awake (eyes open) but unable to move, speak, or respond meaningfully

Anosmia often occurs early but usually neglected ^[5]
Pathophysiological basis: Olfactory bulb and entorhinal cortex (which receives olfactory input) are among the earliest structures affected by tau pathology
Clinically under-recognised — patients rarely complain of it; may contribute to appetite changes and safety risks (unable to smell gas leaks or spoiled food)

2. Falls and Their Consequences

Falls are one of the most clinically important complications of AD.

Mechanism	Explanation
Visuospatial dysfunction	Parietal lobe atrophy → impaired spatial awareness, misjudging distances (stairs, curbs, obstacles)
Gait and balance impairment	Late-stage motor signs (rigidity, bradykinesia, postural instability); also impaired motor planning (apraxia of gait)
Impaired judgment	Frontal lobe dysfunction → attempting activities beyond physical capability; forgetting to use walking aids
Medications	ChEIs (bradycardia → syncope); psychotropics for BPSD (sedation, postural hypotension, extrapyramidal effects)
Environmental factors	Unfamiliar environments (especially in hospital), poor lighting, clutter
Comorbidities	Orthostatic hypotension (common in elderly), visual impairment, peripheral neuropathy (if coexistent diabetes)

Consequence	Mechanism
Hip fracture	Osteoporosis (common in elderly, especially women on chronic corticosteroids or sedentary) + fall → femoral neck/intertrochanteric fracture. Hip fracture in dementia patients carries ~30% 1-year mortality
Subdural haematoma (SDH)	Cerebral atrophy → bridging veins are stretched → more vulnerable to shearing forces during a fall. SDH in an AD patient can present as "worsening dementia" — always consider repeat imaging if there is a step-change in cognition
Head injury / intracranial haemorrhage	As above; also anticoagulant use (e.g., if AF present) ↑ risk
Fear of falling	Psychological consequence → activity restriction → further deconditioning → worsening falls risk (vicious cycle)
Immobility cascade	Fracture → bed rest → pressure ulcers, DVT/PE, pneumonia, contractures, muscle wasting

Clinical Pearl: Chronic SDH Masquerading as Worsening Dementia

An AD patient who has a subacute step-change in cognition (not the usual gradual decline) should have repeat CT brain to exclude chronic SDH. Brain atrophy in AD stretches bridging veins, making them vulnerable. The SDH is treatable (burr hole drainage) — a reversible cause of worsening in an otherwise irreversible disease.

3. Nutritional Complications

Occurs in 30–40% of AD patients and is an independent predictor of mortality
Pathophysiological basis (multifactorial):

Factor	Mechanism
Forgetting to eat	Episodic memory loss → forgets whether they have eaten; forgets how to prepare food
Apraxia	Loses the motor programme for using utensils, cutting food, coordinating the act of eating
Agnosia	May not recognise food as food (visual agnosia)
Anosmia/ageusia	Loss of smell and taste → ↓ appetite, ↓ enjoyment of eating
Hypothalamic involvement	Disrupted appetite regulation centres
Increased energy expenditure	Wandering, agitation, repetitive movements → burn calories without compensatory intake
Depression	Common comorbid BPSD → anorexia
Dysphagia (late stage)	See below

Consequences: sarcopenia (muscle wasting) → further ↑ fall risk, impaired immunity → ↑ infection risk, pressure ulcers, frailty progression

Develops in moderate-to-severe AD as neurodegeneration extends to brainstem swallowing centres and cortical motor planning areas
Pathophysiological basis: The swallowing reflex requires coordinated activity of cranial nerves V, VII, IX, X, XII and their cortical/brainstem centres. Progressive cortical and brainstem neuronal loss disrupts this coordination
Manifests as: coughing/choking during meals, pocketing food in cheeks, prolonged meal times, wet/gurgly voice quality, frank aspiration without coughing (silent aspiration)
Direct consequence → aspiration pneumonia (see below)

4. Infectious Complications

The most common cause of death in AD patients
Pathophysiological basis: Dysphagia (above) → food, liquid, or oral secretions enter the trachea and bronchi → chemical pneumonitis and/or bacterial infection of the lower respiratory tract
Why aspiration pneumonia is so dangerous in AD:
- Patients cannot report symptoms effectively (language impairment)
- Cough reflex is diminished (brainstem involvement)
- Immune function is impaired (malnutrition, immobility, advanced age)
- Recurrent episodes → progressive lung damage
Organisms: oral flora — mixed anaerobes, Streptococcus pneumoniae, Haemophilus influenzae, gram-negative enterics (if institutionalised)

Very common, especially in moderate-severe AD
Pathophysiological basis: Urinary incontinence (see below) → often managed with indwelling catheters or pads → ascending infection. Also: immobility → urinary stasis; inability to maintain hygiene
UTIs are a major precipitant of delirium superimposed on dementia — remember that 2/3 of delirium occurs in dementia patients ^[2]

Late-stage immobility → sustained pressure over bony prominences → ischaemic necrosis of skin and underlying tissue → pressure ulcers (sacrum, heels, trochanters)
Pressure ulcers → secondary bacterial infection → cellulitis → sepsis
Faecal and urinary incontinence → skin maceration → ↑ risk

5. Incontinence

Progresses from urge incontinence (detrusor overactivity from loss of cortical inhibition of the micturition reflex) → functional incontinence (patient can no longer find or use the toilet due to spatial disorientation, apraxia, and immobility) → complete incontinence (loss of all voluntary bladder control in terminal stages)
Pathophysiological basis: The frontal cortex normally exerts tonic inhibition over the pontine micturition centre. As frontal neurodegeneration progresses, this inhibition is lost → involuntary detrusor contractions

Develops later than urinary incontinence
Multifactorial: loss of awareness of rectal fullness, immobility, impaired sphincter control, constipation with overflow

Dementia is the leading risk factor for delirium ^[2]
Any acute illness (UTI, pneumonia, constipation, dehydration, medication change, hospitalisation) can precipitate delirium in an AD patient
Why AD predisposes to delirium: The brain already has reduced "cognitive reserve" (fewer functioning neurons, reduced cholinergic transmission) → any additional insult tips the system into acute failure
Significance: delirium in dementia patients is associated with 35–40% 1-year mortality ^[2]; often accelerates the trajectory of cognitive decline even after the delirium resolves
Clinical challenge: Distinguishing delirium from worsening dementia — look for acute onset, fluctuating consciousness, identifiable precipitant ^[9]

Nausea, vomiting, diarrhoea, anorexia → can worsen malnutrition ^[8]
Bradycardia → syncope → falls → fractures ^[8]
Urinary incontinence (↑ detrusor contraction)
Insomnia, vivid dreams (if taken at night)

Constipation, headache, somnolence ^[8]
Seizure risk (in predisposed patients) ^[8]
Dizziness → falls

Black box warning: ↑ mortality (1.6–1.7×) in elderly dementia patients from cardiovascular events and infections
Extrapyramidal side effects (especially in DLB — pronounced sensitivity to antipsychotic EPSE ^[8])
Sedation → falls → fractures
Metabolic syndrome (weight gain, hyperglycaemia, dyslipidaemia)
QTc prolongation → arrhythmias
Anticholinergic effects (especially with olanzapine, chlorpromazine) → paradoxical worsening of cognition

ARIA-E (Amyloid-Related Imaging Abnormalities — Oedema/Effusion): cerebral oedema, typically asymptomatic but can cause headache, confusion, visual disturbance. ~13% with lecanemab
ARIA-H (Haemorrhage/Hemosiderin): cerebral microhaemorrhages and superficial siderosis. ~17% with lecanemab
Higher risk in APOE ε4 homozygotes (~35% ARIA rate)
Rarely fatal — deaths have been reported, particularly in patients on anticoagulants

Wandering occurs in up to 60% of AD patients
Pathophysiological basis: Combination of spatial disorientation (parietal lobe), impaired judgment (frontal lobe), restlessness (subcortical circuit disruption), and inability to recognise that they are lost
Consequences:
- Getting lost (unable to find way home) → exposure to traffic, weather, danger
- Elopement from care facilities
- Falls during unsupervised wandering
- Exhaustion, dehydration, hypothermia/hyperthermia
- Caregiver distress and burnout

AD patients have impaired reaction time, spatial awareness, judgment, and divided attention — all essential for safe driving
The risk of motor vehicle accidents is 2–8× higher in dementia patients
Legal and ethical obligation: Clinicians should assess driving safety and advise cessation when appropriate; in Hong Kong, the Transport Department requires medical fitness for driving licence renewal
Often a source of significant conflict between patient (who wants independence) and family/clinician (who recognises the danger)

This is a complication of the disease on the family system — not just on the patient.

Complication	Prevalence / Detail
Depression	30–50% of primary caregivers experience clinical depression
Anxiety	Constant worry about patient safety, financial burden, future
Physical health decline	Sleep deprivation (especially with sundowning/nocturnal BPSD), chronic stress → cardiovascular risk
Social isolation	Caregiver tethered to patient → loss of social network, employment
Financial burden	Loss of income (patient and/or caregiver); cost of care (domestic helpers, day centres, residential care — substantial in Hong Kong)
Elder abuse	Caregiver burnout → risk of neglect or abuse (physical, emotional, financial) — important to screen for

The terminal phase of AD is characterised by:

Complication	Mechanism
Aspiration pneumonia (commonest cause of death)	Severe dysphagia + loss of cough reflex + immobility
Sepsis (from UTI, pressure ulcers, pneumonia)	Immunocompromised state (malnutrition, immobility, advanced age)
Cachexia	Complete inability to eat; refusal/inability to accept hand-feeding
Contractures	Prolonged immobility → muscle and tendon shortening → fixed joint deformity → pain, ↑ pressure ulcer risk
Venous thromboembolism (DVT/PE)	Immobility → venous stasis (Virchow's triad)
Total dependence	Bedbound, incontinent, unable to communicate, requiring full nursing care

Category	Key Complications	Pathophysiological Link
Neurological	Seizures, myoclonus, motor signs, akinetic mutism	Progressive neurodegeneration → aberrant circuits, brainstem involvement
Falls	Fractures, SDH, immobility cascade	Visuospatial dysfunction + gait impairment + impaired judgment + medications
Nutritional	Weight loss, malnutrition, dysphagia	Apraxia, agnosia, anosmia, hypothalamic involvement, wandering
Infectious	Aspiration pneumonia (commonest COD), UTI, skin infections	Dysphagia, incontinence, immobility, immunocompromise
Incontinence	Urinary → faecal	Loss of cortical inhibition of micturition; immobility; loss of awareness
Delirium	Delirium superimposed on dementia	Reduced cognitive reserve; any acute insult tips the system
Iatrogenic	ChEI (bradycardia, GI), antipsychotics (mortality, EPS), anti-amyloid (ARIA)	Drug side effects predictable from mechanism
Safety	Wandering, driving accidents, fires, poisoning	Spatial disorientation, impaired judgment, apraxia
Caregiver	Depression, burnout, abuse	Chronic stress, social isolation, financial burden
End-of-life	Aspiration pneumonia, sepsis, cachexia, contractures, DVT/PE	Terminal immobility, complete dependence

High Yield Summary — Complications of Alzheimer's Disease

Aspiration pneumonia is the most common cause of death in AD — from dysphagia (brainstem/cortical motor degeneration) → silent aspiration
Seizures occur in 10–20% (higher in early-onset/familial AD) — Aβ causes neuronal hyperexcitability
Falls are extremely common and dangerous — visuospatial dysfunction + gait impairment + impaired judgment + medications; hip fracture carries ~30% 1-year mortality
Chronic SDH can masquerade as worsening dementia — always re-image if step-change in cognition
Dementia is the leading risk factor for delirium (2/3 of delirium occurs in dementia patients) ^[2] — any acute illness can precipitate; carries 35–40% 1-year mortality
Weight loss/malnutrition is multifactorial (forgetting to eat, apraxia, anosmia, agnosia, wandering) and worsens all other outcomes
Incontinence progresses from urge → functional → complete as cortical inhibition of micturition is lost
Iatrogenic: ChEIs cause bradycardia and GI upset ^[8]; antipsychotics carry black box mortality warning; anti-amyloid therapy causes ARIA
Caregiver depression affects 30–50% of primary carers — screen for it; provide support and respite
End-stage AD: akinetic mutism, bedbound, total dependence → palliative approach

Active Recall - Complications of Alzheimer's Disease

References

^[2] Senior notes: Ryan Ho Fundamentals.pdf, p325 ^[5] Senior notes: Ryan Ho Neurology.pdf, pp130–131 ^[8] Senior notes: Maksim Medicine Notes.pdf, p113 ^[9] AOS material: AOS - Geriatrics.pdf, pp3–4

High Yield Summary

AD is defined by biology (Aβ plaques + tau tangles), not symptoms — 2024 NIA-AA criteria ^[3]
Most common cause of dementia (50–60%); prevalence doubles every 5 years after 65 ^[1]
Risk factors: Age (strongest), female sex, family history, APOE ε4, low education, cardiovascular RFs, head trauma ^[1]^[5]
Genetics: Early-onset (< 1%): APP (Ch21), PSEN1 (Ch14, > 70%), PSEN2 (Ch1) — autosomal dominant. Late-onset: APOE ε4 (~50% of genetic vulnerability), polygenic ^[5]
Amyloid cascade hypothesis: ↑Aβ42 → oligomer toxicity → tau hyperphosphorylation → NFTs → neuronal death ^[5]
Braak staging: Entorhinal cortex → hippocampus → parietal association → generalised neocortex ^[5]
Neuropathology precedes symptoms by 15–20 years ^[5]
Clinical hallmarks: Insidious onset, gradually progressive amnestic syndrome → aphasia, apraxia, agnosia, visuospatial/executive dysfunction; BPSD in 90%; normal neurological exam early
Key distinguishing feature from delirium: Preserved consciousness in AD
Cholinergic deficit (nucleus basalis of Meynert) → basis for cholinesterase inhibitor therapy
10–15% of dementia has reversible causes — always exclude ^[5]

High Yield Summary — Differential Diagnosis of AD

Depression ("pseudodementia") accounts for ~10% of presumed dementia — always screen; consider therapeutic trial of antidepressants ^[7]
Delirium: differentiate by acute onset, fluctuating consciousness, identifiable precipitant — remember 2/3 of delirium occurs in dementia patients ^[2]
10–15% of dementia is reversible ^[5] — mandatory minimum screen: CBC, B12/folate, TFT, RFT, Ca, glucose, CT/MRI brain ^[5]
VaD: stepwise course, focal neuro signs, vascular RFs, infarcts on imaging
DLB: visual hallucinations, fluctuating cognition, RBD, parkinsonism; antipsychotic sensitivity; preserved medial temporal lobe on MRI; DaTscan most helpful to distinguish from AD ^[4]^[5]
FTD: young onset, early behaviour/personality change or language deficit, frontal/temporal atrophy
CJD: rapidly progressive (months), myoclonus, cortical ribboning on MRI
NPH: gait-dementia-incontinence triad, ventriculomegaly disproportionate to atrophy — treatable with shunt
AD copathology with DLB occurs in > 50% of DLB cases ^[4]; mixed AD/VaD is also extremely common
In those < 65, FTD accounts for ~12% and AD only ~1/3 ^[8] — broaden differential in young patients

High Yield Summary — Diagnostics

Dementia diagnosis requires: cognitive decline in ≥1 domain + functional impairment + preserved consciousness + exclusion of delirium ^[7]
AD clinical diagnosis (ICD-10/DSM-5): insidious onset, gradual progression, exclusion of other causes, absence of sudden/apoplectic onset or early focal neurological signs ^[7]
2024 NIA-AA: AD defined biologically — Core 1 biomarkers (A+ T1+) = AD, even without symptoms ^[3]
MoCA preferred over MMSE for cognitive assessment (more sensitive for MCI) ^[5]
Mandatory minimum investigations: CBC, B12/folate, TFT, RFT, Ca, glucose + CT/MRI brain ^[5]^[7]
MRI AD pattern: hippocampal/medial temporal atrophy (early) → generalised atrophy (late) ^[7]
FDG-PET/SPECT AD pattern: bilateral posterior temporal + parietal hypometabolism/hypoperfusion ^[7]^[11]
CSF AD signature: ↓ Aβ42 (or ↓ Aβ42/40 ratio) + ↑ p-tau + ↑ t-tau
Plasma p-tau 217 is the leading blood-based biomarker — set to revolutionise AD diagnosis ^[3]^[13]
DaTscan distinguishes DLB (abnormal) from AD (normal) ^[4]
Amyloid PET is earliest biomarker to become abnormal; negative amyloid PET essentially rules out AD ^[8]

High Yield Summary — Management of AD

Pharmacotherapy does not modify the course of disease (for traditional Rx) ^[8]
ChEIs (donepezil, rivastigmine, galantamine): mild-to-moderate AD; MoA: ↓ ACh breakdown → ↑ cholinergic transmission ^[7]; S/E: N/V, diarrhoea, anorexia, bradycardia; caution in COPD/asthma, PUD ^[8]
Rivastigmine patch: ↓ S/E, ↑ concentration, ↑ compliance ^[8]
Memantine: moderate-to-severe AD; NMDA antagonist; S/E: constipation, headache, somnolence; caution in seizures ^[8]
ChEI + memantine combination is appropriate in moderate-severe AD
Anti-amyloid immunotherapy (lecanemab, donanemab): early AD with biomarker confirmation; 27–35% slowing; ARIA is the key risk; APOE ε4 homozygotes at highest risk
BPSD: non-pharmacological first always; antipsychotics only for safety; black box warning for ↑ mortality in elderly; pronounced antipsychotic sensitivity in DLB ^[8]
Avoid anticholinergic drugs in dementia patients (pharmacological contradiction with ChEIs)
Vascular risk factor management is integral
End-stage: palliative approach — comfort measures, respecting dignity and preferences ^[9]

High Yield Summary — Complications of Alzheimer's Disease

Aspiration pneumonia is the most common cause of death in AD — from dysphagia (brainstem/cortical motor degeneration) → silent aspiration
Seizures occur in 10–20% (higher in early-onset/familial AD) — Aβ causes neuronal hyperexcitability
Falls are extremely common and dangerous — visuospatial dysfunction + gait impairment + impaired judgment + medications; hip fracture carries ~30% 1-year mortality
Chronic SDH can masquerade as worsening dementia — always re-image if step-change in cognition
Dementia is the leading risk factor for delirium (2/3 of delirium occurs in dementia patients) ^[2] — any acute illness can precipitate; carries 35–40% 1-year mortality
Weight loss/malnutrition is multifactorial (forgetting to eat, apraxia, anosmia, agnosia, wandering) and worsens all other outcomes
Incontinence progresses from urge → functional → complete as cortical inhibition of micturition is lost
Iatrogenic: ChEIs cause bradycardia and GI upset ^[8]; antipsychotics carry black box mortality warning; anti-amyloid therapy causes ARIA
Caregiver depression affects 30–50% of primary carers — screen for it; provide support and respite
End-stage AD: akinetic mutism, bedbound, total dependence → palliative approach

Alzheimer's Disease

1. Definition

2. Epidemiology

2.1 Global Burden

2.2 Hong Kong Context

2.3 Sex Differences

3. Risk Factors

3.1 Non-Modifiable Risk Factors

3.2 Modifiable Risk Factors (Lancet Commission 2024 — 14 modifiable factors account for ~45% of dementia risk)

3.3 Protective Factors

4. Anatomy and Function

4.1 Key Neuroanatomical Structures in AD

4.1.1 Hippocampus and Entorhinal Cortex

4.1.2 Parietal Association Cortex

4.1.3 Temporal Neocortex (Beyond Hippocampus)

4.1.4 Frontal Cortex

4.1.5 Nucleus Basalis of Meynert (Basal Forebrain)

4.1.6 Subcortical Nuclei

4.2 The Cholinergic Hypothesis

4.3 Classification by Site of Cortical Involvement

5. Aetiology and Pathophysiology

5.1 Overview of Pathological Hallmarks

5.2 The Amyloid Cascade Hypothesis

5.3 Tau Pathology and Braak Staging

5.4 Genetics of AD

5.4.1 Early-Onset AD (< 65 years, < 1% of cases)

5.4.2 Late-Onset AD (≥ 65 years, > 99% of cases)

5.5 Environmental and Vascular Contributions

5.6 Neuroinflammation

5.7 Gross Pathology

6. Classification

6.1 By Age of Onset

6.2 By Clinical Phenotype

6.3 By Biological Staging (2024 NIA-AA Revised Criteria)

7. Clinical Features

7.1 Overview: The "4 As" of Alzheimer's Disease

7.2 Symptoms (What the Patient/Carer Reports)

7.2.1 Cognitive Symptoms

7.2.2 Behavioural and Psychological Symptoms of Dementia (BPSD)

7.2.3 Functional Decline

7.3 Signs (What You Find on Examination)

7.3.1 Cognitive Examination Findings

7.3.2 Neurological Signs

7.3.3 General Physical Examination

7.4 Stages of Alzheimer's Disease — Clinical Progression

7.5 Key Distinguishing Features of AD vs Other Dementias

8. Summary of Clinical Approach Before Diagnosis/Management

Active Recall - Alzheimer's Disease (Definition to Clinical Features)

References

1. Conditions That Mimic Dementia ("Is This Really Dementia?")

1.1 Depression ("Pseudodementia")

1.2 Delirium

1.3 Amnestic Syndrome

1.4 Non-degenerative Neurological Disorders

1.5 Neurodevelopmental Disorders / Intellectual Disability

1.6 Isolated Disorders of Higher Function

2. Reversible Causes of Dementia ("Must-Not-Miss")

3. Other Neurodegenerative / Irreversible Dementias

3.1 Vascular Dementia (VaD) — 10–20% of dementias [5]

3.2 Dementia with Lewy Bodies (DLB) — ~10% of dementias [5]

3.3 Frontotemporal Dementia (FTD) — ~5% of dementias [5]

3.4 Creutzfeldt-Jakob Disease (CJD)

3.5 Normal Pressure Hydrocephalus (NPH)

3.6 Parkinson's Disease Dementia (PDD)

3.7 Huntington's Disease

4. Summary Comparison Table

5. Diagnostic Reasoning Flowchart

6. Age-Dependent Distribution — A Hong Kong Perspective

Active Recall - Differential Diagnosis of Alzheimer's Disease

1. Diagnostic Criteria

1.1 Step 1 — Establishing the Syndrome: Dementia / Major Neurocognitive Disorder

1.2 Step 2 — Attributing the Syndrome to AD

1.2.1 Clinical/Syndromic Criteria (ICD-10 and DSM-5)

1.2.2 Biological Criteria (2024 NIA-AA Revised Criteria)

2. Diagnostic Algorithm

3. Investigation Modalities

3.1 Cognitive Assessment Tools

3.2 Blood Tests — Screening for Reversible Causes

3.3 Structural Neuroimaging — CT and MRI Brain

CT Brain