ICD-10 requires: (1) Decline in memory and learning; (2) Decline in other cognitive abilities (judgment, thinking, general processing); (3) Duration > 6 months; (4) Impaired performance in daily living; (5) Clear consciousness ^[1]

ICD-10 codes: F00 (AD), F01 (Vascular dementia), F02 (Dementia in other diseases — Pick's, CJD, Parkinson's, Huntington's, HIV), F03 (Unspecified)

MCI: Subjective + Objective cognitive impairment without significant functional impairment. Intermediate stage between normal aging and dementia. Not all patients with MCI will progress to dementia. ^[1]

Why the amnestic vs non-amnestic distinction matters: Amnestic MCI (memory-predominant) has the highest conversion rate to AD. Non-amnestic MCI may progress to FTD or DLB instead.

Over 80% of dementia patients have BPSD. Delusions 60%, Affective symptoms 40%, Anxiety 35%, Verbal outburst 33%, Hallucination 20%, Aggression 13%. ^[1]

Two categories:

• Observed behaviours: screaming, restlessness, wandering, aggression, agitation, culturally inappropriate behaviour
• Elicited psychological symptoms: depression, anxiety, hallucination, delusion

Why BPSD matters:

• It is the main driver of caregiver stress
• It is the main reason for institutionalization
• It is a common exam topic — how to manage BPSD

The percentages on slide 40 are historical study estimates, not fixed rates for every dementia subtype, stage or care setting.

Historical slide figures: over 30 million people worldwide; 6-10% of people over 65 in North America; 9.1% prevalence in Hong Kong; "milder" cognitive impairment 3-23%. ^[1]

These figures reproduce the lecture but should not be treated as current estimates. The WHO reported 57 million people living with dementia in 2021, with nearly 10 million new cases each year; Alzheimer disease may contribute to 60-70% of cases.^[11] The local 9.1% and age-specific figures depend on study date, population and case definition.

1. Alzheimer's Disease (most common); 2. Vascular Dementia; 3. Dementia with Lewy Bodies. Mixed dementia usually means AD mixed with vascular. ^[1]

The lecture lists: Degenerative (AD, FTD, DLB), Endocrine, Mass lesion, Nutritional, Traumatic, Infectious, Autoimmune, Vascular.

Reversible causes ("DEMENTIA" mnemonic from Maksim notes) ^[2]:

~50–60% of all dementia cases. Prevalence increases with age: 10% at 65, 25% at 85. Early onset ( < 65 yo) vs late onset (≥ 65 yo). Duration: diagnosis to death 8–10 years. ^[1]

Risk factors:

• Genetics: PS1, PS2, APP (autosomal dominant, early onset); ApoE ε4 (risk factor for late onset)
• Female sex
• Family history
• Head trauma
• Low education
• Cardiovascular dysfunction (hypertension, diabetes, smoking)

1. Deposition of beta-amyloid peptides/amyloid plaques (extracellular) — Amyloid Cascade Hypothesis. 2. Formation of hyper-phosphorylated tau — Neurofibrillary Tangles (NFTs) (intracellular). 3. AD pathology usually involves the temporal lobe first, affecting hippocampus → memory impairment. 4. Cholinergic deficit: loss of cholinergic biosynthetic machinery, loss of basal forebrain cholinergic neurons → impairment of memory and attention. ^[1]

Understanding the pathology from first principles:

1. Amyloid Cascade Hypothesis: Amyloid Precursor Protein (APP) is a normal transmembrane protein. It can be cleaved by α-secretase (non-amyloidogenic, normal pathway) or by β- and γ-secretase (amyloidogenic pathway). The amyloidogenic pathway produces Aβ peptides (Aβ1-40 and Aβ1-42). Aβ1-42 is more prone to aggregation → oligomers → amyloid plaques → neurotoxicity → neuronal death.

2. Neurofibrillary Tangles (NFTs): Tau is a microtubule-associated protein that normally stabilizes axonal microtubules. In AD, tau becomes hyperphosphorylated → detaches from microtubules → aggregates into paired helical filaments → NFTs → disrupts axonal transport → neuronal death.

NFT expression needed for Aβ toxicity. NFT correlates with AD severity. NFT load higher in patients with ApoE4. Not specific for AD. Tauopathies share common end point. ^[1]

3. Temporal lobe predilection: The entorhinal cortex and hippocampus are affected earliest. This explains why short-term memory is the earliest and most prominent deficit in AD.

4. Cholinergic deficit: The nucleus basalis of Meynert (basal forebrain) provides cholinergic innervation to the cortex. In AD, these neurons degenerate → decreased acetylcholine → impaired memory and attention. This is the basis for cholinesterase inhibitor therapy.

Reading the amyloid-cascade diagram (slide 24): Dominantly inherited AD and non-dominant/sporadic AD enter the diagram by different routes. Pathogenic APP/PSEN1/PSEN2 variants can increase Aβ42 production, whereas common late-onset disease is depicted as impaired Aβ clearance (with APOE as one influence). Both converge on oligomer accumulation, inflammatory/oxidative injury, tau pathology, synaptic loss and dementia. This is a mechanistic model, not proof that every patient follows a single linear sequence.

The amyloid cascade timeline (from lecture slide): β-amyloid deposition begins decades before clinical symptoms (age 30-40), followed by microglial activation, then NFTs, then neuronal loss/neurochemical changes, and finally clinical dementia (age 70-90). ^[1]

Slide 21 compares coronal T1-weighted MR images. The atrophic example has smaller hippocampal/medial-temporal tissue with widening of the adjacent choroidal fissure and temporal horn; the arrow helps localise the hippocampal region. Medial temporal atrophy supports typical amnestic AD and can be graded visually, but it is neither required nor specific and must be interpreted against age, clinical phenotype and the rest of the scan.^[12]

AD Diagnosis requires: Patient history (collaterals very important), Physical examination, Neuropsychological tests, Blood tests: CBC, L/RFT, BG, TSH, B12, folate, VDRL; ECG, CXR, EEG (in specific case); Neuroimaging (CT, MRI; non-essential: PET, SPECT); CSF (total tau, phosphorylated tau, amyloid-beta) — seldom done in HK clinical setting. ^[1]

The slide is a broad investigation list, not a universal order set. Start with collateral history, examination, medication/anticholinergic review, validated cognitive assessment and tests for plausible reversible contributors. Add infection, syphilis/HIV, autoimmune, EEG, ECG, CXR or other studies when the history, examination or planned treatment indicates them.^[12]

Why each investigation:

Mnemonic for basic bloods (from Ryan Ho): I (FOR)GET ABC — Imaging, Glucose, Electrolytes, Thyroid, Anaemia, B12/folate, Calcium ^[4]

"Definite": dementia with AD histopathology (post-mortem). "Probable": dementia demonstrated by clinical examination and neuropsychological testing, absence of other brain diseases. "Possible": dementia present but not typical AD presentation. ^[1]

This is the historical NINCDS-ADRDA framework shown in the lecture: within that framework, "definite" required histopathological confirmation. Contemporary practice combines clinical phenotype with structural imaging and, when it will change diagnosis or treatment, validated CSF/PET or other biomarkers; do not present the old probable/possible/definite scheme as the only current framework.

Cognitive stimulation, Cognitive training, Cognitive rehabilitation, Exercise ^[1]

• Cognitive stimulation: Group activities involving discussion, reminiscence, games — evidence shows modest benefit for cognition and quality of life
• Cognitive training: Practising specific cognitive tasks (computer-based or otherwise)
• Cognitive rehabilitation: Individualized goals, compensatory strategies (calendars, reminders)
• Exercise: Aerobic exercise may slow cognitive decline and improve mood

1. Acetylcholinesterase Inhibitor (AChEI) — donepezil, rivastigmine, galantamine — for mild to moderate AD. Compensates cholinergic deficit. 2. Memantine — for moderate to severe AD — NMDA receptor antagonist. Neuroprotective and disease-modifying in theory. ^[1]

The final phrase is historical speculation: memantine is a symptomatic treatment, not a proven disease-modifying therapy. Current guidance offers donepezil, galantamine or rivastigmine for mild-moderate AD; memantine monotherapy for moderate AD when AChE inhibitors are not tolerated/contraindicated or for severe AD; and considers adding memantine to an AChE inhibitor in moderate-severe disease. Do not stop an AChE inhibitor because of severity alone.^[12]

Slide 42 shows a simplified historical sequence: normal aging → amnestic MCI → mild dementia → loss of functional independence → behavioural symptoms → nursing-home stage → severe stage. ^[1]

Do not use its coloured drug labels as a prescribing algorithm. AChE inhibitors are not routinely indicated for MCI alone; antidepressants treat a diagnosed mood disorder rather than a dementia stage; and antipsychotics are not standard stage-based therapy. Memantine/AChE inhibitor use follows diagnosis, severity, tolerability and specialist/local guidance.^[12]

Historical slide status: aducanumab received accelerated FDA approval in 2021, with disputed clinical benefit and risk of amyloid-related imaging abnormalities (ARIA). ^[1]

Current correction: Biogen discontinued aducanumab development and commercialisation in 2024.^[15] FDA-approved anti-amyloid options now include lecanemab and donanemab for appropriately selected patients in the mild cognitive impairment or mild dementia stage of AD with confirmed amyloid pathology.^[13][14] These are not general treatments for all dementia: benefit is modest, access/licensing varies by jurisdiction, and specialist selection, MRI surveillance and counselling about ARIA (including haemorrhage risk) are essential.

Step 1: Exclude physical illness potentially precipitating BPSD. Step 2: Non-pharmacological approaches — behaviour modifications, environmental modifications. Step 3: Medications — AChEI/memantine, antipsychotic, antidepressant, other neuroleptics. KEY: Keep lowest dose and shortest period if possible. Don't prescribe medications unless significant BPSD. ^[1]

Why exclude physical illness first? — A patient with dementia who becomes acutely agitated may have superimposed delirium from UTI, constipation, pain, or medication side effects. Treating the underlying cause is more effective and safer than adding psychotropics.

Non-pharmacological approaches for BPSD:

• Identify triggers (time of day, environment, hunger, pain)
• Maintain routine, reduce overstimulation
• Redirection, distraction
• Music therapy, aromatherapy, pet therapy
• Environmental modifications: adequate lighting, familiar objects, safety features

When medications are needed:

• Consider an antipsychotic only when the person is at risk of harming themselves/others or agitation, hallucinations or delusions are causing severe distress, after reversible causes and non-drug strategies have been addressed
• Discuss mortality, cerebrovascular, sedation, falls and motor risks; use the lowest effective dose for the shortest time, review at least every 6 weeks, and stop if there is no clear ongoing benefit ^[12]
• SSRIs for depressive/anxious BPSD
• In DLB/Parkinson disease dementia, any antipsychotic can worsen motor features or trigger severe sensitivity; obtain specialist advice whenever possible ^[12]
• Benzodiazepines generally avoided (worsen confusion, increase fall risk)

• Covers similar content from a geriatrician's perspective (Dr. Shea Yat Fung, QMH)
• Mentions topics not covered in the primary lecture: Advanced directives, advanced care planning, feeding issues

• AChEI side effects (bradycardia, GI) are important in the context of polypharmacy
• Beers criteria / STOPP criteria — review medications that may worsen cognition (anticholinergics, benzodiazepines, antihistamines)

• Same lecturer — practical tips for psychogeriatric interviews
• Content of psychiatric history and mental state examination in elderly patients
• Emphasizes: purpose of history taking, collateral informant, mental state examination technique

• Dementia assessment is a key component of CGA
• Multidisciplinary team: geriatrician, psychiatrist, nurse, OT, PT, MSW, speech therapist