GC241 Reference (1) - Alzheimers Dementia - Revised Criteria For Diagnosis And Staging Of Alzheimer S Disease
The revised criteria for diagnosis and staging of Alzheimer's disease define it as a biological construct characterized by the presence of amyloid-beta and tau biomarkers, enabling classification across a clinical continuum from preclinical to dementia stages independent of symptom onset.
Revised Criteria for Diagnosis and Staging of Alzheimer's Disease (2024 AA Workgroup)
Lecture Map
Alzheimer's disease (AD) is now defined biologically — by the presence of AD neuropathologic change (ADNPC) detected via biomarkers — not by clinical symptoms. [1] This is a paradigm shift analogous to how oncology has long defined cancer by histopathology rather than by symptoms alone. An abnormal Core 1 biomarker is sufficient to diagnose AD, even in asymptomatic individuals. Symptoms are a consequence of the disease, not a requirement for diagnosis.
This 2024 document (Jack et al., Alzheimer's & Dementia) is the reference paper for GC 241, which covers common etiologies of cognitive impairment (AD, vascular, Lewy body), imaging and fluid biomarkers, and new advances in AD [2]. Examiners can test:
- The biological definition of AD and why it matters
- Biomarker categorization (Core 1 vs. Core 2; AT(N) → ATNIVS)
- Staging systems (biological stages A–D, clinical stages 0–6, integrated staging)
- The role of blood-based biomarkers (especially p-tau217) and why they are revolutionary
- Copathologies and why clinical judgment remains essential
- How this framework applies to anti-Aβ immunotherapy eligibility
Key GC 241 Learning Objectives: DSM-5 criteria for diagnosis, common etiologies of cognitive impairment (AD, VaD, DLB), imaging and fluid biomarkers, new advances in AD. [2]
Core Concepts and Mechanisms — From First Principles
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. [1]
Think about it this way: a patient with progressive amnesia could have AD, vascular dementia, LATE (limbic-predominant age-related TDP-43 encephalopathy), or even depression. Conversely, the same AD biology can produce different phenotypes — amnestic, language variant, visuospatial, behavioral, or dysexecutive. If you define AD by "forgetful old person," you miss atypical presentations and misdiagnose non-AD causes. By anchoring to biology (the actual proteinopathies in the brain), you get precision.
This mirrors oncology: you wouldn't call something "lung cancer" just because someone has a cough — you need tissue or molecular evidence. Similarly, AD is now defined by its two hallmark proteinopathies:
- Amyloid beta (Aβ) plaques (neuritic plaques)
- Tau neurofibrillary tangles (NFTs)
Fundamental Principle
Symptoms are a result of the disease process and are not necessary to diagnose AD. Unimpaired individuals with abnormal biomarkers are not "at risk for AD" — they already have AD. [1]
ADNPC is defined by the NIA-AA 2012 neuropathologic criteria [1], which require assessment of:
- CERAD neuritic plaque density (none/sparse/moderate/frequent)
- Braak NFT stage (0–VI)
- Thal phase (amyloid distribution)
A diagnosis of intermediate/high ADNPC requires moderate/frequent neuritic plaques AND Braak III–VI tangles. The key insight from the 2024 document: among symptomatic individuals with moderate/frequent neuritic plaques (i.e., what amyloid PET detects), 95% also have Braak III–VI NFTs — meaning they meet criteria for intermediate/high ADNPC. [1] So detecting plaques by biomarker almost always means tangles are also present.
The 2018 NIA-AA framework grouped biomarkers as:
- A = Amyloid beta
- T = Tau
- (N) = Neurodegeneration (in parentheses because it's non-specific)
The 2024 revision refines this:
- T is split into T1 and T2 (different timing, different biology)
- New categories added: I (Inflammation), V (Vascular), S (α-Synuclein)
- Full profile: AT1T2NISV
Biomarker Categorization — The Heart of the Document
| Category | What It Measures | Fluid Analytes | Imaging |
|---|---|---|---|
| Core 1 — A | Aβ proteinopathy | Aβ42, Aβ42/40 ratio | Amyloid PET |
| Core 1 — T1 | Phosphorylated secreted tau (reaction to plaques) | p-tau217, p-tau181, p-tau231 | — |
| Core 2 — T2 | AD tau aggregates (proteinopathy) | MTBR-tau243, p-tau205, non-phosphorylated mid-region tau | Tau PET |
| N (non-specific) | Neuronal injury/degeneration | NfL | Anatomic MRI, FDG PET |
| I (non-specific) | Astrocytic activation | GFAP | — |
| V (copathology) | Vascular brain injury | — | Infarction on MRI/CT, WMH |
| S (copathology) | α-synucleinopathy | αSyn-SAA (CSF only) | DAT SPECT/PET |
This is one of the most examinable concepts:
- T1 biomarkers (p-tau217, 181, 231) become abnormal around the same time as amyloid PET — they are a physiologic reaction to Aβ plaques, essentially a "signal" that plaques are present. They reflect early tau phosphorylation linked to amyloid.
- T2 biomarkers (tau PET, MTBR-tau243) become abnormal later — they signal the actual presence of insoluble AD tau aggregates. They correlate with symptom onset and neurodegeneration.
Clinical implication: A positive T1 marker essentially tells you ADNPC is present (both plaques and tangles are very likely). A positive T2 marker tells you tauopathy is advanced enough to be driving symptoms.
| Feature | Core 1 | Core 2 |
|---|---|---|
| Includes | A biomarkers + T1 + hybrid ratios | T2 biomarkers (tau PET, MTBR-tau243) |
| Timing | Early — coincides with amyloid PET | Later — closer to symptom onset |
| Primary use | Diagnosis of AD | Staging, prognosis, treatment response |
| Can diagnose AD alone? | Yes | Not standalone (rare exceptions) |
| In asymptomatic individuals | Can detect AD before symptoms | Abnormal only later in disease |
| Relation to symptoms | Less directly linked | Strongly linked to cognitive decline |
An abnormal Core 1 biomarker result is sufficient to establish a diagnosis of AD and to inform clinical decision making throughout the disease continuum. [1]
Exam Trap: A−T2+ Profile
The A−T2+ biomarker profile is NOT consistent with a diagnosis of AD. [1] It is rare, often due to values near cutpoints (measurement noise), and neuropathologically corresponds to primary age-related tauopathy (PART), which is not AD. Amyloidosis is nearly always a prerequisite for neocortical AD tauopathy. This is a high-yield discriminator.
Imaging biomarkers measure cumulative effects, capture topographic information, map onto established neuropathologic constructs, and represent insoluble aggregates (for amyloid and tau PET). Fluid biomarkers reflect the net of rates of production/clearance of analytes at a given point in time. [1]
Think of it like this:
- PET = a photograph of the aggregate burden in the brain right now (cumulative, spatial)
- Fluid = a blood test measuring what's currently being shed/secreted (dynamic, snapshot)
This is why they're not always concordant, and why the 2024 criteria break from the 2018 assumption of equivalence within each AT(N) category.
Diagnosis of AD
The following can be diagnostic of AD:
- Amyloid PET (positive visual read)
- CSF hybrid ratios: Aβ42/40, p-tau181/Aβ42, t-tau/Aβ42
- "Accurate" plasma assays — particularly p-tau217 or %p-tau217 (ratio of p-tau217 to non-phosphorylated tau217)
- Combinations of Core 1 biomarkers
"Accurate" is defined as ≥90% accuracy to detect moderate/frequent neuritic plaques at autopsy (or the surrogate: abnormal amyloid PET/approved CSF) in the intended-use population. [1]
The most significant advance in AD diagnostics in recent years has been the development of blood-based markers (BBM). [1]
Why this matters:
- Previously, diagnosing AD biologically required PET (expensive, limited availability) or lumbar puncture (invasive)
- Blood tests (especially plasma p-tau217) now achieve accuracy equivalent to approved CSF assays (~90%) [1]
- This democratizes diagnosis: any clinic with access to a blood draw can potentially diagnose AD
- p-tau217 typically outperforms p-tau181, p-tau231, and plasma Aβ42/40 in head-to-head comparisons [1]
Why plasma Aβ42/40 is less useful: the fold difference between AD+ and AD− individuals is only 10–15% in plasma (vs. ~50% in CSF), giving limited diagnostic range and worse clinical robustness [1].
When using biomarkers quantitatively, a useful approach is to report results with two cutpoints that divide values into confidently normal, confidently abnormal, and indeterminate. [1]
Values in the indeterminate zone should prompt additional testing (e.g., if plasma p-tau217 is indeterminate, proceed to CSF or amyloid PET). This is analogous to how radiology uses "indeterminate" for borderline imaging findings.
Even with biomarkers, clinical judgment is always required [1]:
- Copathology assessment: Is AD the dominant cause of symptoms, or is there comorbid DLB, vascular disease, LATE, etc.?
- Discordant results: Negative biomarker but classic clinical picture → test further
- Confounders: Head trauma, cardiorespiratory arrest (transiently ↑p-tau), renal impairment (alters plasma biomarkers), certain medications, CSF dynamics disorders
- Syndromic assessment: Parkinsonism + hallucinations + positive Core 1 → need to assess AD contribution vs. NSD contribution
Clinical Implication for Testing in Asymptomatic People
At the present time, we recommend against diagnostic testing in cognitively unimpaired individuals outside research studies [1], because no disease-targeted therapies are approved for preclinical AD yet. AD can be diagnosed in asymptomatic individuals, but should not be for clinical purposes currently.
Biological Disease Staging (Stages A–D)
Staging applies only to individuals in whom AD has been diagnosed by Core 1 biomarkers. [1]
The stereotypical unidirectional biomarker sequence: A → T2 → N → C (Amyloid → Tau aggregation → Neurodegeneration → Clinical symptoms)
- Abnormal amyloid PET often exists as an isolated finding in cognitively unimpaired elderly (stage A)
- High neocortical tau PET is rarely seen without abnormal amyloid PET — and is invariably accompanied by neurodegeneration and symptoms
- Symptoms and neurodegeneration correlate with tau PET location/magnitude, NOT amyloid PET
| Stage | Label | Amyloid PET | Tau PET | AT2 Notation |
|---|---|---|---|---|
| A (Initial) | Initial | + | No uptake | A+T2− |
| B (Early) | Early | + | MTL only | A+T2MTL+ |
| C (Intermediate) | Intermediate | + | Moderate neocortical | A+T2MOD+ |
| D (Advanced) | Advanced | + | High neocortical | A+T2HIGH+ |
MTL = medial temporal lobe (hippocampus, entorhinal cortex, amygdala) Neocortical = inferior/lateral temporal, inferior/medial parietal (key areas for predicting cognitive decline)
A large meta-analysis found a 40-fold range in hazard ratios by PET stage: HR 1.5 for stage A, HR 5.6 for stage B, and HR 39.9 for stages C/D (relative to A−T2−), for progression from cognitively unimpaired to dementia. [1]
Core 1 fluid biomarkers can establish that an individual is in stage A or higher, but cannot discriminate between PET stages A–D at present. [1] So the practical approach:
- Blood/CSF Core 1 → confirms AD (stage A+)
- Tau PET → discriminates between A, B, C, D
| Stage | Fluid Biomarker |
|---|---|
| A (Initial) | CSF Aβ42/40, p-tau181/Aβ42, t-tau/Aβ42, accurate plasma assays |
| B (Early) | p-tau205 |
| C (Intermediate) | MTBR-tau243 |
| D (Advanced) | Non-phosphorylated mid-region tau fragments |
This is conceptual/awaiting further validation — but examinable as a framework.
N biomarkers do not always follow the A+ → T2+ → N+ sequence. [1] An individual may have:
- AD (A+) with neurodegeneration from a copathology (e.g., LATE, vascular) → N is "out of proportion" to tau stage
- This is illustrated by the T2N mismatch case: A+T2−N+ (abnormal amyloid PET, unremarkable tau PET, but severe hippocampal atrophy) — suggesting comorbid LATE [1]
Clinical Staging (Stages 0–6)
Clinical staging applies only to individuals on the AD continuum (diagnosed by biomarkers). [1]
| Clinical Stage | Description | Approximate Syndromic Equivalent |
|---|---|---|
| 0 | Deterministic gene (ADAD or Down syndrome), biomarker-negative, asymptomatic | — |
| 1 | Asymptomatic, biomarker-positive only | Preclinical AD |
| 2 | Transitional decline — subtle change, minimal functional impact | Subjective cognitive decline |
| 3 | Objective cognitive impairment, early functional impact (still independent but less efficient) | MCI |
| 4 | Dementia with mild functional impairment (instrumental ADLs affected) | Mild dementia |
| 5 | Dementia with moderate functional impairment (basic ADLs require assistance) | Moderate dementia |
| 6 | Complete dependence for basic ADLs | Severe dementia |
- Stage 0 is new in 2024: applies to individuals with deterministic genetics (ADAD mutations, trisomy 21) who haven't yet developed biomarker positivity or symptoms — they have the disease from birth
- Stage 2 is a transitional stage defined by any of: objective cognitive decline, subjective cognitive decline, OR neurobehavioral symptoms (depression, anxiety, apathy). An individual may be assigned stage 2 based on neurobehavioral symptoms alone, but stages 3–6 require cognitive impairment. [1]
- Clinical staging is based on severity of cognitive/functional impairment, not on phenotype [1] — the same stage could present as amnestic, visuospatial, language, behavioral, or dysexecutive
- "Prodromal AD" is deprecated — such an individual is not in a "prodrome" but has the disease → terminology is "AD clinical stage 3" [1]
- Amnestic ("typical")
- Language variant (logopenic primary progressive aphasia)
- Visuospatial variant (posterior cortical atrophy)
- Behavioral variant
- Dysexecutive variant
These often overlap within an individual.
Biological and clinical stages are quasi-independent variables [1] — they don't move in lockstep because of:
- Copathologies (vascular, LATE, Lewy body) → push clinical stage worse for a given biological stage
- Cognitive reserve/resilience (education, lifestyle) → delay clinical symptoms despite advanced biological stage
Integrated Staging Table [1]
| Clinical 0 | Clinical 1 | Clinical 2 | Clinical 3 | Clinical 4–6 | |
|---|---|---|---|---|---|
| Biological A | X | 1A | 2A | 3A | 4-6A |
| Biological B | X | 1B | 2B | 3B | 4-6B |
| Biological C | X | 1C | 2C | 3C | 4-6C |
| Biological D | X | 1D | 2D | 3D | 4-6D |
The typical expected progression trajectory is along the diagonal (1A → 2B → 3C → 4-6D). [1]
- Above diagonal (worse clinical than expected for biological stage) → likely more copathology
- Below diagonal (better clinical than expected) → exceptional cognitive reserve/resilience
Non-Core Biomarker Categories (NIVS)
- Fluid: NfL (neurofilament light chain) — marker of large-caliber axonal injury. Non-specific (also elevated in MS, ALS, TBI, etc.)
- Imaging: Brain atrophy on MRI, FDG hypometabolism on PET
- Total tau has been removed from the N category [1] — it correlates too closely with p-tau and rises early (behaves more like a T marker), but also rises dramatically in CJD, head trauma, stroke → unclear categorization
- GFAP (glial fibrillary acidic protein) — astrocytic reactivity marker, better in plasma than CSF
- Associated with early amyloid PET, higher risk of incident dementia, faster cognitive decline
- Soluble TREM2 — microglial reactivity marker (CSF only)
- Macroscopic infarction on MRI/CT (cortical, subcortical, lacunes)
- White matter hyperintensities (WMH) — traditionally interpreted as microvascular ischemic injury, but may also reflect axonopathy, autoimmune demyelination, or CAA-related blood-brain barrier dysfunction
- Cerebral amyloid angiopathy (CAA): Aβ deposits in cerebral vessel walls → microbleeds, superficial siderosis, lobar hemorrhage. MRI evidence of CAA increases risk of ARIA with anti-Aβ immunotherapy [1]
- αSyn-SAA (seed amplification assay) in CSF — sensitive and specific for cortical α-synuclein pathology
- Relevant because cortical α-synuclein copathology drives cognitive decline independent of AD pathology
- Less sensitive for MSA (different conformation/cellular location of inclusions)
Risk alleles (including APOE) are regarded as a risk factor for AD, not diagnostic of or a stage of AD. [1] They don't tell you whether ADNPC is present or how severe it is at a given time.
However, APOE genotype is clinically critical for anti-Aβ immunotherapy:
- APOE ε4 homozygotes have substantially greater risk of amyloid-related imaging abnormalities (ARIA) [1]
- APOE screening is recommended in the FDA label for lecanemab
- Counseling around risk is recommended for homozygotes
Copathology Is the Rule, Not the Exception
In older adults, AD most often occurs with copathologies. [1] The proportion of cognitive deficit attributable to AD vs. other neuropathologic entities cannot be known with certainty — only probabilistic estimates based on biomarker combinations and clinical judgment.
T2N Mismatch — An Illustrative Clinical Scenario [1]
The document presents a case of an 89-year-old man with progressive amnestic dementia:
- Amyloid PET: Abnormal (A+)
- Tau PET: Unremarkable (T2−)
- MRI: Marked bilateral hippocampal atrophy (N+)
- Profile: A+T2−N+ → tau PET cannot explain the atrophy → suspect comorbid LATE (TDP-43 encephalopathy)
This case illustrates why biological staging uses only core biomarkers and why N is kept separate.
| Setting | Use |
|---|---|
| Symptomatic patient | Confirm AD as underlying pathology; assess eligibility for anti-Aβ therapy; counsel and tailor symptomatic treatment |
| Clinical trials | Inclusion criteria; stratification by biological stage; monitoring treatment response |
| Asymptomatic individual | Not recommended for clinical diagnostic purposes currently (only in research) [1] |
Anti-Aβ Immunotherapy Context
- Currently approved treatments (e.g., lecanemab) target Aβ and require documentation of Aβ pathology
- The amount of amyloid PET reduction is associated with the degree of clinical benefit [1] — replicated across trials
- Practical workflow: plasma Core 1 biomarker → if positive → tau PET for staging → determine eligibility and inform prognosis
The document explicitly lists four key limitations:
- Lack of certified reference methods/materials for most biofluid assays (except CSF Aβ42)
- Biomarkers are less sensitive than neuropathologic examination for early/mild ADNPC — PET-based staging ≠ Braak neuropathological staging
- Not all relevant diseases have well-characterized biomarkers — you cannot know with certainty all copathologies present in vivo
- The proportion of cognitive deficit attributable to AD vs. other pathologies cannot be known with certainty — only probabilistic estimates
GC 241 Summary Slide: DSM-5 criteria of diagnosis; common etiologies (AD, VaD, DLB); imaging and fluid biomarkers; new advances in AD. [2]
The revised criteria directly inform GC 241's "new advances" section. The GC 169 psychogeriatrics lecture covers practical clinical assessment of dementia [3], while the reference papers on vascular neurocognitive disorder [4] and DLB [5] are the copathologies that the 2024 criteria explicitly accommodate via V and S biomarker categories.
Key connections:
- DLB: The document introduces αSyn-SAA as a CSF biomarker for α-synuclein copathology — directly relevant to distinguishing AD from DLB [5]
- Vascular: WMH, infarctions, and CAA are all categorized under V — connects to new vascular NCD criteria [4]
- Delirium vs. Dementia: Biomarkers help confirm AD in a patient who may have delirium superimposed on dementia — clinical judgment still required [6]
Exam Intelligence
| Trap | Correct Understanding |
|---|---|
| "AD requires symptoms for diagnosis" | No — AD is a biological entity; symptoms are a consequence, not a requirement [1] |
| "A−T2+ = AD" | No — this profile is NOT consistent with AD; it corresponds to PART [1] |
| "All Core biomarkers are interchangeable" | Core 1 biomarkers are generally interchangeable for diagnosis, but Core 2 biomarkers are not standalone diagnostic tests [1] |
| "APOE ε4 can diagnose AD" | No — risk alleles are risk factors, not diagnostic or staging markers [1] |
| "N biomarkers (NfL, MRI atrophy) are specific to AD" | No — N biomarkers are non-specific [1] |
| "Plasma Aβ42/40 is as good as p-tau217" | No — fold difference is only 10-15% in plasma vs. 50% in CSF; p-tau217 outperforms [1] |
| "Preclinical AD = at risk for AD" | No — preclinical AD = the individual already HAS the disease (stage 1) [1] |
| "Prodromal AD" | Deprecated terminology; use "AD clinical stage 3" [1] |
| "Tau PET correlates with amyloid burden" | Symptoms/neurodegeneration correlate with tau PET location/magnitude, NOT amyloid PET [1] |
- What is the minimum accuracy required for a blood-based biomarker to be used as a standalone diagnostic test for AD? → 90% for identification of moderate/frequent neuritic plaques [1]
- Which plasma biomarker is regarded as the most accurate standalone Core 1 test? → p-tau217 (or %p-tau217) [1]
- What does ARIA stand for and what increases its risk? → Amyloid-related imaging abnormalities; APOE ε4 homozygosity [1]
- What is Stage 0 in clinical staging? → Genetically determined AD (ADAD or Down syndrome), biomarker-negative, clinically asymptomatic [1]
After thorough review of all indexed past paper files (2016–2025 Fourth Summative MCQ, SAQ, and Minicase papers), no specific questions directly testing the 2024 revised AD diagnostic/staging criteria from this reference paper were identified in the available past paper context. This is expected as the paper was published in 2024 and is a very recent addition to the GC 241 curriculum.
However, dementia-related questions have appeared in past papers:
2023 Fourth Summative MCQ [7]: Questions on dementia and cognitive impairment appear in the geriatrics/psychiatry sections. The specific stems available in the indexed context do not quote questions directly matching this reference paper's criteria.
2024 Fourth Summative SAQ [8]: SAQ questions in the geriatrics block may test biomarker-based approaches to dementia diagnosis, but specific stems from this paper's framework were not directly quoted in the available indexed context.
Given that this is a newly assigned reference paper, expect questions on Core 1 vs. Core 2 biomarkers, the biological definition of AD, staging (especially integrated biological-clinical staging), and the role of blood-based biomarkers in upcoming summatives.
High Yield Summary
- AD is defined biologically — by ADNPC detected via biomarkers, not symptoms.
- Core 1 biomarkers (amyloid PET, CSF ratios, accurate plasma p-tau217) are sufficient to diagnose AD — even in asymptomatic individuals.
- Core 2 biomarkers (tau PET, MTBR-tau243) provide staging, prognosis, and confidence that AD is driving symptoms.
- T1 vs. T2: T1 (p-tau217/181/231) = early, coincides with amyloid PET, reflects reaction to plaques. T2 (tau PET, MTBR-tau243) = later, reflects actual tau aggregates.
- Biological staging (A→D): A = A+T2−; B = A+T2MTL+; C = A+T2MOD+; D = A+T2HIGH+.
- Clinical staging (0–6): 0 = deterministic gene, pre-biomarker; 1 = asymptomatic biomarker+; 2 = transitional decline; 3 = MCI; 4–6 = mild/moderate/severe dementia.
- Integrated staging combines both axes; typical progression is along the diagonal.
- A−T2+ is NOT AD — it's PART. Amyloidosis is nearly always prerequisite for neocortical AD tauopathy.
- Blood-based biomarkers (especially plasma p-tau217) are the biggest recent advance — accuracy ≥90% for some assays.
- Clinical judgment is essential — copathology is the rule in older adults; AD rarely exists in isolation.
- Do NOT test asymptomatic individuals for clinical purposes currently — only in research.
- APOE ε4 homozygosity increases ARIA risk with anti-Aβ immunotherapy — screen before treatment.
Active Recall - Revised AD Criteria 2024
[1] Lecture slides: GC 241. Reference (1) - Alzheimers Dementia - Revised criteria for diagnosis and staging of Alzheimer s disease.pdf (Jack et al., 2024) [2] Lecture slides: GC 241. A short course of dementia.pdf (Summary slide) [3] Lecture slides: GC 169. My grandmother keeps forgetting things Geriatric psychiatry, Dementia.pdf [4] Lecture slides: GC 241. Reference (2) - New vascular neurocognitive disorder criteria JAMA.pdf [5] Lecture slides: GC 241. Reference (3) - Patel dementia with lewy bodies.pdf [6] Lecture slides: GC 081. Seizure and loss of consciousness Delirium and encephalopathy; epilepsy; coma and brain death; care of unconscious patients; electrophysiology I.pdf [7] Past papers: 2023 Fourth Summative MCQ.pdf [8] Past papers: 2024 Fourth Summative SAQ.pdf
GC241 A Short Course Of Dementia
A structured, condensed educational course designed to provide an overview of dementia, covering its types, pathophysiology, clinical features, diagnosis, and management principles for healthcare learners.
GC241 Reference (2) - New Vascular Neurocognitive Disorder Criteria JAMA
The 2023 JAMA consensus criteria provide an updated diagnostic framework for vascular cognitive impairment, integrating neuroimaging biomarkers of cerebrovascular disease with cognitive assessment to classify vascular contributions to cognitive impairment and dementia.