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Alzheimer Disease

What Do You Need to Know?

Aβ42 & Tau: amyloid plaques (Aβ42) are the pathologic hallmark; neurofibrillary tangles (hyperphosphorylated tau) correlate with clinical severity
Biomarker framework (A/T/N): Amyloid (CSF Aβ42↓, amyloid PET+), Tau (CSF p-tau↑, tau PET+), Neurodegeneration (CSF t-tau↑, FDG-PET↓, MRI atrophy)
Genetics: Early-onset AD — PSEN1 (chr 14, most common familial), APP (chr 21), PSEN2 (chr 1); Late-onset — APOE ε4 (strongest genetic risk factor, NOT deterministic)
Imaging signature: medial temporal/hippocampal atrophy on MRI; temporoparietal hypometabolism on FDG-PET; posterior cingulate involved early
Braak NFT staging: transentorhinal (I–II) → limbic (III–IV) → neocortical (V–VI); correlates with clinical progression
Treatment: cholinesterase inhibitors (mild–moderate), memantine (moderate–severe), anti-amyloid antibodies (lecanemab, donanemab) — monitor for ARIA
Atypical variants: posterior cortical atrophy (visual), logopenic PPA (language), frontal variant — all have AD pathology with different cortical targets

Pathophysiology & Amyloid Cascade Hypothesis

APP Processing

Amyloid precursor protein (APP): transmembrane protein encoded on chromosome 21; normal function includes synaptic plasticity and neuronal survival
Non-amyloidogenic pathway: α-secretase cleaves APP within the Aβ domain → soluble APPα (neuroprotective) → no Aβ produced
Amyloidogenic pathway: β-secretase (BACE1) then γ-secretase cleave APP → Aβ peptides released
Aβ40 vs. Aβ42: Aβ42 is more hydrophobic, more prone to aggregation, and is the predominant species in amyloid plaques
γ-secretase complex contains presenilin 1 or 2 (PSEN1/PSEN2) — mutations increase Aβ42/Aβ40 ratio

Amyloid Cascade Hypothesis

Aβ42 monomers → oligomers (most toxic species) → protofibrils → fibrils → insoluble amyloid plaques
Soluble Aβ oligomers impair synaptic function, induce oxidative stress, trigger neuroinflammation (microglial activation)
Amyloid deposition → downstream tau hyperphosphorylation → neurofibrillary tangles (NFTs) → neuronal death
Key distinction: amyloid plaques correlate poorly with clinical severity; NFT burden correlates with cognitive decline

Tau Pathology

Tau is a microtubule-associated protein; normal function = stabilizes axonal microtubules
Hyperphosphorylation → tau detaches from microtubules → forms paired helical filaments (PHFs) → NFTs
NFTs spread in a stereotyped pattern (Braak staging) from entorhinal cortex → hippocampus → neocortex
Prion-like propagation: tau spreads trans-synaptically along connected neural networks

💎 Board Pearl

Aβ plaques are necessary but not sufficient for AD diagnosis — cognitively normal elderly can have extensive amyloid
NFT burden (not amyloid plaque load) best correlates with clinical severity and cognitive decline
γ-secretase contains presenilin — this links PSEN1/PSEN2 mutations directly to increased Aβ42 production
Down syndrome (trisomy 21) → extra copy of APP gene → virtually all develop AD pathology by age 40

Clinical Stages & Diagnostic Criteria

Clinical Stages of Alzheimer Disease

Stage	Cognition	Function	Key Features
Preclinical AD	Normal	Normal	Biomarker-positive only (amyloid PET+ or CSF Aβ42↓); no symptoms; research framework only
MCI due to AD	Impaired (1–1.5 SD below mean)	Preserved (or minimal impairment)	Amnestic MCI most common; episodic memory loss (hippocampal); ~10–15% convert to AD dementia per year
Mild AD Dementia	Impaired	Impaired IADLs	Repetitive questions, getting lost, difficulty with finances/medications; word-finding difficulty
Moderate AD Dementia	Significantly impaired	Needs assistance with BADLs	Cannot dress/bathe independently; behavioral symptoms (agitation, wandering, sundowning); delusions
Severe AD Dementia	Profoundly impaired	Fully dependent	Loss of speech, incontinence, dysphagia, bed-bound; death from aspiration pneumonia, infection, or inanition

NIA-AA Diagnostic Framework (2018)

Defines AD biologically using the A/T/N system — independent of clinical symptoms
A (Amyloid): CSF Aβ42↓ (or Aβ42/40 ratio↓), amyloid PET positive
T (Tau pathology): CSF p-tau↑ (phosphorylated tau-181 or -217), tau PET positive
N (Neurodegeneration): CSF t-tau↑, FDG-PET temporoparietal hypometabolism, MRI hippocampal/cortical atrophy
A+T+N+ = full AD pathological change; A+T−N− = Alzheimer pathologic change (preclinical)
A− = NOT on the Alzheimer continuum regardless of T or N status

A/T/N Profile	Classification
A+T+N+	Alzheimer disease (full pathological change + neurodegeneration)
A+T+N−	Alzheimer disease (pathological change without neurodegeneration yet)
A+T−N−	Alzheimer pathologic change (amyloid only; preclinical)
A+T−N+	Alzheimer pathologic change + non-AD neurodegeneration
A−T+N+	Non-AD pathologic change (e.g., PART, primary tauopathy)
A−T−N+	Non-AD neurodegeneration (suspected non-Alzheimer pathology — SNAP)
A−T−N−	Normal biomarkers

💎 Board Pearl

Amnestic MCI (episodic memory loss with preserved function) is the classic prodrome of AD; converts to AD dementia at ~10–15% per year
A/T/N framework: you MUST be A+ to be on the Alzheimer continuum — A− with T+ and/or N+ is NOT AD
PART (Primary Age-Related Tauopathy): NFTs limited to medial temporal lobe WITHOUT amyloid — A−T+; distinct from AD

Biomarkers

CSF Biomarkers

Biomarker	Direction in AD	What It Reflects	Notes
Aβ42	↓ Decreased	Amyloid sequestration in plaques (less free in CSF)	Aβ42/40 ratio improves specificity over Aβ42 alone
p-tau (181 or 217)	↑ Increased	Tau phosphorylation (AD-specific tau pathology)	p-tau217 has highest accuracy for differentiating AD from non-AD dementias
t-tau (total tau)	↑ Increased	Neuronal injury/neurodegeneration (non-specific)	Also elevated in CJD (markedly), stroke, TBI; not AD-specific

PET Biomarkers

PET Tracer	Target	AD Pattern	Key Points
Amyloid PET (florbetapir, florbetaben, flutemetamol, Pittsburgh compound B)	Fibrillar Aβ plaques	Diffuse cortical uptake (frontal, parietal, temporal, posterior cingulate/precuneus)	Positive in ~30% of cognitively normal elderly ≥65 yr; negative amyloid PET essentially rules out AD
Tau PET (flortaucipir / AV-1451)	Paired helical filament tau (3R/4R)	Medial temporal → lateral temporal → parietal → frontal (mirrors Braak staging)	More closely correlates with cognitive symptoms than amyloid PET; FDA-approved 2020
FDG-PET	Glucose metabolism (neuronal activity)	Temporoparietal & posterior cingulate/precuneus hypometabolism	Frontal sparing early; primary sensorimotor and visual cortex spared; pattern distinguishes AD from FTD

Plasma Biomarkers

Plasma p-tau217: most promising blood-based biomarker; high accuracy for detecting AD pathology; comparable to CSF p-tau
Plasma p-tau181: elevated in AD; less accurate than p-tau217 but still useful for screening
Plasma Aβ42/40 ratio: decreased in AD; modest accuracy alone; improves when combined with p-tau
Plasma GFAP (glial fibrillary acidic protein): reflects astrocyte activation; elevated early in AD continuum
NfL (neurofilament light chain): non-specific marker of neurodegeneration; elevated in AD but also in FTD, ALS, MS

💎 Board Pearl

CSF Aβ42 is LOW in AD (trapped in plaques) — do not confuse with tau which is HIGH
Negative amyloid PET has high negative predictive value — essentially rules out AD as the cause of dementia
CSF t-tau markedly elevated (>10×) → think CJD, not AD (AD has modest elevation)
p-tau217 is emerging as the best single blood-based biomarker for AD detection
FDG-PET pattern: AD = temporoparietal hypometabolism; FTD = frontal/anterior temporal hypometabolism — key differentiator

Genetics

Early-Onset Familial AD (Autosomal Dominant)

Gene	Chromosome	Protein	Key Features
PSEN1	14	Presenilin 1 (γ-secretase component)	Most common cause of early-onset familial AD; onset 30–60 yr (mean ~45); >300 mutations; nearly 100% penetrance; may present with seizures, myoclonus, spastic paraparesis
APP	21	Amyloid precursor protein	Mutations near secretase cleavage sites → ↑Aβ42 production; onset 40–65 yr; duplications cause AD + cerebral amyloid angiopathy (CAA)
PSEN2	1	Presenilin 2 (γ-secretase component)	Rarest of the three; later onset (40–75 yr); incomplete penetrance; originally described in Volga German families

Late-Onset (Sporadic) AD — Genetic Risk Factors

Gene/Allele	Chromosome	Effect	Key Details
APOE ε4	19	Risk factor (↑)	Strongest genetic risk factor for late-onset AD; 1 copy → 3–4× risk; 2 copies (ε4/ε4) → 8–12× risk; impairs Aβ clearance; NOT deterministic (many ε4 carriers never develop AD)
APOE ε2	19	Protective (↓)	~40% reduced risk compared to ε3; delays onset; ε2/ε2 is most protective; associated with type III hyperlipoproteinemia
APOE ε3	19	Neutral (reference)	Most common allele (~78% of population); considered baseline risk
TREM2	6	Risk factor	Microglial receptor; R47H variant → 2–4× increased AD risk; impairs microglial clearance of Aβ

Down Syndrome & AD

Trisomy 21: three copies of chromosome 21 → three copies of APP gene → lifelong Aβ overproduction
Virtually all individuals with Down syndrome develop AD neuropathology by age 40
Clinical dementia onset typically in the 50s; accelerated course
Higher risk of early-onset seizures with AD

💎 Board Pearl

PSEN1 (chr 14) = most common cause of early-onset familial AD — NOT APP
APOE ε4 is a risk factor, NOT a deterministic gene — it does not cause AD; many carriers never develop disease
APOE ε4 homozygotes (ε4/ε4): 8–12× increased risk + higher ARIA rates with anti-amyloid antibodies
Down syndrome (trisomy 21): extra copy of APP on chr 21 → AD pathology by age 40; clinical dementia in 50s
Early-onset familial AD = autosomal dominant, <5% of all AD; accounts for only ~1% of total AD cases

Neuroimaging

Structural MRI

Hippocampal atrophy: earliest and most sensitive structural finding; medial temporal lobe volume loss on coronal T1
Entorhinal cortex atrophy: precedes hippocampal atrophy; earliest region affected
Posterior parietal atrophy: precuneus involvement; correlates with episodic memory and visuospatial deficits
Progressive pattern: medial temporal → lateral temporal → parietal → frontal (mirrors Braak staging)
Medial temporal atrophy (MTA) score: visual rating scale on coronal MRI; MTA ≥2 supports AD
Primary motor, sensory, and visual cortices are relatively spared until late

FDG-PET Patterns by Dementia Type

Dementia	FDG-PET Pattern
AD	Temporoparietal + posterior cingulate/precuneus hypometabolism; frontal sparing early
FTD (behavioral variant)	Frontal + anterior temporal hypometabolism
DLB	Temporoparietal + occipital hypometabolism (occipital involvement distinguishes from AD)
PCA (visual variant AD)	Occipitoparietal hypometabolism

💎 Board Pearl

AD on FDG-PET: temporoparietal + posterior cingulate hypometabolism with frontal sparing — this pattern is the classic board answer
DLB vs. AD on FDG-PET: both have temporoparietal hypometabolism, but DLB uniquely includes occipital hypometabolism
Hippocampal atrophy on coronal MRI is the most tested structural finding in AD

Neuropathology & Staging

Microscopic Hallmarks

Finding	Composition	Location	Key Details
Neuritic (senile) plaques	Aβ42 core + dystrophic neurites + activated microglia	Extracellular; neocortex > hippocampus	Required for definite AD diagnosis (NIA-AA neuropathologic criteria); correlate poorly with clinical severity
Diffuse plaques	Aβ without neuritic changes	Widespread cortex	Can be seen in normal aging; NOT counted for AD diagnosis (CERAD scoring counts neuritic plaques only)
Neurofibrillary tangles (NFTs)	Hyperphosphorylated tau (paired helical filaments)	Intraneuronal; entorhinal → hippocampus → neocortex	Correlate with clinical severity; Braak staging based on NFT distribution
Neuropil threads	Tau-positive dystrophic neurites	Neuropil surrounding plaques and tangles	Abundant; contribute to tau pathology burden
Granulovacuolar degeneration	Intraneuronal vacuoles with dense granules	Hippocampal pyramidal neurons	Not specific to AD but prominent in hippocampus
Hirano bodies	Actin-containing eosinophilic rod-shaped inclusions	Hippocampal CA1	Non-specific; seen in aging and AD

Braak Neurofibrillary Tangle Staging

Stage	Region	Clinical Correlate
I–II (Transentorhinal)	Transentorhinal cortex, entorhinal cortex	Preclinical; cognitively normal or subtle memory changes
III–IV (Limbic)	Hippocampus (CA1), amygdala, thalamus	MCI; early clinical symptoms; episodic memory impairment
V–VI (Neocortical)	Association neocortex (temporal, parietal, frontal)	Dementia; moderate to severe AD; widespread cognitive decline

Thal Amyloid Phases

Phase	Region of Amyloid Deposition
1	Neocortex (frontal, parietal, temporal, occipital)
2	Allocortex (entorhinal, hippocampus, amygdala, cingulate)
3	Diencephalon (striatum, basal forebrain, thalamus)
4	Brainstem
5	Cerebellum

Key contrast: Thal phases (amyloid) spread top-down (neocortex → brainstem → cerebellum); Braak staging (tau) spreads bottom-up (entorhinal → hippocampus → neocortex)

Cerebral Amyloid Angiopathy (CAA)

Aβ40 (not Aβ42) deposits in walls of cortical and leptomeningeal blood vessels
Present in >80% of AD brains; can occur independently of AD
Clinical consequences: lobar intracerebral hemorrhage, cortical superficial siderosis, microbleeds
Boston criteria v2.0: lobar hemorrhage + cortical superficial siderosis + lobar microbleeds on MRI
CAA increases risk of ARIA with anti-amyloid antibody therapy

💎 Board Pearl

Neuritic plaques (NOT diffuse plaques) are required for neuropathologic AD diagnosis — CERAD scoring counts neuritic plaques only
Braak NFT stages correlate with clinical severity: I–II = preclinical; III–IV = MCI; V–VI = dementia
Thal (amyloid) = top-down spread (cortex → cerebellum); Braak (tau) = bottom-up spread (entorhinal → neocortex) — opposite patterns
CAA: Aβ40 in vessel walls (not Aβ42); causes lobar hemorrhages; present in >80% of AD brains
NIA-AA neuropathologic criteria (ABC score): A = Thal amyloid phase, B = Braak NFT stage, C = CERAD neuritic plaque score

Treatment

Cholinesterase Inhibitors (ChEIs)

Drug	Mechanism	Indication	Key Side Effects / Notes
Donepezil	Reversible AChE inhibitor	Mild–severe AD (only ChEI approved for all stages)	Nausea, diarrhea, insomnia, vivid dreams, bradycardia; once-daily dosing; available as transdermal patch
Rivastigmine	Pseudo-irreversible AChE + BuChE inhibitor	Mild–moderate AD; also approved for PDD	GI side effects; transdermal patch preferred (better tolerability); only ChEI approved for Parkinson disease dementia
Galantamine	Reversible AChE inhibitor + allosteric nicotinic receptor modulator	Mild–moderate AD	Dual mechanism; GI side effects; avoid in severe hepatic/renal impairment

Cholinergic hypothesis: nucleus basalis of Meynert degeneration → cortical ACh deficit → memory impairment
Modest symptomatic benefit; do NOT slow disease progression
Monitor for bradycardia, syncope, GI effects; avoid in sick sinus syndrome

NMDA Receptor Antagonist

Memantine: uncompetitive NMDA receptor antagonist; reduces glutamate excitotoxicity
Approved for moderate–severe AD; often combined with donepezil (Namzaric = combination)
Generally well tolerated; side effects: dizziness, headache, confusion

Anti-Amyloid Monoclonal Antibodies

Drug	Target	Approval/Status	Key Trial / Notes
Aducanumab	Aggregated Aβ (plaques + oligomers)	FDA accelerated approval 2021 (controversial); withdrawn 2024	EMERGE/ENGAGE trials; inconsistent efficacy; reduced amyloid on PET; high ARIA rates (~35% ARIA-E)
Lecanemab	Aβ protofibrils (soluble aggregates)	FDA full approval 2023	CLARITY AD trial; 27% slowing of decline on CDR-SB at 18 months; ARIA-E ~13%, ARIA-H ~17%; IV q2 weeks
Donanemab	N-terminal pyroglutamate Aβ (deposited plaques)	FDA approved 2024	TRAILBLAZER-ALZ 2; 35% slowing of decline in low/medium tau; dosing stops when amyloid cleared; ARIA-E ~24%

ARIA (Amyloid-Related Imaging Abnormalities)

ARIA-E: vasogenic edema/sulcal effusions; usually asymptomatic; resolves with dose interruption; on MRI = FLAIR hyperintensity
ARIA-H: microhemorrhages or superficial siderosis; on MRI = GRE/SWI hypointensities
Risk factors for ARIA: APOE ε4 carriers (especially homozygotes), pre-existing CAA/microbleeds, higher doses, anticoagulant use
APOE ε4 homozygotes (ε4/ε4): ARIA-E rate up to ~35–40% with anti-amyloid antibodies
Monitoring: baseline MRI + periodic MRIs (at least before doses 5, 7, 14 for lecanemab); APOE genotyping recommended before starting therapy
Symptomatic ARIA: headache, confusion, visual disturbance; rarely serious (macrohemorrhage, death)

💎 Board Pearl

Donepezil is the only ChEI approved for all stages (mild through severe) of AD
Rivastigmine is the only ChEI also approved for Parkinson disease dementia (PDD)
Memantine is indicated for moderate–severe AD — NOT mild AD
ARIA risk is highest in APOE ε4 homozygotes — APOE genotyping should be performed before initiating anti-amyloid therapy
Lecanemab targets protofibrils (soluble); donanemab targets deposited plaque (pyroglutamate Aβ) — different mechanisms
ChEIs and memantine provide symptomatic benefit only; anti-amyloid antibodies are the first disease-modifying therapies

Atypical Presentations

Atypical AD Variants

Variant	Core Deficit	Atrophy Pattern	Key Features
Posterior Cortical Atrophy (PCA)	Visuospatial / visuoperceptual	Occipitoparietal, posterior temporal	Progressive visual dysfunction (simultanagnosia, optic ataxia, oculomotor apraxia = Balint syndrome); alexia; visual agnosia; environmental disorientation; memory relatively preserved early; most common cause is AD pathology; young onset (50s–60s)
Logopenic Primary Progressive Aphasia (lvPPA)	Word-finding / sentence repetition	Left posterior temporal & inferior parietal (angular gyrus, posterior superior temporal)	Frequent word-finding pauses; impaired sentence/phrase repetition; phonologic errors; spared grammar and motor speech; underlying pathology is AD in ~60–70% of cases
Frontal Variant AD	Executive / behavioral	Frontal lobes	Executive dysfunction, apathy, or disinhibition mimicking bvFTD; younger onset; AD pathology confirmed at autopsy; biomarkers (amyloid PET, CSF) distinguish from FTD
Corticobasal Syndrome (CBS) due to AD	Asymmetric apraxia / parkinsonism	Asymmetric frontoparietal	Limb apraxia, alien limb, myoclonus, cortical sensory loss, asymmetric rigidity; ~25% of CBS cases have AD pathology (not CBD)

Key Differentiating Feature of lvPPA from Other PPAs

PPA Variant	Fluency	Repetition	Single-Word Comprehension	Grammar	Typical Pathology
Logopenic (lvPPA)	Reduced (word-finding pauses)	Impaired	Preserved	Preserved	AD (~60–70%)
Nonfluent/Agrammatic (nfvPPA)	Effortful, halting	Relatively preserved	Preserved	Impaired	Tau (4R, CBD, PSP)
Semantic (svPPA)	Fluent	Preserved	Impaired	Preserved	TDP-43 (FTLD)

💎 Board Pearl

PCA (visual variant AD): Balint syndrome (simultanagnosia + optic ataxia + oculomotor apraxia) with occipitoparietal atrophy; memory preserved early; most cases are AD pathology
lvPPA: the only PPA variant where the most common underlying pathology is AD; key finding = impaired sentence repetition with preserved grammar
~25% of corticobasal syndrome (CBS) is caused by AD pathology (not CBD) — biomarkers help differentiate
All atypical AD variants share the same amyloid/tau pathology — they differ only in which cortical region bears the greatest burden

Differential Diagnosis

AD vs. Other Common Dementias

Feature	AD	DLB	FTD (bvFTD)	Vascular Dementia	NPH
Core Deficit	Episodic memory (hippocampal)	Attention, visuospatial, fluctuations	Behavior, executive function, personality	Executive, processing speed	Gait, urinary, cognitive (triad)
Age at Onset	Typically >65	>50	45–65 (younger than AD)	Variable	>60
Memory	Early, prominent encoding deficit	Fluctuating; retrieval > encoding	Relatively preserved early	Retrieval deficit (improves with cues)	Subcortical pattern (slow retrieval)
Hallucinations	Late feature	Early, visual (detailed, recurrent)	Uncommon	Uncommon	Uncommon
Motor	Normal until late	Parkinsonism; RBD	Normal early	Focal deficits; gait disorder	Magnetic gait (wide-based, shuffling)
MRI	Hippocampal atrophy	Relatively preserved hippocampus	Frontal/anterior temporal atrophy	White matter disease; lacunar infarcts	Ventriculomegaly out of proportion to sulcal atrophy
FDG-PET	Temporoparietal ↓	Temporoparietal + occipital ↓	Frontal/anterior temporal ↓	Multifocal ↓	Global ↓ (nonspecific)

Normal Aging vs. MCI vs. AD Dementia

Feature	Normal Aging	MCI	AD Dementia
Subjective complaints	Occasional word-finding, name recall	Noticeable decline (self or informant)	Significant, often minimized by patient (anosognosia)
Objective testing	Within normal range for age	1–1.5 SD below mean	≥2 SD below mean; multiple domains
Daily function	Fully independent	Independent (or minimal difficulty with complex tasks)	Impaired IADLs (mild) → BADLs (moderate–severe)
Progression	Stable over years	May be stable, improve, or progress to dementia (~10–15%/yr to AD)	Progressive decline; no reversal

Reversible Causes of Cognitive Decline to Exclude

Metabolic: hypothyroidism (TSH), B12 deficiency, hepatic/uremic encephalopathy, hyponatremia
Infectious: HIV, syphilis (RPR/VDRL), Lyme (endemic areas)
Structural: NPH, subdural hematoma, brain tumor
Psychiatric: depression (pseudodementia) — key mimic; responds to antidepressants
Toxic/Drug: anticholinergics, benzodiazepines, opioids, alcohol
Minimum workup: CBC, CMP, TSH, B12, RPR; MRI brain

Clinical Pearl

Pseudodementia (depression): patients complain about memory (vs. AD patients often unaware); answer "I don't know" (vs. AD patients confabulate); onset is more acute; responds to antidepressant treatment
DLB vs. AD: relatively preserved hippocampi on MRI + occipital hypometabolism on FDG-PET favors DLB; early visual hallucinations + parkinsonism + fluctuating cognition = DLB
Always check for reversible causes before diagnosing a neurodegenerative dementia

References

Jack CR Jr, Bennett DA, Blennow K, et al. NIA-AA Research Framework: toward a biological definition of Alzheimer's disease. Alzheimers Dement. 2018;14(4):535-562.
Knopman DS, Amieva H, Petersen RC, et al. Alzheimer disease. Nat Rev Dis Primers. 2021;7(1):33.
van Dyck CH, Swanson CJ, Aisen P, et al. Lecanemab in early Alzheimer's disease (CLARITY AD). N Engl J Med. 2023;388(1):9-21.
Sims JR, Zimmer JA, Evans CD, et al. Donanemab in early symptomatic Alzheimer disease (TRAILBLAZER-ALZ 2). JAMA. 2023;330(6):512-527.
Braak H, Braak E. Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol. 1991;82(4):239-259.