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Alzheimer's Disease

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1. EPIDEMIOLOGY

• ~55 million people worldwide are living with dementia; AD accounts for 60-70% of all cases
• Total U.S. health care cost related to dementia in 2024: $360 billion (~$25,000/patient)
• AD can manifest as early as the 3rd decade, but is most prevalent in the elderly
• 10% of persons >70 years and 20-40% of individuals >85 years have clinically identifiable memory loss
• Sex difference: Women are twice as likely to develop AD as men - not entirely explained by longevity; APOE4 has a stronger effect in women

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2. DISEASE STAGING (Biological Continuum)

Preclinical biomarker changes may precede symptoms by 20 years or more - defining the key window for early intervention.

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3. CLINICAL MANIFESTATIONS

Typical (Amnestic) Presentation

• Begins with insidious episodic memory loss - often initially dismissed as benign aging ("subjective cognitive decline")
• Progresses to deficits in executive function, language, and visuospatial abilities
• Behavioral/neuropsychiatric symptoms: depression, social withdrawal, anxiety in early disease; agitation, delusions, paranoia in later stages
• Sleep disorders, falls, seizures (especially in early-onset/autosomal dominant forms) occur

Atypical Variants (~20% of cases - PG-important!)

Late-Stage Disease

• Profoundly amnesic, agraphia, acalculia, ideomotor apraxia
• Motor features: hyperactive deep tendon reflexes, Babinski signs, frontal release signs (grasp/suck)
• Myoclonus in some patients
• Eventually: akinetic mutism, dysphagia, incontinence
• Death typically from aspiration pneumonia or sepsis from pressure ulcers

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4. PATHOLOGY

Gross

• Cortical atrophy - widened sulci, shrunken gyri
• Atrophy begins in medial temporal lobes (entorhinal cortex, hippocampus) → inferior temporal, lateral/medial parietal, dorsolateral frontal cortices
• Relatively spares primary motor/sensory cortex, basal ganglia, thalamus, cerebellum until late

Microscopic Hallmarks

• Extracellular deposits of amyloid beta (Aβ)
• Core surrounded by dystrophic neurites, reactive astrocytes, microglia
• Aβ derives from abnormal proteolytic cleavage of Amyloid Precursor Protein (APP) by β- and γ-secretases (normally cleaved by α-secretase - non-amyloidogenic pathway)
• Key isoforms: Aβ42 (more fibrillogenic, deposits first) and Aβ40

• Intraneuronal accumulations of hyperphosphorylated tau filaments (paired helical filaments)
• Tau normally stabilizes microtubules; in AD, hyperphosphorylation causes it to dissociate and aggregate
• Braak staging tracks NFT spread: Transentorhinal (I-II) → Limbic (III-IV) → Neocortical (V-VI)

• Aβ deposition in walls of cortical and leptomeningeal blood vessels
• Increases risk of lobar hemorrhage

• Reduction in choline acetyltransferase → loss of cholinergic neurons in nucleus basalis of Meynert → basis for cholinergic hypothesis and AChE inhibitor therapy
• Also affects noradrenergic (locus coeruleus), serotonergic (raphe nuclei) systems

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5. GENETICS

Autosomal Dominant (Early-Onset AD, <1% of cases)

Down syndrome (trisomy 21) → extra copy of APP gene → early Aβ deposition; virtually all have AD pathology by age 40

Susceptibility Gene (Sporadic AD)

• APOE ε4 allele (chromosome 19): Major genetic risk factor
  • 1 copy: 2-3x increased risk (stronger in women)
  • 2 copies: 10-15x increased risk in both sexes
  • APOE4 impairs Aβ clearance and promotes aggregation
  • APOE ε2 allele is protective
• TREM2 mutations: increase AD risk ~3-fold; impairs microglial phagocytosis of Aβ
• Over 75 other genetic risk loci identified via GWAS

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6. PATHOPHYSIOLOGY - THE AMYLOID CASCADE HYPOTHESIS

1. Abnormal Aβ production OR impaired clearance → Aβ42 accumulates
2. Oligomeric Aβ is synaptotoxic → impairs LTP, synaptic transmission
3. Aβ plaques form → tau hyperphosphorylation triggered
4. NFTs spread along neuronal networks (Braak stages)
5. Neuronal/synaptic loss → clinical dementia

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7. BIOMARKERS (Critical for PG - This is a Major Update in Harrison's 22E)

CSF Biomarkers

• ↓ Aβ42 (sequestered in plaques) and ↑ p-tau is the classic AD CSF signature
• Aβ42/Aβ40 ratio is more accurate than Aβ42 alone

Imaging Biomarkers

• Amyloid PET (florbetapir, flutemetamol, florbetaben): detects amyloid plaques in vivo; positive scan shows increased cortical uptake
• Tau PET: tracks NFT burden and spread - correlates more closely with cognitive decline
• FDG-PET: shows temporoparietal hypometabolism - characteristic pattern
• MRI: medial temporal lobe and hippocampal atrophy; used to track progression

Plasma Biomarkers (major advance in 22E)

• Plasma p-tau217 is now considered a highly accurate, scalable blood-based test for AD pathology
• Approaching CSF sensitivity; will transform population screening

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8. DIAGNOSIS

Clinical Criteria

1. Characteristic clinical syndrome (amnestic or typical variant)
2. Biomarker confirmation (CSF or PET) when available
3. Exclusion of other causes

Key Workup

• Cognitive testing: MMSE, MoCA; neuropsychological battery
• MRI brain: exclude structural causes, assess hippocampal atrophy (medial temporal lobe atrophy scale)
• Labs: TSH, B12, folate, CBC, BMP, LFTs, RPR (to exclude reversible dementias)
• CSF: Aβ42/Aβ40, p-tau, total tau when diagnosis is uncertain
• Amyloid/Tau PET: when clinical diagnosis is uncertain, biomarker-guided therapy is planned, or early-stage disease
• APOE genotyping: done in some centers for risk stratification; NOT standard of care for diagnosis

Differential Diagnosis of Dementia (from Harrison's)

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9. TREATMENT

A. Symptomatic Pharmacotherapy

• Rationale: nucleus basalis of Meynert cholinergic loss → increase ACh by blocking degradation
• Donepezil (most widely used): mild to severe AD; once daily
• Rivastigmine: mild to moderate; also inhibits butyrylcholinesterase; available as transdermal patch (preferred - better GI tolerance)
• Galantamine: mild to moderate; also allosterically modulates nicotinic receptors
• Side effects: nausea, vomiting, diarrhea, bradycardia, syncope
• Donepezil is FDA-approved for severe AD (unlike the others)

• Memantine: moderate to severe AD; blocks excessive NMDA glutamate receptor activation (excitotoxicity)
• Can be combined with AChEIs
• Side effects: dizziness, confusion, constipation

B. Disease-Modifying Therapies (Anti-Amyloid - Major Update 2025)

• Eligibility: Early symptomatic AD (MCI or mild dementia) with confirmed amyloid pathology on PET or CSF
• Key adverse effect: ARIA (Amyloid-Related Imaging Abnormalities)
  • ARIA-E: edema/effusion on MRI
  • ARIA-H: microhemorrhages/hemosiderosis on MRI
  • Risk is higher in APOE ε4 homozygotes - requires careful patient selection
  • Monitoring with serial MRI is mandatory
• These agents represent the first class to modify the biological course of AD

C. Management of Neuropsychiatric Symptoms

• Depression/anxiety: SSRIs (sertraline, citalopram) - avoid TCAs (anticholinergic)
• Agitation/psychosis: Low-dose quetiapine or risperidone; use cautiously (black-box warning: increased mortality in elderly with dementia)
• Sleep disturbance: Melatonin, trazodone; avoid benzodiazepines
• Seizures: Levetiracetam preferred (fewer drug interactions)

D. Non-Pharmacological & Caregiver Support

• Structured activities, regular exercise, cognitive stimulation
• Caregiver education and support (caregiver burden is immense)
• Advance care planning: driving cessation, financial/legal decisions, end-of-life preferences
• Mediterranean diet: meta-analyses show reduced risk of cognitive impairment (Fekete et al., Geroscience 2025)

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10. PROGNOSIS

• Median survival from diagnosis: 8-10 years, but range is 1-25 years
• Faster decline associated with: younger onset, early psychosis, myoclonus, extrapyramidal signs
• Death usually from aspiration pneumonia, UTI/sepsis, or pulmonary embolism

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11. KEY EXAM POINTS FOR PG

1. Most common cause of dementia = AD (60-70%); most common neuropathology in elderly
2. Pathological hallmarks = Neuritic plaques (Aβ) + NFTs (hyperphosphorylated tau) + CAA
3. APP cleavage: Normal = α-secretase (non-amyloidogenic); Abnormal = β+γ-secretase → Aβ42
4. Genetics: PSEN1 (most common mutation) > APP > PSEN2; APOE ε4 = major risk factor; APOE ε2 = protective
5. Braak staging = NFT spread from entorhinal → limbic → neocortex
6. MRI: Medial temporal lobe / hippocampal atrophy earliest; FDG-PET: temporoparietal hypometabolism
7. CSF: ↓Aβ42, ↑p-tau181 = classic signature; Aβ42/Aβ40 ratio more accurate
8. Plasma p-tau217 = most promising blood biomarker (2025 update)
9. AChEI: Donepezil (mild-severe), Rivastigmine (patch), Galantamine; Memantine for moderate-severe
10. Anti-amyloid biologics: Lecanemab (2023) and Donanemab (2024); monitor for ARIA on MRI; requires confirmed amyloid pathology
11. Nucleus basalis of Meynert = site of cholinergic neuronal loss; basis for AChEI use
12. DLB vs AD: DLB has visual hallucinations + parkinsonism + fluctuating cognition + REM sleep behavior disorder
13. NPH triad: Wet (incontinence) + Wacky (dementia) + Wobbly (gait)
14. Preclinical AD may start 20 years before symptoms

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