Alzheimer Disease

Risk factors

• Advancing age (strongest)
• Female sex
• APOE epsilon-4 allele (one copy ~3x risk, two copies ~12x risk); APOE2 protective
• Family history; autosomal dominant early-onset AD: APP, PSEN1, PSEN2 mutations
• Down syndrome (trisomy 21 → triplicated APP; nearly universal AD pathology by age 40)
• Cardiovascular risk factors: hypertension (midlife), diabetes, dyslipidemia, smoking, obesity
• Low educational attainment / cognitive reserve
• Traumatic brain injury, hearing loss, social isolation, depression

Pathophysiology

Imbalanced production and clearance of amyloid-beta (Abeta42) → extracellular plaques. Tau becomes hyperphosphorylated and aggregates into intraneuronal neurofibrillary tangles, beginning in the entorhinal cortex and hippocampus (medial temporal) and spreading to neocortex (Braak staging). Synaptic loss, neuronal death, and cholinergic deficit (degeneration of the nucleus basalis of Meynert) produce the cognitive phenotype. Cerebral amyloid angiopathy frequently coexists.

Clinical presentation

Differential diagnosis

• Vascular dementia — Stepwise decline, focal neurologic findings, vascular risk factors, white matter disease and infarcts on imaging; often coexists with AD ('mixed')
• Lewy body dementia — Fluctuating cognition, visual hallucinations, parkinsonism (within 1 yr of dementia), REM sleep behavior disorder, neuroleptic sensitivity
• Frontotemporal dementia — Behavioral/personality change (bvFTD) or progressive aphasia (primary progressive aphasia) in younger patients (50-70); memory relatively preserved early
• Normal pressure hydrocephalus — 'Wet, wacky, wobbly' — urinary incontinence, cognitive impairment, magnetic gait; ventriculomegaly out of proportion to atrophy; CSF tap test responsive
• Pseudodementia (depression) — Subacute, 'I don't know' answers, lack of effort, prior psychiatric history; improves with treatment of depression
• Reversible causes — Hypothyroidism, B12 deficiency, neurosyphilis, HIV, medications (anticholinergics, benzodiazepines), chronic subdural hematoma, alcohol use
• Mild cognitive impairment (MCI) — Cognitive decline beyond age-expected but ADLs intact; ~10-15% per year progress to dementia
• Creutzfeldt-Jakob disease — Rapidly progressive dementia, myoclonus, ataxia, periodic sharp waves on EEG, cortical ribboning on DWI

Diagnostic workup

Diagnostic algorithm

flowchart TD
  A[Cognitive complaint<br/>± informant concern] --> B[Cognitive screen<br/>MoCA / MMSE / Mini-Cog]
  B --> C{Impairment<br/>+ functional decline?}
  C -->|No, screen normal| D[Reassure, recheck<br/>in 6-12 mo]
  C -->|Cognitive but ADLs intact| E[Mild Cognitive<br/>Impairment]
  C -->|Yes| F[Dementia syndrome]
  F --> G[Reversible-cause<br/>workup + MRI]
  G --> H{Vascular,<br/>NPH, mass?}
  H -->|Yes| I[Treat underlying cause]
  H -->|No| J{Pattern}
  J -->|Insidious memory + temporoparietal atrophy| K[Probable AD]
  J -->|Fluctuating + hallucinations + parkinsonism| L[DLB]
  J -->|Behavioral / aphasic, age <70| M[FTD]
  K --> N[Cholinesterase inhibitor<br/>± memantine]
  K --> O[Anti-amyloid mAb<br/>if early AD + amyloid+]

Treatment

Complications

• Progressive functional dependence and institutionalization
• Wandering, falls, fractures
• Aspiration pneumonia (often terminal)
• Pressure ulcers, malnutrition, weight loss
• Caregiver burden and depression
• Polypharmacy and adverse drug events
• Driving and firearm safety concerns

PANCE pearls

• Memory loss alone does not equal dementia — must impair daily function. Memory loss with preserved function = mild cognitive impairment (MCI).
• Hallmark of AD memory loss is impaired storage (no benefit from cues), distinguishing it from subcortical or depression-related retrieval failure (which improves with cues).
• Always screen for reversible causes (TSH, B12, depression) and review medication list for anticholinergics.
• APOE4 testing is NOT recommended for routine diagnosis or risk prediction; it does inform ARIA risk before starting anti-amyloid therapy.
• Avoid restraints and antipsychotics for delirium superimposed on dementia when possible — address underlying medical cause first.
• Late-onset visual hallucinations without dementia in elderly with vision loss may be Charles Bonnet syndrome, not Alzheimer or DLB.

References

• AAN 2018 — Practice Guideline Update: Mild Cognitive Impairment (Petersen et al., Neurology 2018)
• NIA-AA 2011/2018 — Diagnostic Guidelines for Alzheimer's Disease (McKhann et al., Alzheimers Dement 2011; Jack et al., 2018 Research Framework)
• CLARITY-AD Trial — Lecanemab in Early Alzheimer's Disease (van Dyck et al., NEJM 2023)
• TRAILBLAZER-ALZ 2 — Donanemab in Early Symptomatic Alzheimer Disease (Sims et al., JAMA 2023)