Alzheimer disease

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"Alzheimer disease"[MeSH Terms] AND treatment

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Alzheimer Disease

Overview

Alzheimer disease (AD) is the most common cause of dementia, accounting for approximately 70% of dementia cases in the United States. It is a progressive neurodegenerative disorder defined - since the 2018 NIA-AA research framework - biologically by the presence of both amyloid and tau pathology, separating the biological disease from the clinical syndrome. The disease was first described in 1906 by Alois Alzheimer, who identified the hallmark inclusions (amyloid plaques and neurofibrillary tangles) in a woman in her 50s with paranoia, memory loss, and aphasia.

Bradley and Daroff's Neurology in Clinical Practice, p. 2038
Adams and Victor's Principles of Neurology, 12th Edition

Epidemiology

Affects 11% of people aged 65 and older; 32% of those aged 85 and older
5.7 million Americans had AD dementia as of 2018; projected to reach 15 million by 2060
MCI is more common in men, but AD dementia prevalence is higher in women (partly due to longer lifespan)
Lifetime risk from age 45: ~10% in men, ~20% in women
Incidence rises sharply with age: 2 new cases/1,000 per year (age 65-74) to 37/1,000 (age 85+)

Cumulative Age-Specific Risk (Framingham Study):

Age Interval	AD Risk - Male	AD Risk - Female
65-80 years	6.3%	12%
65-100 years	25%	28.1%

Thompson & Thompson Genetics and Genomics in Medicine, p. 1555

Pathology and Pathogenesis

Hallmark Lesions

Amyloid (senile) plaques - extracellular deposits of amyloid-beta (Aβ), a 39-42 amino acid peptide derived from cleavage of the amyloid precursor protein (APP). Aβ aggregates into insoluble fibrils with characteristic beta-sheet secondary structure
Neurofibrillary tangles (NFTs) - intraneuronal aggregates of hyperphosphorylated tau protein; distributed in a stereotyped progression (Braak stages) from hippocampus/entorhinal cortex to association cortices

The Amyloid Cascade Hypothesis

The dominant hypothesis holds that Aβ deposition is the initiating event, triggering downstream tau pathology, synaptic failure, neuroinflammation, and neuronal loss. However, the relationship between plaques and tangles remains incompletely understood; tau PET studies suggest tau deposition in the inferior temporal and parietal cortices correlates more closely with cognitive impairment and cortical atrophy than amyloid alone.

Other proposed mechanisms include:

Abnormal calcium regulation
Neuroinflammation
Insulin signaling disruption
Cholesterol metabolism derangement
Aberrant cell-cycle reentry
Synaptic failure (the "synaptic failure hypothesis" - DeKosky and Scheff)

Cerebrovascular disease (lacunar infarcts, white matter disease) accelerates amyloid deposition and tangle formation, worsening dementia progression.

Adams and Victor's Principles of Neurology, p. 1073

Genetics

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

Three genes cause familial AD with onset in the 3rd-5th decade:

APP (chromosome 21) - encodes amyloid precursor protein; mutations increase Aβ42 production
PSEN1 (presenilin 1) - most common early-onset gene
PSEN2 (presenilin 2)

Sporadic / Late-Onset AD (>99% of cases)

Complex inheritance; no mendelian pattern but familial aggregation (λ ≈ 4). MZ twin concordance ~50%, DZ ~18%.

APOE ε4 - the Major Genetic Risk Factor

APOE gene has 3 alleles: ε2, ε3, ε4 (due to arginine/cysteine substitutions)
ε4 allele found 2-3x more frequently in AD patients vs. controls
Apolipoprotein E is a constituent of amyloid plaques and binds Aβ peptide
ε4 is a risk modifier, not a deterministic mutation
ε2 is potentially protective
Thompson & Thompson Genetics and Genomics in Medicine, p. 1572-1576

Clinical Features and Stages

Prodromal / Preclinical

Cognitive decline begins an average of 7.5 years before diagnosis
Biomarker abnormality alone (without cognitive symptoms) carries lower dementia risk than when cognitive deficits are present

Mild Cognitive Impairment (MCI)

Objective cognitive decline without significant functional impairment
Amnestic MCI (especially memory + one other domain) is the typical prodrome to AD

Dementia Due to AD

Characteristic neuropsychological profile:

Memory: Prominent anterograde amnesia; rapid forgetting; impaired recognition; intrusion errors; lack of primacy effect on word lists
Language: Paraphasias, anomia, semantic impairment
Visuospatial: Constructional dyspraxia, spatial disorientation
Executive function: Motor planning deficits
Anosognosia: Impaired insight into cognitive deficits (very characteristic)
Gradual, insidious onset; continuous progression

Atypical Phenotypes

Posterior Cortical Atrophy (PCA): Prominent early visuospatial deficits - simultanagnosia, optic ataxia, oculomotor apraxia (Balint syndrome), with relatively spared memory
Logopenic aphasia: Prominent word-finding deficits
Frontal/behavioral variant: Behavioral and executive changes predominating

DSM-5 Terminology

"Major neurocognitive disorder due to Alzheimer disease" - requires significant cognitive decline from a previous level interfering with everyday functioning.

Biomarkers and Diagnosis (AT(N) Framework)

The 2018 NIA-AA research framework defines AD biologically using three biomarker categories:

Category	Biomarker	Test
A - Amyloid	β-amyloid plaques	Decreased CSF Aβ42 or amyloid PET+
T - Tau	Neurofibrillary tangles	Elevated CSF phospho-tau or tau PET+
(N) - Neurodegeneration	Neuronal injury	MRI atrophy, FDG-PET hypometabolism

A+T+ = Alzheimer disease (biological)
A+T- = Alzheimer pathological change only
Definitive diagnosis historically required postmortem neuropathological examination

Updated appropriate use criteria for amyloid and tau PET were published in 2025 by the Alzheimer's Association (PMID: 39776249).

Neuropsychological Assessment

More sensitive than MRI for tracking disease progression. A full battery assessing verbal memory (word lists, stories), visual memory, naming, semantic memory, visuospatial abilities, and executive functions is recommended.

Treatment

Symptomatic Treatments

Cholinesterase Inhibitors (AChEIs)

Work by inhibiting acetylcholinesterase in the synaptic cleft, increasing acetylcholine availability. Effective for mild-to-moderate AD; donepezil is the only AChEI approved for severe AD.

Drug	Class	Dosing Notes
Donepezil	Reversible, piperidine-based	5-10 mg/day; near 100% oral bioavailability; long half-life
Rivastigmine	Pseudoirreversible carbamate	Also available as transdermal patch; inhibits both AChE and BuChE
Galantamine	Reversible; also allosteric nicotinic modulator	Extended-release once daily

Memantine (NMDA Receptor Antagonist)

Approved for moderate-to-severe AD
Blocks excessive NMDA receptor activation (excitotoxicity)
Not FDA-approved for mild AD (clinical trials showed lack of efficacy in mild subgroup), though widely used in practice
Commonly combined with a cholinesterase inhibitor

Disease-Modifying Therapies (Anti-Amyloid Monoclonal Antibodies)

This is the most significant recent development:

Lecanemab (Leqembi) - FDA approved January 2023 (full approval July 2023); also EU-approved April 2025. Given as IV infusion q2 weeks; targets soluble amyloid protofibrils. A subcutaneous weekly at-home maintenance formulation (Leqembi IQLIK) became available after 18 months of IV treatment.
Donanemab (Kisunla) - FDA approved July 2024; given as monthly IV infusions; targets aggregated amyloid; treatment can be paused/stopped after sufficient plaque clearance.

Both are indicated for early symptomatic AD (MCI or mild dementia) with confirmed amyloid pathology. Key safety concern: Amyloid-Related Imaging Abnormalities (ARIA) - edema (ARIA-E) or microhemorrhages (ARIA-H), requiring MRI monitoring. APOE ε4 carriers have higher ARIA risk.

The European Union and EU authorized both drugs in 2025 after re-examination procedures, as reported in a 2026 benefit-risk analysis.

Non-Pharmacological

A recent meta-analysis (PMID: 39797935) showed the Mediterranean diet is associated with reduced risk of cognitive impairment, dementia, and AD. Other modifiable risk factors include cardiovascular disease management, cognitive reserve building, sleep, and physical activity.

Differential Diagnosis

Other causes of dementia to exclude:

Lewy body dementia (parkinsonism, fluctuating cognition, visual hallucinations)
Frontotemporal dementia (behavioral/language changes, younger onset)
Vascular dementia (stepwise decline, focal deficits)
Normal pressure hydrocephalus (wet, wobbly, wacky triad)
Reversible causes: hypothyroidism, B12 deficiency, CNS infection, medications

An important new entity: LATE (Limbic-predominant Age-related TDP-43 Encephalopathy) - recently described and can mimic AD; 2025 clinical criteria were published (PMID: 39807681).

Prognosis

AD is uniformly progressive and ultimately fatal. Average survival after diagnosis is 8-10 years but ranges widely. Death typically results from aspiration pneumonia, urinary sepsis, or inanition.

Key Sources:

Bradley and Daroff's Neurology in Clinical Practice (primary neurology reference)
Adams and Victor's Principles of Neurology, 12th ed.
Kaplan & Sadock's Comprehensive Textbook of Psychiatry (pharmacological treatment)
Thompson & Thompson Genetics and Genomics in Medicine, 9th ed. (genetics)
PMID: 39776249 - Updated amyloid/tau PET appropriate use criteria (2025)
PMID: 39807681 - LATE clinical criteria (2025)
PMID: 39797935 - Mediterranean diet meta-analysis (2025)

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