Alzheimer disease (AD) is the most common neurodegenerative disease and the leading cause of dementia. Its pathology — extracellular β-amyloid plaques, intracellular neurofibrillary tangles of hyperphosphorylated tau, and progressive neuronal and synaptic loss — is the substrate of the clinical syndrome and the target of all modern AD therapeutics. The pathologic features were described by Alois Alzheimer in 1906; the molecular details have been worked out over a century since, and the years 2023 and 2024 brought the first FDA approvals of disease-modifying anti-amyloid antibody therapies — lecanemab (accelerated approval January 2023, traditional approval July 2023) and donanemab (approved July 2024) — that target amyloid plaques. This page covers AD pathology, staging systems, and the modern integrative framework.

The Pathologic Hallmarks

β-Amyloid Plaques

• Diffuse plaques: Aβ deposits without dense cores; early lesions, often in association cortex.
• Neuritic plaques (senile plaques): dense Aβ core surrounded by dystrophic neurites (degenerating axons and dendrites containing phospho-tau, ubiquitin), activated microglia, and reactive astrocytes. The classic “senile plaque.”
• Cored plaques: dense central core, characteristic on Bielschowsky silver and Aβ IHC.
• Composition: Aβ42 predominates in parenchymal plaques (vs Aβ40 in CAA).
• Distribution: cortex, hippocampus, basal ganglia, cerebellum (especially in genetic forms with strong CAA).

Neurofibrillary Tangles (NFTs)

• Hyperphosphorylated tau: paired helical filaments forming intracellular bundles in neuronal cytoplasm.
• Bielschowsky silver: classic stain; tangles appear as dense intracellular structures.
• Tau IHC (AT8 most common phospho-tau antibody): highly sensitive.
• Composition: both 3R and 4R tau isoforms (mixed tauopathy).
• Distribution: follows Braak staging (transentorhinal → entorhinal → hippocampus → limbic → neocortex).

Neuropil Threads

Hyperphosphorylated tau accumulating in dendrites and axons throughout the neuropil. Visible on tau IHC. Indicate widespread neurodegenerative process.

Granulovacuolar Degeneration

Small intracytoplasmic vacuoles containing dense granules, especially in CA1 hippocampal neurons. Associated with severe AD.

Hirano Bodies

Rod-shaped eosinophilic cytoplasmic inclusions in CA1 hippocampus. Common in aging and AD; sensitive but not specific.

Neuronal and Synaptic Loss

• Progressive neuronal loss in selectively vulnerable regions.
• Synaptic loss correlates more strongly with cognitive decline than plaque burden.
• Atrophy of hippocampus, entorhinal cortex, and association cortex; relative sparing of motor and primary sensory cortex.

Cerebral Amyloid Angiopathy

Aβ40 in vessel walls; coexists in 80-90% of AD cases. See CAA page.

Braak Staging of NFT Pathology

Thal Phases of Aβ Deposition

NIA-AA Criteria (2012, updated 2018)

The modern AD diagnosis is built from three measures:

• A: Aβ pathology (Thal phase). 0 (none) → 3 (Thal phases 1-2) → 4 (3-4) → 5 (5).
• B: Tau (Braak stage). 0 (none) → 1 (I-II) → 2 (III-IV) → 3 (V-VI).
• C: CERAD plaque score (neuritic plaque density). 0-3.

The combined “ABC” score generates the NIA-AA AD neuropathologic change rating (none, low, intermediate, high).

The Biological Definition (2018 update)

The 2018 NIA-AA framework redefined AD biologically, using the A/T/N (or A/T/N/V) framework based on biomarkers:

• A: Aβ (CSF Aβ42, amyloid PET).
• T: tau (CSF p-tau, tau PET).
• N: neurodegeneration (MRI atrophy, FDG PET, CSF total tau).
• V: vascular component.

This framework allows AD diagnosis during life based on biomarkers — and underlies the modern clinical trials that have produced anti-Aβ antibody therapies.

The 2024 Revised NIA-AA Criteria

The 2024 NIA-AA revised criteria for diagnosis and staging of AD (Jack et al., Nat Med, 2024) further codified the biological definition. They anchor AD diagnosis in validated core biomarkers (amyloid PET / CSF Aβ42-40 ratio / qualifying plasma assays; tau PET / CSF p-tau / qualifying plasma assays) and emphasize a unified biological framework that bridges research and clinical use more directly than the 2018 framework did alone. The 2024 criteria explicitly recognize that an individual can be biologically defined as having AD on the basis of biomarkers — independent of clinical syndrome — with separate clinical staging. The framework distinguishes:

• Neuropathologic assessment at autopsy: governed by NIA-AA “ABC” scoring of plaques, tangles, and neuritic plaques.
• Biological diagnosis during life: governed by the 2024 revised criteria, anchored in core biomarkers.
• Clinical syndrome staging: cognitive and functional severity, separate from biological diagnosis.

Genetic Forms of AD

Early-Onset Familial AD (< 5% of all AD)

• APP (amyloid precursor protein): chromosome 21; AD with prominent CAA.
• PSEN1 (presenilin 1): chromosome 14; most common cause; very young onset possible.
• PSEN2 (presenilin 2): chromosome 1.
• Down syndrome (trisomy 21): essentially universal AD pathology by age 40-50 due to APP gene dosage.

Late-Onset AD Genetics

• APOE4: most important risk allele. Heterozygous: 3-fold risk; homozygous: 12-15 fold; affects age of onset.
• APOE2: protective.
• TREM2, SORL1, ABCA7, CR1, BIN1, MS4A6A, CD2AP, EPHA1, CD33, CLU, PICALM: GWAS hits; each modest effect.

Clinical-Pathologic Correlations

• Typical AD: amnestic dementia with progression to language, executive, visuospatial impairment.
• Atypical AD presentations:
  • Posterior cortical atrophy: parieto-occipital predominant; Balint syndrome features, visuospatial deficits, alexia.
  • Logopenic primary progressive aphasia (lvPPA): temporoparietal AD pathology presenting as language disorder.
  • Frontal variant AD: behavioral, executive deficits initially; tau preference for frontal cortex.
  • Corticobasal syndrome: can be AD pathology in some cases.

Co-Pathology (Common in Older Patients)

Pure AD is uncommon in the elderly; mixed pathologies are the rule:

• AD + CAA: 80-90%.
• AD + cerebrovascular pathology (lacunes, microinfarcts): very common.
• AD + Lewy body pathology (limbic or neocortical Lewy bodies): 30-50%.
• AD + TDP-43 pathology (LATE — limbic-predominant age-related TDP-43 encephalopathy): 20-50% in late life.
• AD + hippocampal sclerosis of aging.
• AD + age-related tauopathy.

Mixed pathologies contribute to clinical heterogeneity and complicate trial interpretation.

Cellular Reactions in AD

• Activated microglia around plaques (visible on Iba1, CD68 IHC).
• Reactive astrocytes around plaques.
• Inflammatory cytokines locally elevated.
• TREM2-related microglial activation (variable across APOE genotypes).

Modern AD Therapeutics

• Symptomatic: cholinesterase inhibitors (donepezil, rivastigmine, galantamine); memantine.
• Disease-modifying (anti-Aβ antibodies):
  • Aducanumab (controversial; withdrawn 2024).
  • Lecanemab: approved 2023; modest cognitive benefit.
  • Donanemab: approved 2024; similar mechanism.
• ARIA monitoring: amyloid-related imaging abnormalities; risk increased with CAA, APOE4 homozygosity.
• Future approaches: anti-tau, microglial modulation, BTK inhibitors, anti-inflammatory.

🔍 Did You Know?

The 2024 approval of lecanemab and donanemab as the first disease-modifying therapies for Alzheimer disease marks a historic transition. For thirty years, AD treatment was symptomatic only — cholinesterase inhibitors and memantine modestly improving symptoms without affecting underlying disease. The new antibodies bind aggregated Aβ species (oligomers and protofibrils preferred by lecanemab; pyroglutamate-modified Aβ plaques by donanemab) and clear them from the brain. The clinical effect is modest — slowing decline by about 25-35% over 18 months — but it is real and disease-modifying. The treatment requires biomarker confirmation of AD (amyloid PET or CSF Aβ42/p-tau), monthly to bi-monthly infusions, and serial MRI surveillance for ARIA (amyloid-related imaging abnormalities — edema, microbleeds). The therapy is contraindicated in patients with significant CAA on screening MRI (multiple lobar microbleeds or cortical superficial siderosis) because of high ARIA risk. APOE4 homozygotes have higher ARIA rates and reduced efficacy. The era of AD therapeutics is fundamentally different now: neuropathology directly informs prescribing decisions, the diagnostic workup requires biomarker confirmation rather than just clinical syndrome, and family counseling about treatment is far more nuanced than the cholinesterase inhibitor era. Anti-tau therapies are now in trials, and microglial-targeted therapies (BTK inhibitors crossing the BBB) are emerging. The next decade will likely transform AD treatment as fully as the prior decade transformed our biomarker definition of the disease.

Pitfalls and Pearls

• AD = Aβ plaques + tau NFTs + neuronal loss + atrophy.
• Braak NFT staging: transentorhinal → entorhinal → hippocampus → limbic → neocortex.
• Thal Aβ phases: neocortex → allocortex → diencephalon → brainstem → cerebellum.
• NIA-AA “ABC” rating: A (Aβ), B (Braak tau), C (CERAD neuritic plaques).
• A/T/N biomarker framework: amyloid (CSF Aβ42, PET) + tau (p-tau, PET) + neurodegeneration (atrophy, FDG-PET).
• Aβ42 dominant in plaques; Aβ40 dominant in CAA.
• Tau is mixed 3R+4R in AD; 3R only in Pick, 4R only in PSP/CBD.
• APOE4: strongest genetic risk factor for late-onset AD.
• APP, PSEN1, PSEN2: autosomal dominant early-onset familial AD.
• Down syndrome: universal AD pathology by 40-50.
• Posterior cortical atrophy: atypical AD with visuospatial / Balint features.
• Logopenic PPA: AD pathology presenting as language disorder.
• Co-pathology is common: AD + Lewy + TDP-43 (LATE) + vascular + hippocampal sclerosis.
• Lecanemab, donanemab: anti-Aβ antibodies; biomarker confirmation required; ARIA monitoring.
• ARIA risk increased with CAA + APOE4 homozygosity: pre-treatment MRI screen mandatory.

References

1. Love S, Budka H, Ironside JW, Perry A, eds. Greenfield’s Neuropathology. 9th ed. CRC Press; 2015.
2. Braak H, Braak E. Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol. 1991;82(4):239-259.
3. Thal DR, Rüb U, Orantes M, Braak H. Phases of Aβ-deposition in the human brain and its relevance for the development of AD. Neurology. 2002;58(12):1791-1800.
4. 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.
5. van Dyck CH, Swanson CJ, Aisen P, et al. Lecanemab in early Alzheimer’s disease. N Engl J Med. 2023;388(1):9-21.
6. Sims JR, Zimmer JA, Evans CD, et al. Donanemab in early symptomatic Alzheimer disease. JAMA. 2023;330(6):512-527.