Amyloid plaques

Amyloid plaques are extracellular deposits of misfolded beta-amyloid protein that accumulate in the brain decades before any cognitive symptoms appear. Along with tau tangles, they are the defining pathological feature of Alzheimer's disease, and were among the first abnormalities described by Alois Alzheimer in 1906.

What they're made of

The protein amyloid precursor protein (APP) is normally produced by neurons. In healthy brains, it is cleaved by enzymes into harmless fragments. In Alzheimer's, an alternative cleavage pathway produces a slightly longer fragment called beta-amyloid 42 (Aβ42), which is prone to clumping.

The clumps progress through stages:

1. Monomers: individual misfolded Aβ molecules
2. Oligomers: small soluble clumps. Increasingly suspected to be the most neurotoxic form.
3. Fibrils: long thread-like aggregates
4. Plaques: the final dense, insoluble deposits

Where they appear

Plaque deposition follows a stereotyped sequence. It begins in the basal cortical areas, spreads to allocortical and limbic regions including the hippocampus, and eventually involves the cerebellum and brainstem in the latest stages.

This pattern is captured by the Thal staging system at autopsy and by amyloid PET imaging in life.

How they're detected

In the past, plaques could only be confirmed at autopsy. In modern practice they can be detected in living patients by:

• Amyloid PET imaging using tracers like florbetapir, florbetaben, or flutemetamol that bind to plaques
• CSF biomarkers: low CSF Aβ42 (paradoxically, because the protein gets stuck in the brain instead of clearing into the CSF)
• Blood biomarkers: a rapidly maturing field, with plasma Aβ42/40 ratios approaching clinical utility

Why they matter therapeutically

Plaques have been the dominant target of Alzheimer's drug development for two decades. Recent monoclonal antibodies (lecanemab, donanemab) can clear amyloid plaques effectively, and produce modest but real slowing of cognitive decline in early Alzheimer's.

Whether amyloid is the cause of Alzheimer's or one of several drivers remains debated. Plaques can be present in the brains of cognitively normal older adults, and the correlation between plaque burden and symptom severity is imperfect.

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For broader context on how amyloid fits into Alzheimer's pathology, see our entries on dementia and Alzheimer's disease.