3 Clinical psychopharmacology3.3 Pharmacodynamics
3.3.3.6 The Amyloid Cascade Hypothesis
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Written by Resident Doctor Committee · Published
The hypothesis
The amyloid cascade hypothesis places amyloid-beta accumulation first in Alzheimer's disease, with tau, glial and synaptic changes following from it.
Tau pathology is the main rival account of the first change.
Amyloid accumulates 15 to 20 years before symptoms, but tau and neuronal loss track symptom severity more closely.
Processing of amyloid precursor protein (APP)
Route | Cleavage | Product |
|---|---|---|
Non-amyloidogenic | Alpha secretase cuts inside the amyloid-beta sequence | No intact amyloid-beta |
Amyloidogenic | Beta then gamma secretase cut at either end of the sequence | Amyloid-beta, mainly 40 and 42 |
Beta secretase (BACE1) makes the cut without which no amyloid-beta forms, so inhibiting it lowers production at source as a disease-modifying target.
Amyloid-beta 42 aggregates more readily than amyloid-beta 40, and presenilins form the catalytic part of gamma secretase.
Pathogenic variants in APP, presenilin 1 and presenilin 2 cause autosomal dominant early-onset disease.
Where the pathology sits
Amyloid-beta collects in and around vessel walls and, failing to clear across them, damages the blood-brain barrier.
Tau normally stabilises microtubules but aggregates into tangles inside neurones.
Anti-amyloid treatment
Lecanemab is a passive anti-amyloid monoclonal antibody that binds soluble amyloid-beta protofibrils so they are cleared before plaque forms.
These antibodies have phase 3 evidence of slowing clinical decline only in Alzheimer's disease, where amyloid-beta is the upstream driver, not in vascular dementia.
BACE1 inhibitors lowered amyloid but gave disappointing efficacy and cognitive adverse effects.
Amyloid-related imaging abnormalities, which are oedema or haemorrhage, are commoner with APOE epsilon-4, especially in homozygotes, so treatment needs MRI monitoring.