Overview
Alzheimer's disease is the most common cause of dementia, a neurodegenerative brain disease that begins with memory loss and gradually erodes language, judgement and the ability to manage daily life. In 1906 the German psychiatrist Alois Alzheimer reported unusual plaques and fibrillary tangles in the brain of Auguste Deter, a woman in her fifties who had shown memory impairment and delusions, and published the case in 1907. With population ageing, the number of patients has grown sharply, making it a central public health issue.
Hallmark pathology
- Amyloid plaques: extracellular deposits of aggregated amyloid-beta (Aβ) peptide.
- Neurofibrillary tangles: inside neurons, tau protein, which normally stabilises microtubules, becomes hyperphosphorylated and tangled. Tau lesions start in the entorhinal cortex and hippocampus and spread to the neocortex, tracking cognitive decline closely.
- Loss of neurons and synapses: the hippocampus and cortex shrink and the acetylcholine system involved in memory is damaged, the rationale for existing cholinesterase inhibitor drugs.
- Neuroinflammation: activation of microglia and astrocytes also appears to contribute to progression.
How amyloid-beta is made
Amyloid-beta is produced when amyloid precursor protein (APP) in the neuronal membrane is cut in turn by beta-secretase (BACE1) and gamma-secretase. In 1984 Glenner and Wong first purified the protein and determined its amino acid sequence. The 42-amino-acid form, Aβ42, is especially prone to aggregate into oligomers and fibrils that eventually form plaques. Presenilins (PSEN1, PSEN2) are core components of gamma-secretase.
The amyloid cascade hypothesis
Hardy and Higgins (1992) proposed the amyloid cascade hypothesis: the accumulation of amyloid-beta is the primary cause of Alzheimer's disease and sets off a chain of events leading to tau pathology, neuronal dysfunction and death, and dementia.
- Genetic evidence: early-onset familial Alzheimer's is caused by mutations in APP, PSEN1 or PSEN2, all of which increase Aβ production or the proportion of Aβ42.
- Down syndrome: people with Down syndrome, who have an extra copy of chromosome 21 carrying the APP gene, very commonly develop Alzheimer pathology from middle age.
- APOE ε4: the strongest genetic risk factor for late-onset disease, thought to reduce the clearance of Aβ.
- Biomarkers: amyloid PET and cerebrospinal fluid or blood tests show Aβ changes a decade or more before symptoms, supporting the hypothesis.
Drug development and criticism
- Long record of failure: from the 2000s, BACE inhibitors, gamma-secretase inhibitors and several antibodies failed to slow cognitive decline in trials, fuelling scepticism.
- Anti-amyloid antibodies: in the phase 3 CLARITY AD trial, lecanemab slowed cognitive and functional decline in early disease by about 27% over 18 months, and the US FDA converted it to traditional approval on 6 July 2023; Korea's Ministry of Food and Drug Safety approved it in May 2024. Donanemab received FDA approval on 2 July 2024.
- Limitations: debate continues over whether the effect is clinically meaningful, along with amyloid-related imaging abnormalities (ARIA) such as brain swelling and microbleeds, high cost and the burden of infusions.
- Alternative hypotheses: tau, neuroinflammation, vascular and metabolic or insulin resistance hypotheses (links with metabolic syndrome) have been proposed, and many researchers see amyloid as necessary but not sufficient.
Prevention and care
Evidence is growing that managing risk factors such as hypertension, diabetes, physical inactivity, smoking, hearing loss and social isolation can lower dementia risk. Early diagnosis together with exercise, cognitive activity and social participation matters, linking to discussions of successful ageing.
References
- Alzheimer, A. (1907). Über eine eigenartige Erkrankung der Hirnrinde. Allgemeine Zeitschrift für Psychiatrie und psychisch-gerichtliche Medizin, 64, 146–148.
- Glenner, G. G., & Wong, C. W. (1984). Alzheimer's disease: Initial report of the purification and characterization of a novel cerebrovascular amyloid protein. Biochemical and Biophysical Research Communications, 120(3), 885–890.
- Hardy, J. A., & Higgins, G. A. (1992). Alzheimer's disease: The amyloid cascade hypothesis. Science, 256(5054), 184–185.
- Hardy, J., & Selkoe, D. J. (2002). The amyloid hypothesis of Alzheimer's disease: Progress and problems on the road to therapeutics. Science, 297(5580), 353–356.
- van Dyck, C. H., et al. (2023). Lecanemab in early Alzheimer's disease. New England Journal of Medicine, 388(1), 9–21.