Alzheimer’s disease

The two key hallmarks are amyloid plaques (clumps of beta-amyloid between cells) and neurofibrillary tangles of altered tau protein inside neurons. Neurodegeneration develops: connections break down, cells die and the brain atrophies. The hippocampus and entorhinal cortex — the memory areas — are affected first.

Broadly, a preclinical stage is distinguished (changes in the brain and biomarkers are present, symptoms are not), a stage of mild cognitive impairment due to Alzheimer’s disease, and dementia proper — mild, moderate and severe. Early symptoms: forgetting recent events, repeating questions, trouble with planning. The spread of tau pathology by Braak stages correlates with the severity of impairment more closely than the amount of amyloid.

The amyloid hypothesis (since 1992) proposes that the accumulation of beta-amyloid triggers the disease. Honestly about the disputed part: amyloid is also found in cognitively healthy people, the link between the number of plaques and the severity of symptoms is weak, and many anti-amyloid drugs have failed in trials. At the same time, the new antibodies (lecanemab, donanemab) do clear amyloid and modestly slow decline — this partly supports the hypothesis but does not rule out the role of tau and neuroinflammation.

The main factor is age; among genetic factors the APOE-e4 variant is significant. The modifiable factors largely overlap with the general dementia factors: hypertension, diabetes, obesity, physical inactivity, hearing loss, smoking, and also elevated homocysteine. Vascular health and physical and mental activity help lower the risk.