In 1906, the German psychiatrist Alois Alzheimer presented a case at a meeting in Tübingen: Auguste Deter, age 51, with progressive memory loss, disorientation, paranoia, and eventually complete loss of recognition. At post-mortem her brain showed extracellular plaques between neurons and intracellular tangles within them. The talk was poorly attended; the paper barely noticed. A century later, Alzheimer's disease is the leading cause of dementia, affecting an estimated 55 million people worldwide, projected to triple by 2050, and despite thirty years of intensive pharmaceutical investment, the first disease-modifying drugs were approved only in 2023–24.
Alzheimer's accounts for 60–70% of dementias. Two pathological hallmarks define it: amyloid-β plaques (extracellular aggregates of aberrantly cleaved amyloid precursor protein) and neurofibrillary tangles (intracellular aggregates of hyperphosphorylated tau protein). The pathology spreads in a characteristic anatomical sequence — entorhinal cortex first, then hippocampus, then association cortices, eventually most cortical areas — and the clinical sequence matches: early episodic memory loss, then executive function, language, and visuospatial deficits, eventually global dementia. APOE-ε4 is the strongest common genetic risk factor (3–4× for heterozygotes, ~12× for homozygotes); GWAS has implicated dozens of other genes, many in immune and lipid pathways. Aging is the strongest risk factor of all (incidence roughly doubles every 5 years after 65), and the Lancet Commission on Dementia (2024) estimates ~45% of cases could be prevented or delayed by addressing modifiable factors — hypertension, diabetes, hearing loss, social isolation, low physical activity, depression.
The first disease-modifying drugs — aducanumab (2021, controversial), lecanemab (2023), donanemab (2024) — are anti-amyloid antibodies that clear plaques and produce modest slowing of clinical decline (~25–35% reduction in rate of progression over 18 months in early disease) at substantial cost ($26,000–$32,000/year) and with non-trivial side effects (ARIA — amyloid-related imaging abnormalities including brain swelling and microhemorrhages in 10–30% of treated patients). Whether these drugs are worth the cost and risk is being actively adjudicated; insurance coverage is limited and conditional. Anti-tau antibodies are in development; GLP-1 agonists (semaglutide) are being studied for prevention. The deep open question is whether modifying amyloid is enough — or whether the amyloid hypothesis, after thirty years, has finally been validated as causal but as only one component of a more complex disease.