Alzheimer's Disease

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, those two lesions still anchor the dominant theory of the disease — the amyloid hypothesis — and the disease itself has become the leading cause of dementia, affecting an estimated 55 million people worldwide, projected to triple by 2050. The damage begins quietly, in the memory circuits of the hippocampus, years before a diagnosis is possible — and for most of the intervening century the diagnosis could be confirmed only at autopsy, by finding the very plaques and tangles Alzheimer had drawn. 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 amyloid hypothesis — that plaque accumulation is the initiating event from which tangles, neuronal death, and dementia follow — has organized the field since the 1990s, yet it has had a punishing history: dozens of drugs that lowered amyloid failed to slow patients' decline, and a celebrated 2006 Nature paper identifying a specific soluble amyloid species as a memory toxin was found in 2022 to rest on apparently doctored images and was eventually retracted, casting doubt on a line of work that had shaped a generation of research and steered hundreds of millions of dollars in funding. The pathology spreads in a characteristic anatomical sequence — entorhinal cortex first, then hippocampus, then association cortices, eventually most cortical areas — which is why the earliest, most telling damage falls on the hippocampus, the brain's hub for forming new memories, so the first clinical sign is typically the loss of recent events while older ones persist. The clinical sequence matches the spread: early episodic memory loss, then executive function, language, and visuospatial deficits, eventually global dementia and loss of independence over a course that often runs eight to ten years. 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.