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categories: ["longevity", "foundations"]categories: ["longevity", "foundations"]tags: ["dementia", "neurodegeneration", "amyloid", "tau", "aging", "brain", "apoe"]tags: ["dementia", "neurodegeneration", "amyloid", "tau", "aging", "brain", "apoe"]summary: "The neurodegenerative disease responsible for most dementia, driven above all by age, and the disease that decides whether added years of life come with a working mind."summary: "The neurodegenerative disease responsible for most dementia, driven above all by age, and the disease that decides whether added years of life come with a working mind."updated: "2026-08-23"updated: "2026-10-28"humanEvidence: "Two anti-amyloid antibodies slowed cognitive decline by roughly a quarter to a third over 18 months in phase 3 trials; no treatment has stopped or reversed the disease in people."humanEvidence: "Two anti-amyloid antibodies slowed cognitive decline by roughly a quarter to a third over 18 months in phase 3 trials; no treatment has stopped or reversed the disease in people."issues: ["Tau-directed therapeutics and non-amyloid drug programmes are mentioned only in passing."]issues: ["Tau-directed therapeutics and non-amyloid drug programmes are mentioned only in passing."]------lines 48–53 → 48–5534 unchanged lines not shown
## Plaques, tangles, and the amyloid hypothesis## Plaques, tangles, and the amyloid hypothesis Alois Alzheimer described the disease from a single autopsy: Auguste Deter, who died in 1906 in her mid-fifties after five years of progressive memory loss and delusions, and whose cortex showed the plaques and neurofibrillary tangles that still define the diagnosis.[^alzheimer1907] The plaques are aggregates of amyloid-β, a peptide cleaved from the amyloid precursor protein; the tangles are hyperphosphorylated tau. Both are misfolded-protein assemblies that spread between cells in a templated, prion-like manner, which is why the disease is read as the clinical face of [[proteostasis]] failure. Around that core sit most of the other [[hallmarks-of-aging]]: chronically activated microglia tie the disease to [[inflammaging]], senescent glia accelerate pathology in mice, and disturbed [[sleep-and-longevity|sleep]] precedes diagnosis by years. Whether the adult hippocampus makes new neurons at all is the dispute covered under [[stem-cell-exhaustion]].Alois Alzheimer described the disease from a single autopsy: Auguste Deter, who died in 1906 in her mid-fifties after five years of progressive memory loss and delusions, and whose cortex showed the plaques and neurofibrillary tangles that still define the diagnosis.[^alzheimer1907] The plaques are aggregates of amyloid-β, a peptide cleaved from the amyloid precursor protein; the tangles are hyperphosphorylated tau. Both are misfolded-protein assemblies that spread between cells in a templated, prion-like manner, which is why the disease is read as the clinical face of [[proteostasis]] failure. Around that core sit most of the other [[hallmarks-of-aging]]: chronically activated microglia tie the disease to [[inflammaging]], senescent glia accelerate pathology in mice, and disturbed [[sleep-and-longevity|sleep]] precedes diagnosis by years. Whether the adult hippocampus makes new neurons at all is the dispute covered under [[stem-cell-exhaustion]]. Sleep and pathology may be connected through [[glymphatic-system|glymphatic]] clearance, the flow of cerebrospinal fluid along the spaces around blood vessels that mouse studies suggest carries amyloid-β and tau out of brain tissue. Its impairment is a hypothesised contributor to their accumulation, not an established one: how much bulk flow occurs is itself disputed, and the human evidence is indirect. In a 2026 *Science Advances* study, Liu and colleagues reported that ten-minute daily sessions of 40.68 MHz ultrashort-wave stimulation, a form of [[non-invasive-neuromodulation|non-invasive neuromodulation]], increased glymphatic flow in 5×FAD Alzheimer's model mice over a week, with less amyloid-β staining and better scores on two memory tests than untreated mice. The result is confined to mice. The field's organizing idea, stated by Hardy and Higgins in 1992, is the amyloid cascade hypothesis: amyloid-β accumulation is the initiating event, and tau pathology, inflammation, synapse loss, and dementia follow downstream.[^hardy1992] The strongest evidence has always been genetic. The hypothesis's persistent embarrassment is anatomical: tangle burden tracks symptoms far better than plaque burden does, and a substantial minority of cognitively normal older people carry a plaque load that would support a diagnosis.The field's organizing idea, stated by Hardy and Higgins in 1992, is the amyloid cascade hypothesis: amyloid-β accumulation is the initiating event, and tau pathology, inflammation, synapse loss, and dementia follow downstream.[^hardy1992] The strongest evidence has always been genetic. The hypothesis's persistent embarrassment is anatomical: tangle burden tracks symptoms far better than plaque burden does, and a substantial minority of cognitively normal older people carry a plaque load that would support a diagnosis. removed, struck through added, underlinedLine numbers count the serialised markdown of each revision, frontmatter included.
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