Preprint: two distinct biological pathways protect cognitively intact centenarians from Alzheimer's disease, a study of 112 brains finds
Preprint: two distinct biological pathways protect cognitively intact centenarians from Alzheimer's disease, a study of 112 brains finds
Researchers at Amsterdam University Medical Centers examined brain tissue from 112 people who lived past 100 with their cognition intact. They posted their results on 21 September as a preprint, a paper that has not yet undergone peer review. Preserved cognition at that age, their data suggest, can arise through two fundamentally different scenarios of what happens inside the brain.
In Alzheimer's disease, a protein called amyloid-beta first accumulates in the brain, clumping into plaques between neurons. Then a second protein, tau, deposits inside neurons and gradually destroys them, which is what impairs memory. The standard model treats amyloid as the trigger: amyloid sets tau in motion, and tau then strikes the hippocampus and neighboring regions of the temporal lobe that support memory.
The team led by Henne Holstege has been running the Amsterdam 100-plus Study since 2013. In 2025 they showed that roughly two thirds of cognitively intact centenarians accumulate very little amyloid, which accounts for their preserved cognition. But about a third carried amyloid loads comparable to those seen in Alzheimer's patients, and some of them still retained good memory. That group became the focus of the new study.
The authors divided the 112 brain donors into groups: 44% had accumulated almost no amyloid, while 56% had amyloid loads typical of Alzheimer's disease. To make sense of the second group, the researchers first tested a marker that, in younger people, clearly separates Alzheimer's disease from the harmless age-related accumulation of tau without amyloid: the ratio of tau between two adjacent hippocampal subregions. In centenarians, that ratio drew no distinction. The team then mapped tau across nine regions of the medial temporal lobe and found the separation in the presubiculum, the entorhinal cortex, and the fusiform gyrus, all adjacent to the hippocampus. In half of the high-amyloid individuals (28% of the full sample), tau had spread into these regions in a pattern matching Alzheimer's disease, and their memory scores were worse. In the other half (also 28%), amyloid levels were just as high, but tau had barely reached those regions, and their cognition remained as sharp as in people who had no amyloid at all.
A finer classification (available for 107 of 112 donors) revealed an even more varied picture: 39% fit neither the Alzheimer's nor the aging pattern of tau, and in some individuals with high amyloid, tau behaved as it does in harmless aging. Both scenarios can coexist in a single brain. Cognition in people with the aging and resilient tau patterns was notably higher than in those with the Alzheimer's and mixed patterns (p=0.004). A regression adjusting for tau confirmed the same finding: the association between amyloid and memory nearly disappeared, while the association with tau persisted. The risk, in other words, comes not from amyloid itself but from its ability to trigger tau specifically in these regions.
An earlier finding from the same cohort already hinted at a mechanism: the HLA-II variant Hap-B was associated with less pronounced tau pathology independently of amyloid.
A similar case has been reported before: a 115-year-old Dutch woman whose brain was examined after death showed almost no amyloid and none of the structural damage characteristic of dementia, although some tau was present. The new study shows that her case represents one of two routes to preserved cognition at extreme age.
The study itself is a statistical snapshot of postmortem brains: the authors compared pathology to each donor's last cognitive assessment, which had been administered on average nine months before death. The authors see in their findings a basis for two protective strategies: some interventions could aim to prevent amyloid accumulation, while others could block amyloid's ability to trigger tau in people who already carry it.