How sharp centenarians dodge Alzheimer’s: two different kinds of protection

Alzheimer’s disease leaves two kinds of debris in the brain. Amyloid-beta clumps together into plaques between nerve cells. Tau, a protein that normally stabilises the inner skeleton of nerve cells, gets too many phosphate groups attached (it becomes p-tau) and forms tangles inside them. The leading theory, the amyloid cascade, says amyloid comes first and pushes tau to spread, and that tau spreading is what damages thinking.

Both become more common with age, yet some people reach 100 with a sharp mind. The 100-plus Study in Amsterdam follows centenarians who say they are cognitively healthy, tests them every year, and asks them to donate their brain after death. A new preprint analyses 112 of these brains.

What they did

The team measured how much amyloid and p-tau sat in nine small regions in and around the hippocampus, the memory hub of the brain, and compared these patterns with the centenarians’ last test results and with brains from people with Alzheimer’s disease and from people with “tau-only” changes typical of old age (called PART).

What they found

Everyone had some tau. All 112 brains had at least some p-tau. Reaching 100 apparently means carrying some, but that did not by itself mean decline.
Group 1: no amyloid build-up (44%). These centenarians had little or no amyloid spreading. They showed the pattern of normal old-age tau, not Alzheimer’s.
Group 2: amyloid, but tau held back (28%). Of the 56% with substantial amyloid, about half had tau spread into the regions next to the hippocampus as in Alzheimer’s. The other half did not: they carried the amyloid but resisted the spread of tau, and they kept their test scores up.
Tau, not amyloid, tracked with thinking. When both were considered together, more p-tau in the regions bordering the hippocampus went with worse memory and reasoning. Amyloid itself, once tau was taken into account, showed little link.
The affected group. Centenarians with an Alzheimer’s-like tau pattern (high amyloid and high tau) had clearly lower scores than the others.

What could protect them?

The study does not test mechanisms, but the authors point to genetic clues from their own and others’ work: a gene variant (APOE ε2) that is more common in centenarians and protects against amyloid, a variant of a gene called TMEM106B that they report protects against tau build-up (in papers not yet published), and rare mutations in families with inherited Alzheimer’s whose carriers had lots of amyloid but little tau.

What to keep in mind

This is a preprint and has not been peer-reviewed. The centenarians enrolled because they felt cognitively healthy, so they are a select group. Brain tissue shows the state at death only, and cognitive tests were done months before. The reference groups were small (7 and 11 people). And centenarians with little amyloid at death might have built up more if they had lived longer, as the authors note.

Why it matters

The results support the amyloid cascade but add an important twist: amyloid does not automatically lead to tau spreading and decline. If scientists can find out what holds tau back in these brains, it could lead to treatments for people who already have amyloid, a complement to drugs that try to remove amyloid itself.