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A few people with partial resistance to ��������𾱳����’s disease are causing a rethink of the condition’s biological causes that could lead to new treatments.

Their experience suggests that a protein called tau, which builds up inside brain cells in people with ��������𾱳����’s, could be as crucial, if not more so, than the current chief suspect, a protein called beta-amyloid.

Drugs are in development that aim to reduce the memory loss and confusion of ��������𾱳����’s by lowering levels of amyloid, but their effects are very small – so small, in fact, they may not be approved for use in countries with more cost-conscious health services.

The people with partial resistance to ��������𾱳����’s are part of a community living in Colombia with high levels of a risky gene variant called PSEN1-280A, discovered in the 1980s. The variant is thought to have been introduced by a Spanish conquistador in the 17th century. Those with it live in an isolated region of the Andes mountains, spread across about 25 families.

The gene encodes an enzyme involved in making amyloid and people with one copy of the risky variant were thought to inevitably develop ��������𾱳����’s in their 40s.

But in 2019, a woman was discovered who, as well as carrying the harmful mutation, , which gave partial protection against what otherwise would have been her genetic fate of early-onset ��������𾱳����’s. Instead, she didn’t develop the dementia until her 70s.

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Now, while studying this Colombian community, at University Medical Center Hamburg-Eppendorf in Germany and his colleagues have found a second similar case: a Colombian man who carries both the harmful mutation PSEN1-280A and one copy of a different rare variant, called RELN-COLBOS. This also gave him partial protection, as he similarly developed ��������𾱳����’s in his 70s.

“Once may be chance, twice sounds like something different,” says Sepulveda-Falla. “There might be even more protected cases yet to be detected.”

Both the man and woman had extensive build-up of amyloid in their brain, as expected given they had PSEN1-280A, but their levels of tau were lower than is usually seen in ��������𾱳����’s – hinting that high tau is chiefly responsible for the symptoms of memory loss and confusion.

“Tau is more important [than amyloid],” says Sepulveda-Falla. “I think we have enough evidence to say it.”

The man also had a sister with both the harmful mutation and one copy of the newly discovered protective variant. She seems to have been slightly protected, as she had severe dementia when she was first evaluated at 64.

In separate research, the team found that a few people in the Colombian community have a single copy of the Christchurch protective mutation, as well as the risky ��������𾱳����’s variant, and they also seem to have a moderate delay of dementia onset, says Sepulveda-Falla.

Because the woman who had two copies of Christchurch had a long delay to her condition, “it seems this is pretty much a dose dependent effect”, he says. No further details are available on the separate research as it hasn’t yet been published.

The two protective gene variants affect tau in different ways. The damage to brain cells in ��������𾱳����’s is usually linked with a build-up of tau that has been chemically modified in a process called phosphorylation.

When the team gave the protective RELN-COLBOS gene variant to mice, it reduced their phosphorylation of tau.

Interestingly, while the woman with the Christchurch mutation had low levels of phosphorylated tau throughout her brain, the man with the RELN-COLBOS variant lacked phosphorylated tau in a small part of the brain called the entorhinal cortex. This is found on each side of the head, next to the hippocampi, the brain’s memory centres.

It is suspected that in the early stages of ��������𾱳����’s disease, .

“The fact that [the man] was able to delay the initiation of damage for 30 years with reduction in phosphorylation in this specific area is a very significant finding,” says at University College London.

Treatments called antisense oligonucleotides are in development that , says Fowler. “If we can only protect this one area seemingly that’s enough.”

at UK charity the ��������𾱳����’s Society says the findings support the idea that while amyloid is important among the condition’s causes, it isn’t the only factor. “Understanding this kind of resilience could highlight other future targets for drugs,” he says.