The “beginning of the end” for Alzheimer’s disease may be related to a woman who never had the disease.

As reported by the journal Sciencepublicizing a related study, despite a strong genetic risk, a woman who carried two copies of a rare genetic variant linked to late-onset Alzheimer’s called APOE3 Christchurch appeared resistant to the disease’s cognitive decline.

Now scientists have observed how mice with a similar set of genetic mutations responded to treatment for Alzheimer’s-like symptoms.

Similar to humans, the mice appeared to have fewer neurological defects associated with advanced stages of the disease, with a key factor being how the brain’s cleaning cells (microglia) respond to the disease’s pathology.

This gives new hope for developing Alzheimer’s treatments that focus on eliciting these specific responses.

The research team from the University of Washington School of Medicine says this answer helps break the link between early-stage Alzheimer’s without symptoms and late-stage cognitive decline.

Both the genetic – called autosomal dominant Alzheimer’s disease (ADAD) – and non-genetic forms of Alzheimer’s take about 30 years to develop.

There are no symptoms for the first 20 years or so as amyloid slowly builds up in the brain.

When amyloid levels in the brain reach a critical point, several destructive processes begin to work together.

A protein called tau begins to tangle and spread, slowing the brain’s metabolism and causing tissue to shrink, leading to cognitive decline.

“One of the biggest unanswered questions in the field of Alzheimer’s is why amyloid accumulation leads to tau pathology,” said neuroscientist David Holtzman.

“Any protective factor is very interesting because it gives us new information about how the disease works,” he added.

Several members of the Colombian woman’s family had been diagnosed with ADAD, with symptoms appearing in their 40s.

In the case of this particular family, the disease was caused by a mutation in a gene called presenilin-1, which is associated with an increased tendency to form amyloid plaques, with amyloid accumulation starting around the age of 20.

One member of the family achieved the seemingly impossible: She remained cognitively healthy into her 70s despite having inherited the presenilin-1 mutation. Those in her relatives who carried only one copy of APOE3ch still showed signs of cognitive decline at a younger age.

The 2019 study hypothesized that the woman’s extra mutations delayed the process by slowing the rapid spread of the tau protein.

“This woman’s case was very, very unusual because she had amyloid pathology but no tau pathology and very mild cognitive symptoms that came on late,” Holtzman explained.

But since this particular set of genetic mutations has been documented in only one person in the world, it was impossible to determine whether other factors were involved in her remarkable cognitive health. So Holtzman and his colleagues studied mice that had been genetically modified to produce excess amyloid and inserted a gene with the APOE3ch mutation. They then gave them intravenously a small amount of tau – which was expected to cause problems in brains already full of amyloid.

In the mouse models, as in the case of the Colombian woman, tau did not spread as expected. The reason was the microglia around the amyloid plaques were extremely active and efficient in clearing the protein.

“These microglia take up tau and degrade it before its pathology can effectively spread to the next cell,” explained the researcher.

“This blocked a large part of the downstream process – without tau pathology, we don’t have neurodegeneration, atrophy and cognitive problems,” he added.

The protective effects of APOE3ch are unclear in late-onset Alzheimer’s disease and could vary depending on a person’s ancestry or whether other genetic mutations are involved. This is an important area that needs further study, according to the team.