Rare genetic finding may help in search for Alzheimer's therapies

Being born with two copies of a rare genetic mutation may have staved off Alzheimer's disease for three decades in a woman at risk for an inherited early-onset form of the mind-robbing disease, U.S. researchers reported Monday, in a paper that could lead to new approaches to treatment.

The report in Nature Medicine describes a woman from a Colombian family whose members carry a gene called presenilin-1, which predisposes them to develop early-onset Alzheimer's, typically in their 40s, said study co-author Dr. Eric Reiman, executive director of the Banner Alzheimer's Institute in Phoenix, Ariz.

"In this case, the person didn't develop cognitive impairment for nearly 30 years after that," Reiman said.

The difference, scientists believe, is that the woman also carried two copies of a rare mutation in the APOE3 gene called APOE3 Christchurch. Scientists believe these mutations helped delay signs of cognitive decline until the woman was in her 70s.

It's well known that abnormal versions of two proteins, amyloid and tau, are involved in Alzheimer's disease. Amyloid forms plaques outside of brain cells, while tau forms tangles within the cells. Many drugs being studied to prevent dementia focus on removing amyloid, but this woman's case suggests tau might be the real culprit.

Presenilin-1 increases accumulation of amyloid, which was present in abundance in the brain of the woman in the study. "This is a person who has been overproducing amyloid since birth," Reiman said. But she had little tau clogging her neurons and she has remained cognitively intact far longer than other members of her family.

The two copies of APOE3 Christchurch apparently protected her mental abilities despite all the amyloid plaques, the researchers say.

The data suggests that APOE3 Christchurch blocks a crucial step that's thought to trigger tau accumulation and other toxic events leading to neurodegeneration and cognitive impairment, said co-author Yakeel Quiroz, director of the familial dementia neuro-imaging lab at Massachusetts General Hospital and Harvard Medical School in Boston.

The findings turn some of the Alzheimer's principles on its head, said Dr. Samuel Gandy, associate director of the Alzheimer's Disease Research Centre at the Icahn School of Medicine at Mount Sinai in New York City.

Those are: amyloid is the protein harming the brain and the importance of the APOE gene is in the APOE4 variation, which seems to speed the disease, Gandy said.

"This paper will cause an earthquake among those of us spending our lives trying to match up clinical manifestations with genetic mistakes," Gandy said in an email. "It's back to the drawing board for us."

Earlier studies had suggested tau protein might be the primary perpetrator in dementia, said Tamar Devora Gefen, a neuropsychologist and associate director of the clinical core of the Northwestern Alzheimer's Disease Centre in Chicago.

Most trials so far "focused on the obliteration of amyloid," Gefen said in an email. "This study, like many others, shifted its focus onto tau, which is a necessary step toward intervention discovery."

The study "is yet another example of the power of 'one' a single case study that has the potential to impact many," Gefen said.