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Gene variation may protect against Alzheimer’s disease

Brain images of a woman with an inherited condition that causes early-onset Alzheimer’s disease show high levels of amyloid plaques (top) but limited tau (bottom) for her age. Blue represents lowest levels and red represents highest. Arboleda-Velasquez et al., Nature Medicine

Alzheimer’s disease is the most common cause of dementia in older adults. Brain changes associated with the disease include abnormal clumps (amyloid-β plaques), tangled bundles of fibers (tau tangles), and the eventual death of nerve cells. These changes lead to a progressive decline in memory and thinking skills.

In the search for potential therapies, researchers have been studying known genetic causes of Alzheimer’s. Some rare forms of Alzheimer’s can be caused by variations in a single gene. These variants almost always cause symptoms by the time carriers reach middle age—several decades earlier than the typical age of onset of the most common form of the disease.

Researchers led by Drs. Yakeel Quiroz from Harvard Medical School and Francisco Lopera from the University of Antioquia have been studying an extended family in Columbia, South America who are affected by one such variant, in a gene called PSEN1. Of more than 6,000 people in the family, about 1,200 carry the Alzheimer’s-causing PSEN1 mutation.

With the exception of a single woman, all of the family members with the PSEN1 mutation have developed symptoms of mild cognitive impairment and Alzheimer’s dementia in their 40s. This woman didn’t develop any symptoms of cognitive decline until her 70s.

The woman volunteered to undergo comprehensive testing, including brain imaging and whole-genome sequencing, to look for possible protective factors. The study was funded in part by NIH’s National Institute on Aging (NIA), Office of the Director (OD), and National Institute of Neurological Disorders and Stroke (NINDS). Results were published on November 25, 2019, in Nature Medicine.

Brain imaging showed that the woman had high levels of amyloid-β plaques in her brain. However, she had low levels of tau tangles. She also had less damage to her brain than would normally be seen in people with Alzheimer’s.

Whole-genome sequencing revealed that she carried two copies of a rare variation in the gene APOE, called APOE3ch. Different variations of APOE have previously been linked to either protection from or increased risk of Alzheimer’s disease. In an analysis of 117 other family members, 6% had one copy of APOE3ch. But the single copy alone didn’t appear to provide protective effects.

The team performed further work to understand how two copies of APOE3ch might protect the brain. They found that the variation reduced the ability of the APOE protein to bind a type of sugar found on the surface of brain cells called heparan sulphate proteoglycans (HSPGs). This binding is thought to help tau tangles develop.

The researchers tested whether they could use this knowledge to protect cells that produce normal APOE. They made antibodies that targeted the region where the APOE3ch mutation is. These antibodies reduced the binding of normal APOE to HSPGs to levels seen with APOE3ch.

The findings suggest that therapies to reduce the binding of APOE and HSPG may be a potential way to treat or prevent Alzheimer’s disease.

“Sometimes close analysis of a single case can lead to discovery that could have broad implications for the field,” says NIA Director Dr. Richard J. Hodes.