Weill Cornell Medicine receives federal grant to study new gene therapy for Alzheimer's disease

The National Institute on Aging of the National Institutes of Health has awarded a five-year grant initially worth $8.37 million for Weill Cornell Medicine researchers to study a new gene therapy for Alzheimer's disease in people who have a high genetic risk of developing the condition. The research could garner nearly $14 million in total if prescribed milestones are reached for years three through five.

The grant will allow researchers to study a treatment for patients with apolipoprotein E4 (APOE4) gene variants inherited from both parents, a group known as APOE4 homozygotes. These people have up to a 15-fold increased risk of developing Alzheimer's, "and it occurs earlier and is more aggressive," said Dr. Ronald G. Crystal, principal investigator and chair of the Department of Genetic Medicine at Weill Cornell Medicine.

For the gene therapy, researchers are combining APOE2, a common variant that protects people from Alzheimer's, with APOE Christchurch, a rare and beneficial variant originally found in a family living in Colombia. People with the APOE Christchurch gene mutation are highly protected from the build-up of protein fragments called amyloid that clump together in the brain to form plaques, and tau protein, which forms tangles and interferes with the brain's function. This protection occurs even in people who have other gene mutations that would normally result in early-onset Alzheimer's disease.

"We thought if we added the APOE2 protective variant to the APOE Christchurch mutation that this would be a super potent protective therapy against APOE4," said Dr. Crystal, who is also the Bruce Webster Professor of Internal Medicine. Preclinical studies of mice with tau buildup and amyloid features of Alzheimer's disease received this combined gene therapy and experienced improved survival and fewer pathological signs of the disease.