The National Institute on Aging has awarded Weill Cornell Medicine a five-year grant initially worth $8.37 million to develop a gene therapy aimed at people who carry two copies of the APOE4 gene variant, one from each parent. The award could reach nearly $14 million if the team meets specified milestones in years three through five.
APOE4 homozygotes face up to a 15-fold higher risk of Alzheimer's, and the disease tends to strike them earlier and progress more aggressively, according to Dr. Ronald G. Crystal, the study's principal investigator and chair of the Department of Genetic Medicine at Weill Cornell Medicine. That combination of high risk and early onset makes the group a logical target for a preventive approach rather than a treatment given after symptoms appear.
The therapy itself is a hybrid. Researchers are combining APOE2, a relatively common variant known to lower Alzheimer's risk, with APOE Christchurch, a rare mutation first identified in a Colombian family. Carriers of APOE Christchurch appear strongly shielded from the accumulation of amyloid plaques and tau tangles, even when they also carry mutations that would otherwise cause early-onset disease. Crystal's reasoning was that stacking the two protective variants might yield an especially potent counterweight to APOE4.
So far the evidence comes from animal work: mice engineered to develop tau and amyloid pathology survived longer and showed fewer disease-related changes in the brain after receiving the combined gene therapy. That is an encouraging starting point rather than proof of benefit in people, and the structure of the grant, with funding tied to milestones, reflects how much still has to be demonstrated before such a therapy could be tested clinically.