WGS Study Identifies New Mutations Associated with Alzheimer’s

A recently published whole genome sequencing study has identified 13 mutations associated with Alzheimer's. The collaborative team from Massachusetts General Hospital, the Harvard T. H. Chan School of Public Health, and Beth Israel Deaconess Medical Center report these findings in Alzheimer's & Dementia: The Journal of the Alzheimer's Association.

"It was always kind of surprising that whole-genome screens had not identified Alzheimer's genes that are directly involved with synapses and neuroplasticity," says lead researcher Rudolph Tanzi. "This paper brings us to the next stage of disease-gene discovery by allowing us to look at the entire sequence of the human genome and assess the rare genomic variants, which we couldn't do before," says Dmitry Prokopenko, lead author.

In their quest to find rare AD gene variants, Tanzi, Prokopenko and their colleagues performed WGS analyses on the genomes of 2,247 individuals from 605 families that include multiple members who have been diagnosed with AD. They also analyzed WGS datasets on 1,669 unrelated individuals. The study identified 13 previously unknown rare gene variants associated with AD. Strikingly, these gene variants were associated with functioning of synapses, development of neurons, and neuroplasticity.

"With this study, we believe we have created a new template for going beyond standard GWAS and association of disease with common genome variants, in which you miss much of the genetic landscape of the disease," says Tanzi, who sees potential for their methods to be used to study the genetics of many other conditions. Moreover, he plans to use 'Alzheimer's in a dish'—three-dimensional cell culture models and brain organoids he and his colleagues have developed over the past decade—to explore what happens when the rare mutations this paper identified are inserted in neurons. "That could help guide us in novel drug discovery," says Tanzi.