In a new study, a team of scientists led by senior author Cyril P. Pottier, an assistant professor of neurology and of psychiatry at WashU Medicine, successfully identified three new genetic modifiers of Alzheimer’s disease development and progression in individuals who carry known autosomal dominant Alzheimer’s disease mutations. Their findings were published in Lancet Neurology.
Previous studies had identified three key genes — amyloid precursor protein (APP), presenilin1 (PSEN1) and presenilin2 (PSEN2) — associated with dominantly inherited Alzheimer’s disease, as well as 279 variants in those genes that lead to Alzheimer’s disease. But it hasn’t been clear what drives differences in disease onset and progression among individuals with the same disease-causing variants.
Researchers, including first author Maulikkumar P. Patel, a postdoctoral research associate in the WashU Medicine Department of Neurology, analyzed genomic data from 101 carriers of autosomal dominant Alzheimer’s disease gene mutations who were already showing symptoms of Alzheimer’s disease. They found three genetic loci — specific chromosomal locations where particular genes are found — that were associated with earlier onset of Alzheimer’s disease symptoms and higher levels of tau proteins, which are linked to Alzheimer’s disease. The authors said the study may inform genetic counseling for affected families, guide design of clinical trials and help develop new treatments for preventing or slowing down Alzheimer’s disease in the larger population.
Importantly, these three loci were present in 27% of dominantly inherited Alzheimer’s disease mutation carriers, making them much more common than the extremely rare modifier variants — such as the Christchurch variant — that had previously been identified. In addition, the three loci were associated with higher Alzheimer’s disease risk regardless of which gene variant the individual had. These two factors could make the newly discovered loci more useful for future research and help individuals regardless of their Alzheimer’s disease gene mutation status.
Read more on the WashU Medicine Department of Neurology website.
Patel M, Feng W, Mckay NS, Millar PR, Liu M, Yang C, et al. Identification of genetic modifiers of autosomal dominant Alzheimer’s disease: a genome-wide association study. The Lancet Neurology, Jun 1, 2026. DOI: 10.1016/S1474-4422(26)00123-7
