New Genes and Variants Discovered to Contribute to Alzheimer’s Risk

What: Researchers have highlighted 11 genetic mutations that may predispose people to developing Alzheimer’s disease (AD) – including seven gene variants that have not been previously linked to AD.

Where: Teerlink CC et al., “Analysis of High-Risk Pedigrees Identifies 11 Candidate Variants for Alzheimer’s Disease,” Alzheimer’s & Dementia, 2021.

BrightFocus Connection: This project was supported in part by a 2020-22 Alzheimer’s Disease Research (ADR) postdoctoral fellowship to co-first author Justin Miller, PhD, formerly of Brigham Young University and now of the University of Kentucky. Senior author John S.K. Kauwe, PhD, of Brigham Young University–Hawaii has served on the BrightFocus ADR Scientific Review Committee.

Why It Is Important: Past research has shown that variants in more than 30 genes can contribute to the risk, severity, and progression of Alzheimer’s disease (AD). Some of these variants, (ie, genes with permanent changes in their DNA sequences, sometimes referred to as “mutations”) have shown up in multiple families with AD. But researchers estimate that many rare variants determining the course of AD still have to be discovered.

In this new study, Dr. Miller, Dr. Kauwe, and collaborators referenced the Utah Population Database, which includes genealogy and cause of death, as well as stored DNA. The researchers identified 19 high-risk families in which there was a high incidence of death from AD. They specifically focused on pairs of cousins who both had AD and looked for gene variants they had in common. Once they had identified those variants, they cross-referenced them with other databases with information for both healthy individuals and those with AD, which resulted in 11 variants that appear to be associated with a greater risk of AD.

Of those 11 variants, four—in the genes ABCA7, TTR, and NOTCH3—had previously been linked to AD. Reproducing those findings lends support to evidence showing these genes are involved in AD pathology. The remaining seven variants—in the genes PELI3, FCHO1, SNAP91, COX6A2, MUC16, and PIDD1—are rare enough that their connection to AD had not been observed before and may provide insight into increased mortality rate in high-risk individuals.

Identifying new genetic variants is exciting because the more that is known about the genetic risks for AD and how that translates into biological consequences, the better chance researchers and clinicians have to assess risk and reach an early diagnosis. Downstream studies can also begin to look at the signaling pathways and proteins associated with these genetic variants to better determine a mechanistic role in exacerbating AD pathology. These studies will ultimately result in more effective, personalized treatments.