Genetics & Genomics

November 8, 2022

Alzheimer’s risk factor and cognition

Vanderbilt researchers found that a protein with roles in innate immunity worsens memory at baseline in carriers of APOE-e4, the strongest genetic risk factor for Alzheimer’s disease, further implicating neuroinflammation in cognitive decline.

A genetic variant of apolipoprotein E (APOE), a protein involved in fat metabolism, is the strongest common genetic risk factor for Alzheimer’s disease (AD) and contributes to worse cognition in older adults. However, many people who have the variant (APOE-e4) remain cognitively normal as they age, suggesting there may be neuroprotective modifiers of APOE effects. 

Mabel Seto, PhD, Timothy Hohman, PhD, and colleagues used whole blood RNA sequencing (RNAseq) data from 324 older adults to identify genes that modify the association between APOE-e4 and cognitive performance. 

They report in Neurobiology of Aging that higher expression of RNASE6, which has roles in innate immunity, was associated with worse memory at baseline among APOE-e4 carriers. The researchers replicated the findings in independent RNAseq data from the brain prefrontal cortex. 

RNASE6 has been previously observed in a gene network with other AD-related inflammatory genes. The findings add to studies implicating neuroinflammation in cognitive decline and suggest that data from blood can provide information about biological changes in the brain.

The current study uses data from the Vanderbilt Memory and Aging Project. Co-authors include Rebecca Weiner, Logan Dumitrescu, PhD, Emily Mahoney, Shania Hansen, Vaibhav Janve, PhD, Omair Khan, Dandan Liu, PhD, Yanling Wang, MD, PhD, Vilas Menon, PhD, Philip De Jager, MD, PhD, Julie Schneider, MD, David Bennett, MD, Katherine Gifford, PsyD, and Angela Jefferson, PhD. 

This research was supported in part by the National Institutes of Health (grants AG049164, AG046373, AG059941, AG059716, AG034962, HL111516, NS100980, AG056534, AG015819 OD023680, TR000445, TR002243) and the Vanderbilt Memory & Alzheimer’s Center.