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Genetic clues found for cognitive resilience to Alzheimer’s disease

Three genetic variants may be associated with cognitive resilience in Alzheimer’s disease, according to the results of a large, genome-wide association study (GWAS). The study, funded in part by NIA, identified novel genetic variants, genes and biological pathways that are associated with cognitive resilience, or protection, from memory and thinking issues connected to Alzheimer’s disease despite the presence of neuropathology in the brain. Notably, the researchers did not see a connection between cognitive resilience and the genetic variations in the APOE gene that are associated with a higher risk of developing Alzheimer’s. The findings, published in Brain, provide new insights into the biology of cognitive resilience and may suggest new pathways and targets for development of Alzheimer’s treatments.

Older woman sitting at a desk holding a hardcover book.In the Alzheimer’s brain, abnormal levels of the naturally occurring protein, beta-amyloid, clump together to form plaques that collect between brain nerve cells and interfere with cell function. However, about 30% of people with significant amyloid plaque buildup do not develop the memory and thinking problems associated with Alzheimer’s disease. Researchers do not yet understand the biology behind this cognitive protection.

To learn more about genetic factors linked to cognitive resilience in Alzheimer’s disease, a team led by researchers at Vanderbilt University Medical Center conducted a GWAS study. GWAS is a research approach that connects DNA differences, called genetic variations, in a group of people with a certain disease or trait. Genetic variants may increase or decrease a person’s risk of developing a particular disease.

Using DNA samples from a past clinical trial on Alzheimer’s disease and three studies on aging and cognition, the scientists scanned complete sets of DNA, or genomes, from more than 5,100 people. The study data included amyloid brain scans, autopsy, and cognition test results. For each person, the scientists compared the amount of amyloid plaque present and the cognitive test results to develop a measurement of resilience. Next, they looked for genetic patterns in the DNA of the people with high resilience scores.

Three genetic variants linked to cognitive resilience were identified near the ATP8B1 gene. This gene makes a protein that helps with liver metabolism, the process of breaking down fats to produce energy for the body. While more research is needed to determine whether the ATP8B1 gene is responsible for resilience, the researchers saw some signs to suggest that lower levels of this protein in the brain and liver may confer cognitive resilience.

The scientists also found that the level of resilience — whether it was high or low — was associated with genetic patterns for traits related to levels of education, cardiovascular disease risk, and some mental health disorders, such as obsessive-compulsive disorder. For example, people with a genetic risk for smoking and a younger age of starting smoking had lower cognitive resilience. Whereas people with genetic traits linked to higher levels of education showed higher cognitive resilience.

This study provides important new insights into the genetics and biological factors that protect some people from the cognitive symptoms of Alzheimer’s disease and may inform new approaches for treatments. While this was the largest GWAS study to date on cognitive resilience to Alzheimer’s disease, additional studies are needed with more racial and economic diversity to better reflect the general population.

This research was supported in part by NIA grants F31-AG059345, K01-AG049164, K24-AG046373, K99-AG061238, P30-AG010161, R01-AG003949, R01-AG017216, R01-AG018023, R01-AG025711, R01-AG032990, R01-AG034962, R01-AG046171, R01-AG056534, R01-AG057914, R01-AG059716, R01-AG15819, R01-AG17917, R01-NS100980 R13-AG030995, R21-AG05994, RF1-AG051550, P30-AG19610, P50-AG005136, P50-AG016574, U01-AG006576, U01-AG006786, U01-AG024904, U01-AG032984, U01-AG046139, U01-AG046152, U01-AG061356, U01-AG006781, U24-AG041689, and 3U01-AG024904-09S4.

These activities relate to NIA's AD+ADRD Research Implementation Milestone 2.S, “Determine interrelationships among cerebro- and cardiovascular disease, VCID risk factors, aging, resilience, genetics, amyloid, tau, and neurodegeneration including along the life course.”

Reference: Dumitrescu L, et al. Genetic variants and functional pathways associated with resilience to Alzheimer's disease. Brain. 2020;143(8):2561-2575. doi: 10.1093/brain/awaa209.