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Study Links Gene Variant with Alzheimer’s Disease Resilience

Dr. Bekris’ team has found that Alzheimer’s disease resilience may be modulated by interactions between a TNFRSF1B gene variant and the protein sTNFR2.

04/27/2021



Cognitive resilience in Alzheimer’s disease (AD) may be influenced by interactions between variants of the gene TNFRSF1B and the soluble form of the protein TNFR2 (sTNFR2), according to a recent study published in Frontiers in Aging Neuroscience.

The findings point towards new disease-related biomarkers and drug targets for treating AD, which are both desperately needed as AD therapies remain elusive and the number of people living with dementia is greater than ever before.

Exploring the genetics of AD resilience

Resilience in AD refers to the phenomenon in which certain patients maintain relatively healthy cognition despite displaying hallmark AD-related brain changes, such as amyloid plaques and tau neurofibrillary tangles (caused by the buildup of the proteins beta amyloid and tau, respectively).

“If we can gain comprehensive understanding of the genetic and biological mechanisms governing resilience, we can take a big step towards developing therapeutics that promote resilience in those at risk for AD,” said Lynn Bekris, PhD, associate staff in the Genomic Medicine Institute and the study’s senior author.

Accumulating evidence suggests inflammation-related genes and pathways play important roles in AD development, but their potential contribution to resilience has not been fully explored. In this study, the researchers utilized data from 236 patients across two cohorts to investigate if resilience is impacted by TNFRSF1B and sTNFR2, which have been linked to inflammatory responses.

TNFRSF1B gene variant and related sTNFR2 influence AD resilience

The researchers analyzed how levels of sTNFR2 (encoded by TNFRSF1B) and two TNFRSF1B gene variants—rs976881 and rs1061622—affect three indicators of AD severity, including cerebrospinal fluid (CSF) biomarkers of neurodegeneration and tau; MRI measurements of hippocampal and whole brain volumes; and test scores measuring cognitive function.

“We found that the interaction between TNFRSF1B variant rs976881 and CSF TNFR2 levels modulates multiple severity markers and cognitive domains associated with Alzheimer’s disease,” said Jagan Pillai, MD, PhD, a neurologist in the Lou Ruvo Center for Brain Health at Cleveland Clinic and the study’s first author. “While further studies are warranted, our findings suggest that rs976881 could serve as a marker of resilience in AD and that sTNFR2 may be a prime drug target for AD therapies aimed at improving clinical outcomes.”

The researchers will next explore what might affect TNFR2 levels, with possible factors being comorbidities, the microbiome and diet.

The study was funded in part by the National Institute on Aging (part of the National Institutes of Health), Alzheimer’s Association, Keep Memory Alive Foundation, and the Jane and Lee Seidman Fund.




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