A Novel Genetic Association for Tau Deposition in Older Adults

The following article is part of coverage from the American Academy of Neurology’s Annual Meeting (AAN 2020). Due to the global COVID-19 pandemic, the Academy made the necessary decision to cancel the meeting originally scheduled for April 25–May 1, 2020, in Toronto. While live events will not proceed as planned, readers can click here catch up on the latest research intended to be presented at the meeting.

Although tau deposition plays is an important role in the pathophysiology of Alzheimer disease, the heritable influences pertaining to the susceptibility and resistance to tau deposition are not fully understood. Results of a study intended to be presented at the annual meeting of the American Academy of Neurology (AAN 2020) led investigators to believe they have identified a novel genetic association for tau deposition, with resistance to entorhinal cortex (ERC) deposition, in older adults.

The availability of tau-positron emission tomography (tau-PET) has allowed for the testing for common genetic variants that have been postulated to be associated with ERC tau burden, which is considered to be a sensitive marker of early tau deposition. Using regional tau-PET and genome-wide genotype data from the population-based Mayo Clinic Study of Aging, researchers sought to identify the genetic factors that may be associated with tau deposition in older adults.

The study sample included 754 individuals over age 50 (mean age 72.4 years, 54.6% men, 87.4% cognitively impaired). Following genotyping with the Illumina GSA array and standard quality control, investigators identified 515,206 single nucleotide polymorphisms (SNPs) available for analysis. A genome-wide association study of ERC tau was carried out using an additive genetic model and covarying for age and sex. A post-hoc stratified analysis utilized amyloid positivity (global PiB>1.48) as a discriminator.

Investigators noted a genome-wide significant association for rs75546066, in an intergenic region on chromosome 9, with the minor allele (A, frequency = 2.7%) associated with lower ERC tau (P = 2.85×10-8; β = -0.49), and with a stronger effect in amyloidnegative (β = -0.51) vs amyloid-positive (β = -0.23) individuals.

No associations were observed for ERC tau burden in SNPs which define apolipoprotein E4, or for genotyped SNPs which were previously associated with Alzheimer disease. Three SNPs within microtubule-associated protein tau showed nominal associations to ERC tau burden, including rs3785883 (P = .04; β = 0.07); this was previously associated with higher cerebrospinal fluid tau in an independent cohort.

While results of this study highlight a novel genetic association for tau deposition, investigators believe it also suggested “tau deposition may have a genetic architecture distinct from known [Alzheimer disease] risk genes.” These findings have the potential to aid in enhanced risk prediction and therapeutic targeting for this population of older adults.

Reference

Ramanan V, Wang X, Przybelski S, et al. Genome-wide Association Study of Tau PET in the Mayo Clinic Study of Aging. Intended to be presented at the 2020 annual meeting of the American Academy of Neurology.

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