New Gene Variants Linked to Tau Deposits in Alzheimer's

Megan Brooks

March 09, 2020

TORONTO ― Novel gene variants associated with the development of tau deposits in the brain, a key biological feature of Alzheimer disease (AD), have been identified.

Investigator Vijay Ramanan, MD, PhD, behavioral neurology fellow, Mayo Clinic, Rochester, Minnesota, noted that this is the first genome-wide study of tau positron-emission tomography (PET) and that it identifies variations in DNA profiles associated with tau load in the brain.

"These early results represent an important step to better understanding why some individuals have a greater susceptibility to tau accumulation while others are more resistant," Ramanan told Medscape Medical News.

"As we learn more about that process, the longer-term hope would be to use that information to better predict who may become symptomatic from the disease and to develop targets for treatment based on those individualized profiles," he added.

The findings were released in advance of presentation at the upcoming American Academy of Neurology (AAN) 2020 Annual Meeting.

Genome-Wide Associations

The researchers assessed genetic profile and regional tau-PET data for 754 participants (mean age, 72.4 years; 54.6% men; 87% cognitively unimpaired) in the Mayo Clinic Study of Aging.

They found that individuals with novel genetic variants on chromosomes 1 and 5 had a higher amount of tau in their brains compared with their counterparts who had more typical gene sequences in those regions.

The genetic variants were found in 2% to 3% of the group, and those individuals had about 10% higher tau levels than patients who did not have the variants.

Specifically, investigators identified genome-wide significant associations with higher tau for rs76752255 in protein phosphatase 2 regulatory subunit B (PPP2R2B), an enzyme of the PPP2R2B gene on chromosome 5, and for rs115862481 in an intergenic region on chromosome 1. Each minor allele had a stronger association in amyloid-positive than amyloid-negative individuals.

In addition, three single-nucleotide polymorphisms (SNPs) within microtubule-associated protein tau (MAPT) genes displayed nominal associations to tau burden. These included rs3785883, which previously was found to be associated with higher levels of cerebrospinal fluid tau in an independent cohort.

However, no associations with tau burden were identified for the SNPs defining apolipoprotein E (APOE) ɛ4 or for genotyped SNPs previously associated with AD in large case-control studies.

"The fact that these variants are new, coupled with the lack of strong signal for tau in APOE, reinforces the concept that Alzheimer's disease is complex and that across patients, different sets of genes may be involved in entering into the AD pathway vs modifying its course or symptomatic expression," Ramanan said.

"Lots of exciting work is ongoing to try to disentangle those issues, and this study is a valuable step on that path," he added.

Ramanan said there is a great need for a better understanding of the factors that influence tau deposition, particularly since the burden and location of tau buildup in the brain are closely related to cognitive symptoms of AD.

He noted that the approach of "imaging genetics" ― using brain scans that capture disease biomarkers and connecting those with data on the genome to improve knowledge about risk and treatment targeting ― has been growing. However, only recently has it become possible to apply that framework to tau.

Ramanan emphasized that replication studies and functional characterization of these novel genetic findings are needed.

"Distant" Clinical Implications

Commenting on the study for Medscape Medical News, Howard Fillit, MD, founding executive director and chief science officer of the Alzheimer's Drug Discovery Foundation, said that there is currently "a fair amount of this kind of work going on" in assessing polygenetic risk in AD. This includes examining APOE as well as "a whole bunch of other genes" associated with the disease.

"Far and away, the APOE genetic association with Alzheimer's risk is the most powerful one. In and of themselves, none of these other risk genes cause Alzheimer's disease, they only contribute to risk," Fillit noted.

"This study found some new genes that were associated with susceptibility to tau deposition, but at the end of the day, they are just associations. They don't prove causality," he added.

"It's interesting, but really hard to know what to conclude from it; and the clinical implications, I think, are rather distant," Fillit concluded.

The study was supported by the National Institutes of Health; the Gerald and Henrietta Rauenhorst Foundation; the Alexander Family Alzheimer's Disease Research Professorship of Mayo Clinic; the Mayo Foundation for Medical Education and Research; a Liston Award; the Elsie and Marvin Dekelboum Family Foundation; the Schuler Foundation; and Avid Radiopharmaceuticals, which supplied the imaging agent used by researchers to detect tau in the brain. Ramanan and Fillit have reported no relevant financial relationships.

American Academy of Neurology (AAN) 2020 Annual Meeting: Abstract 4055. To be presented in April 2020.

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