Gene Discovered Associated with Aging Brain Pathologies

Investigators have discovered a gene associated with susceptibility to the common Tau form of brain pathology that accumulates in several different conditions, including Alzheimer’s disease, certain forms of dementia, and Parkinsonian syndromes, as well as chronic traumatic encephalopathy that occurs with repeated head injuries. The gene and its product may serve as a marker for loss of brain function with advancing age, and as a potential drug therapy target.

In their study report, investigators at Rush University Medical Center (Chicago, IL, USA) and Brigham and Women’s Hospital (Boston, MA, USA) describe the identification and initial validation of a genetic variant within the gene for protein tyrosine phosphatase receptor-type delta (PTPRD).

“Aging leads to the accumulation of many different pathologies in the brain,” said co-principal investigator Dr. David Bennett, director of the Alzheimer Disease Center at Rush. “One of the most common forms of pathology is the neurofibrillary tangle (NFT) that was at the center of our study,” he said, “The NFT is thought to be more closely related to memory decline than other forms of aging-related pathologies, but there are still very few genes that have been implicated in the accumulation of this key feature.”

Using autopsies from 909 individuals participating in studies of aging based at Rush University, the team assessed the human genome for evidence that a genetic variant could affect NFT. “The variant that we discovered is common: Most people have one or two copies of the version of the gene that is linked to accumulating more pathology as you get older," said lead author Dr. Lori Chibnik, Brigham and Women’s Hospital, "Interestingly, tangles can accumulate through several different mechanisms, and the variant that we discovered appears to affect more than one of these mechanisms.”

The reported results also offer an important new lead as the field of neurodegeneration searches for robust novel drug targets, especially given the recent disappointing results in Alzheimer’s disease trials targeting amyloid, the other major form of pathology related to Alzheimer’s, for which there are currently no preventive therapies, only symptomatic treatments. Tau pathology is more closely connected to loss of brain function with advancing age and may be more impactful as a target. The advent of new techniques to measure Tau in the brains of living individuals with positron emission tomography (PET) could offer indication for therapies targeting Tau.

PTPRD is an intriguing new candidate that deserves further evaluation. “This study is an important first step," said Dr. De Jager, co-principal investigator at Brigham and Women’s Hospital, "However, the result needs further validation, and the mechanism by which the PTPRD gene and the variant that we have discovered contribute to the accumulation of NFT remains elusive. Other studies in mice and flies implicate PTPRD in memory dysfunction and worsening of Tau pathology, suggesting that altering the level of PTPRD activity could be helpful in reducing an individual’s burden of Tau pathology.”

The study, by Chibnik LB et al, was published online March 21, 2017, in the journal Molecular Psychiatry.