Gene Variant May Influence Alzheimer's Disease Risk

A variation in the PTPRD gene may increase the creation of neurofibrillary tangles in the brain.

Many studies have shown a link between the accumulation of the Tau protein in the brain and Alzheimer’s disease, dementia, Parkinson’s disease, and chronic traumatic encephalopathy.

In a new study published by Molecular Psychiatry, the authors discovered and validated a variant of the protein tyrosine phosphatase receptor-type delta (PTRD) gene. The study focused on the neurofibrillary tangles (NFT), which occur in the brains of patients with Alzheimer’s and other neurodegenerative diseases.

“Aging leads to the accumulation of many different pathologies in the brain, and one of the most common forms of pathology are NFT,” said co-principal investigator David Bennett, MD.“The NFT is more closely related to memory decline than other forms of aging-related pathologies, so understanding the genetics behind it is crucial to fighting these illnesses, but there are still very few genes that have been implicated in the accumulation of this key feature of Alzheimer’s disease and other brain diseases.”

While symptomatic treatments for Alzheimer’s disease exist, there is no option that can prevent or even slow disease progression.

In the study, the authors examined brain tissue samples from 909 deceased patients with varied levels of cognitive ability. Patients included had very high functioning to moderate-to-severe dementia, with nearly two-thirds diagnosed with Alzheimer’s disease.

In patients with Alzheimer’s disease, the authors examined their genomes in search of a variant that may influence NFT, and discovered the PTRD variant, according to the study.

“We found that this variant is the second strongest variant associated with NFT after the widely-known APOE variant,” Dr Bennett said.

The authors were able to confirm their findings in another study that included 369 brains.

“The variant that we discovered is common: Most people have 1 or 2 copies of the version of the gene, which is linked to accumulating more pathology as you get older," said lead author Lori Chibnik, PhD, MPH. "Interestingly, tangles can accumulate through several different mechanisms, and the variant that we discovered appears to affect more than one of these mechanisms.”

These findings offer novel leads in the search for targeted treatments, which are needed due to the negative results from trials of drugs targeting amyloid beta in Alzheimer’s disease, according to the study.

Since Tau is closely related to cognitive decline experienced with age, it may present an effective treatment option. Additionally, new methods used to measure Tau in living patients using PET scans offers a biomarker, which can be used to guide the use of Tau-targeting drugs, according to the study.

“This study is an important first step. However, the result needs further validation, and the mechanism by which the PTPRD gene and the variant in it that we have discovered contribute to the accumulation of NFT remains elusive,” said co-principal investigator Philip De Jager, MD, PhD. “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.”