A unique genetic variation in the MAPT gene was associated with an increased risk of Pick’s disease, a rare form of frontotemporal dementia, according to a recent study published in The Lancet Neurology.  

Tamar Gefen, ‘15 PhD, ‘12 MS, assistant professor of Psychiatry and Behavioral Sciences in the Division of Psychology, was a co-author of the study.  

Pick’s disease is defined by the presence of abnormal substances, called Pick bodies, in the frontal and temporal lobes of the brain. The disease causes stark changes in a patient’s behavior and personality while other cognitive abilities such as memory are unaffected.  

Currently, the disease can only be officially diagnosed by analyzing post-mortem brain tissue and, therefore, has remained understudied.  

“It can often be misdiagnosed as a psychiatric disorder, but really what is happening is that Pick’s disease is targeting the parts of the brain responsible for controlling and regulating our personality and personhood,” Gefen said.  

Pick bodies are composed of specialized tau proteins encoded by the MAPT gene. The MAPT gene contains two haplotypes or sets of closely linked DNA variations that were inherited together: H1 and H2. 

Previous work has established the MAPT H1 haplotype as a major genetic risk factor for certain tauopathies, or neurodegenerative disorders characterized by the accumulation of abnormal tau protein.  

In the current study, the investigators aimed to understand the association of the MAPT H2 haplotype with Pick’s disease risk, age onset and disease duration. The team performed their analysis using data from the Pick’s Disease International Consortium, which was established to enable the collection of data from individuals with Pick’s disease worldwide.  

Specifically, the investigators collected brain samples from 338 patients with Pick’s disease (61 percent male and 39 percent female; 100 percent white) from 35 brain banks and hospitals in North America, Europe and Australia between January 2020 and January 2023. More than 1,300 neurologically healthy controls (47 percent male and 53 percent female; 100 percent white) were also recruited from the Mayo Clinic between March 1998 and Sept 2019.  

Brain samples and patients were then genotyped for the MAPT H1 and H2 haplotype-defining variant rs8070723. Next, the investigators genotyped and constructed the six-variant-defined MAPT H1 sub-haplotypes (rs1467967, rs242557, rs3785883, rs2471738, rs8070723 and rs7521).  

From their two-part analysis, the investigators discovered that the MAPT H2 haplotype was associated with an increased risk of Pick’s disease compared with the H1 haplotype in patients of European ancestry. However, the H2 haplotype was not associated with age onset or disease duration.  

According to Gefen, the current findings are groundbreaking because they may directly lead to earlier and more accurate diagnoses and inform the development of new genetically-based therapeutics for patients.  

“One element to this study worth highlighting is that it took an international consortium from around the world to collect enough brain samples from the generous brain donation of participants. The Mesulam Center that houses the NIA-funded Northwestern Alzheimer’s Disease Research Center holds one of the largest clinically characterized cohorts of individuals with Pick’s disease. What an honor it was to contribute so substantially to this work, the outcome of which has a direct impact on patients’ lives,” Gefen said.  

The work was supported by the Wellcome Trust, Rotha Abraham Trust, Brain Research UK, the Dolby Fund, Dementia Research Institute (Medical Research Council), the U.S. National Institutes of Health, and the Mayo Clinic Foundation.