A study published in The Lancet Neurology found that a MAPT genetic variant is associated with an increased risk of an FTD tau pathology called Pick’s disease. This MAPT gene variant is incidentally associated with a decreased risk of a different FTD pathology.  

Pick’s Disease Driven by Three-Repeat Tau Dysfunction 

While originally used to refer to FTD disorders, the term “Pick’s disease” is now used to refer to a specific form of FTD pathology comprised of abnormal tau protein. Normally, three-repeat (3R) tau helps stabilize vital structures in neurons called microtubules, though in Pick’s disease, they form abnormal accumulations called “Pick bodies” that can drive neurodegeneration. Pick bodies are most commonly associated with behavioral variant FTD, though they can less commonly be found in other FTD-tau disorders like corticobasal syndrome (CBS).  

Tau is encoded by the MAPT gene, and variations in this gene are associated with tau dysfunction and FTD. However, the authors note that different “haplotypes” (groups of DNA variants inherited from a single parent) are associated with different risk levels. For example, the haplotype MAPT H1 is associated with an increased risk of 4R tauopathies like progressive supranuclear palsy (PSP). The other major MAPT haplotype, H2, is associated with a decreased risk of 4R disorders – however, the authors note that this has not been confirmed for Pick’s disease and 3R disorders.  

As noted by the authors, Pick’s disease is understudied, with an unclear genetic cause as a result. Due to the rarity of Pick’s disease and the inability to diagnose it until someone has died, large-scale studies are challenging to conduct.  

MAPT H2 Haplotype Associated with Higher Risk of Pick’s Disease 

To tackle the need for large-scale studies, the authors formed the Pick’s Disease International Consortium to combine resources to collect data from affected people worldwide. The consortium’s first goal was to investigate the role of MAPT H2 and its influence on Pick’s disease risk. Researchers at the Mayo Clinic Brain Bank in Jacksonville, Fla., and the Dementia Research Institute at University College London (UCL) in the United Kingdom worked to collect data from individuals in the Americas and Asia, with UCL researchers additionally obtaining data from people in Europe and Australia.  

Because international criteria for neuropathological diagnosis of Pick’s disease do not yet exist, the consortium developed its own criteria for the study. Only samples that had Pick bodies and tested negative for 4R tau clumps were accepted. Frozen brain tissue from 338 people whose samples met the consortium’s criteria was obtained for the study and compared against data from blood samples provided by 1,312 control participants.  

The H2 haplotype was found to have the most significant association with Pick’s disease risk. Weaker associations with other haplotypes were discovered but did not hold up well under repeated analysis. The authors note that because H2 creates 3R tau risk but is associated with protection against 4R tau, the MAPT H1 haplotype might inversely increase 4R tau risk and reduce 3R risk. The study’s findings could have implications for potential disease-modifying treatments that focus on reducing tau expression, providing insight into some of the pathological mechanisms of Pick’s disease.  

There are multiple genes that can create FTD risk; families can learn of their potential risk through genetic testing. However, AFTD strongly recommends consulting a genetic counselor before proceeding with genetic testing to discuss its potential impact. 

If you have any questions about genetic FTD or Pick’s disease or simply need to talk to somebody who understands what you are going through, AFTD’s HelpLine is here for you. Contact the HelpLine at 1-866-507-7222 or info@theaftd.org.