Evaluating MAPT p.A152T as a risk factor for the 3R tauopathy Pick's disease

Area of Science:

• Neurogenetics
• Tauopathies
• Neurodegenerative Diseases

Background:

• Understanding the genetic basis of tauopathies, including Pick's disease, is crucial for developing effective treatments.
• The MAPT p.A152T variant is a known risk factor for Alzheimer's disease and progressive supranuclear palsy, but its association with Pick's disease is unestablished.

Purpose of the Study:

• To investigate the prevalence of the MAPT p.A152T variant in a large cohort of Pick's disease patients.
• To determine if the MAPT p.A152T variant is associated with an increased risk of developing Pick's disease.
• To explore the potential impact of the MAPT p.A152T variant on MAPT transcript expression in other tauopathies.

Main Methods:

• Genotyping of 401 neuropathologically confirmed Pick's disease cases to identify MAPT p.A152T carriers.
• Comparison of variant frequency in Pick's disease cases with previously reported data from healthy controls.
• Bulk RNA sequencing in Alzheimer's disease and progressive supranuclear palsy cases carrying the A152T variant to assess MAPT transcript expression.

Main Results:

• Only one MAPT p.A152T mutation carrier was identified in the Pick's disease cohort (0.12% frequency).
• The frequency of MAPT p.A152T in Pick's disease cases was lower than in healthy controls (0.20%), suggesting no association with 3-Repeat tauopathy risk.
• Bulk RNA sequencing did not reveal significant differences in 4-Repeat tau levels, although preliminary data suggest potential nuanced effects requiring further investigation.

Conclusions:

• The MAPT p.A152T variant does not appear to be a risk factor for Pick's disease.
• The variant may be associated with 4-Repeat or mixed tau pathologies, necessitating further functional studies.
• Long-read sequencing in larger cohorts may elucidate more complex roles of the MAPT p.A152T variant in tauopathies.