Evaluating pathogenic dementia variants in posterior cortical atrophy.

Area of Science:

• Neuroscience
• Genetics
• Ophthalmology

Background:

• Posterior Cortical Atrophy (PCA) is an understudied visual impairment syndrome often linked to posterior Alzheimer's disease (AD) pathology.
• Previous case studies suggested mutations in genes like PSEN1, PSEN2, GRN, MAPT, and PRNP may be associated with PCA.

Purpose of the Study:

• To determine the frequency and spectrum of mutations in known dementia genes within a cohort of PCA patients.
• To compare variant frequencies in PCA patients against a large population control group.

Main Methods:

• A customized exome array (NeuroX) was used to screen 124 European-American subjects with PCA or posterior AD neuropathology for variants in AD, frontotemporal dementia, and prion disease genes.
• Frequencies of pathogenic or potentially pathogenic variants were compared to approximately 4300 European-American population controls from the NHLBI Exome Sequencing Project.

Main Results:

• Two rare variants, TREM2 Arg47His and PSEN2 Ser130Leu, were identified and not previously reported in PCA.
• No other pathogenic or potentially pathogenic variants were detected in the screened dementia genes.
• The study validated previously reported APOE ε4 association in PCA.

Conclusions:

• This systematic variant screen in a PCA cohort identified two rare mutations in TREM2 and PSEN2.
• The findings highlight the utility of the NeuroX platform for genetic screening in PCA.
• Further research is warranted to understand the role of these mutations in PCA pathogenesis.