Department of Human Genetics Doctoral Candidate, Vibha Acharya, MS, will defend the following dissertation on “Genetics of Cognitive Decline in Older Individuals in Population-Based Cohorts.”

COMMITTEE CHAIR: M. Ilyas Kamboh, PhD 

Committee Members:

• Beth E. Snitz, PhD
• Kang-Hsien Fan, PhD
• Eleanor Feingold, PhD
• Mary Ganguli, MD, MPH

ABSTRACT:

Cognitive decline, the deterioration of previously acquired cognitive ability, is a normal characteristic of aging. Due to the world population demographic shifting towards the aging population, cognitive decline is a huge public health concern. Although cognitive decline has substantial genetic influence, there is limited understanding about the genetic contributors of cognitive aging. We leveraged three longitudinal cohorts to derive cognitive slopes across five neurocognitive domains (attention, executive function, memory, language, visuospatial function) and global cognitive function by fitting a linear mixed effect model adjusting for age, education and sex.  Genome-wide analysis was then conducted for each domain within each cohort adjusting for the first four genetic principal components of ancestry followed by meta-analysis using the inverse-variance based fixed effect. Gene-based and gene-set enrichment analyses were implemented in FUMA to understand the underlying biology of cognitive-implicated genes. We extended our analyses further to understand the genetic architecture of cognitive decline in males and females separately and among three different APOE genotype subgroups: APOE2 carriers, APOE 3/3 homozygous and APOE4 carriers. Additionally, the role of rare variants in cognitive decline was explored using SKAT-O.

We detected a novel association near RASEF on chromosome 9 to be associated with decline of attention and this association was found to be confined to the APOE 3/3 group in the APOE-stratified analysis. We replicated association of APOE4 with the decline of memory and global cognitive function.  In the gene-based analysis, we detected another novel association of TMRSS11D, a protein known to activate viral spike protein and facilitate entry of several viruses, including SARS-CoV-2, with the decline of global cognitive function. NDUFA12 was associated with the decline of executive function in females but not in males. APOE- stratified analysis helped to identify the association of hearing-loss associated genes (DTWD2, DMXL1 and HSD17B4) with the decline of language in APOE4 carrier group. Rare variant association analysis detected the association of EVC with the decline of global cognitive function. Gene-set enrichment analysis showed that there are both shared and unique pathways within domain abilities and several of these pathways were specific to sex and APOE subgroup, highlighting the importance of stratified analysis.