Genomic Architecture of a Key Alzheimer's Disease Mimic: CARTS

Brain diseases other than Alzheimer’s disease (AD) are common but understudied causes of dementia. A particularly prevalent subtype of non-Alzheimer’s dementia is termed hippocampal sclerosis dementia, or cerebral age-related TDP-43 with sclerosis (CARTS). This neuropathology (NP) defined disease affects ~20% of elderly, with substantial impact on cognition, but is typically misdiagnosed as AD during life. Our long-term goal is to resolve the genomic factors that modulate CARTS severity and heterogeneity. To accomplish this, we will establish, test, and apply a robust pipeline to elucidate the mechanisms influenced by genetic risk factors for CARTS, factoring in other non-AD brain pathologies. This requires an integrated, multidisciplinary team with expertise in NP, molecular biology, neuroimaging, “large data” analyses, and, in particular, statistical genomics. Our central hypothesis, based on considerable preliminary data, is that CARTS risk-modifying alleles discovered via candidate gene and genome-wide association studies (GWAS) are proxies for phenomena more directly involved in disease etiology.