GRN rs5848 variant associates with TDP-43 pathology and cancer in opposite directions.
Epidemiologic studies have reported that cancer survivors have a relatively low risk of developing dementia, but the mechanisms underlying that inverse relationship are mostly unknown. The Granulin (GRN) gene single nucleotide variant rs5848 T allele is associated with increased risk of limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) and hippocampal sclerosis of aging (HS-Aging). The T allele is also associated with lower expression of the cognate protein progranulin (PGRN), which is a mitogen implicated in neoplasia. We examined whether the rs5848 variant associated with LATE-NC/HS-Aging pathology and cancer in the same cohort. This study leveraged genotype data from the Alzheimer's Disease Genomics Consortium (n = 8121) and the Alzheimer's Disease Sequencing Project (n = 3231), with cancer history and neuropathology data drawn from the National Alzheimer's Coordinating Center. The rs5848 T allele was associated with higher odds of LATE-NC (p < 0.001) and was also associated with lower odds of cancer (p = 0.012). Established TMEM106B, APOE, and BIN1 risk alleles for Alzheimer's disease showed no associations with cancer, implying that the GRN-related associations could not be completely explained by selection bias in the study sample. The finding of a specific allele with opposite correlative impact on cancer risk and dementia-related pathology has potential therapeutic implications.