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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\u2019s Disease Genomics Consortium (n\u2009=\u20098121) and the Alzheimer\u2019s Disease Sequencing Project (n\u2009=\u20093231), with cancer history and neuropathology data drawn from the National Alzheimer\u2019s Coordinating Center. The rs5848 T allele was associated with higher odds of LATE-NC (p\u2009&amp;lt;\u20090.001) and was also associated with lower odds of cancer (p\u2009=\u20090.012). Established TMEM106B, APOE, and BIN1 risk alleles for Alzheimer\u2019s 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.<\/jats:p>","DOI":"10.1093\/jnen\/nlag051","type":"journal-article","created":{"date-parts":[[2026,5,1]],"date-time":"2026-05-01T12:28:17Z","timestamp":1777638497000},"page":"1003-1019","source":"Crossref","is-referenced-by-count":0,"title":["<i>GRN<\/i>\n                    rs5848 variant associates with TDP-43 pathology and cancer in opposite directions"],"prefix":"10.1093","volume":"85","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-3793-6927","authenticated-orcid":false,"given":"Khine Zin","family":"Aung","sequence":"first","affiliation":[{"name":"Division of Biomedical Informatics, Department of Internal Medicine, University of Kentucky , Lexington, KY,","place":["United States"]},{"name":"Sanders-Brown Center on Aging, University of Kentucky , Lexington, KY,","place":["United 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