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LATE-NC often co-occurs with hippocampal sclerosis (HS) pathology. It is currently unknown why some individuals with LATE-NC develop HS while others do not, but genetics may play a role. Previous studies found associations between LATE-NC phenotypes and specific genes: <jats:italic>TMEM106B<\/jats:italic>, <jats:italic>GRN<\/jats:italic>, <jats:italic>ABCC9<\/jats:italic>, <jats:italic>KCNMB2<\/jats:italic>, and <jats:italic>APOE<\/jats:italic>. Data from research participants with genomic and autopsy measures from the National Alzheimer\u2019s Coordinating Center (NACC; n\u2009=\u2009631 subjects included) and the Religious Orders Study and Memory and the Rush Aging Project (ROSMAP; n\u2009=\u2009780 included) were analyzed in the current study. Our goals were to reevaluate disease-associated genetic variants using newly collected data and to query whether the specific genotype\/phenotype associations could provide new insights into disease-driving pathways. Research subjects included in prior LATE\/HS genome-wide association studies (GWAS) were excluded. Single nucleotide variants (SNVs) within 10\u00a0kb of <jats:italic>TMEM106B<\/jats:italic>, <jats:italic>GRN<\/jats:italic>, <jats:italic>ABCC9<\/jats:italic>, <jats:italic>KCNMB2<\/jats:italic>, and <jats:italic>APOE<\/jats:italic> were tested for association with HS and LATE-NC, and separately for Alzheimer\u2019s pathologies, i.e. amyloid plaques and neurofibrillary tangles. Significantly associated SNVs were identified. When results were meta-analyzed, <jats:italic>TMEM106B, GRN,<\/jats:italic> and <jats:italic>APOE<\/jats:italic> had significant gene-based associations with both LATE and HS, whereas <jats:italic>ABCC9<\/jats:italic> had significant associations with HS only. In a sensitivity analysis limited to LATE-NC\u2009+\u2009cases, <jats:italic>ABCC9<\/jats:italic> variants were again associated with HS. By contrast, the associations of <jats:italic>TMEM106B, GRN,<\/jats:italic> and <jats:italic>APOE<\/jats:italic> with HS were attenuated when adjusting for TDP-43 proteinopathy, indicating that these genes may be associated primarily with TDP-43 proteinopathy. None of these genes except <jats:italic>APOE<\/jats:italic> appeared to be associated with Alzheimer\u2019s-type pathology. In summary, using data not included in prior studies of LATE or HS genomics, we replicated several previously reported gene-based associations and found novel evidence that specific risk alleles can differentially affect LATE-NC and HS.<\/jats:p>","DOI":"10.1186\/s40478-021-01250-2","type":"journal-article","created":{"date-parts":[[2021,9,15]],"date-time":"2021-09-15T09:02:44Z","timestamp":1631696564000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":60,"title":["Analysis of genes (TMEM106B, GRN, ABCC9, KCNMB2, and APOE) implicated in risk for LATE-NC and hippocampal sclerosis provides pathogenetic insights: a retrospective genetic association study"],"prefix":"10.1186","volume":"9","author":[{"given":"Adam J.","family":"Dugan","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter T.","family":"Nelson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuriko","family":"Katsumata","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lincoln M. 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