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While numerous studies have established substantial genetic contribution for LOAD, the interpretation of heritability estimates remains challenging. These challenges are further complicated by the binary nature of LOAD status, where estimation and interpretation require additional considerations. Through a systematic review, we identified LOAD heritability estimates from 6 twin studies and 17 genome-wide association studies, all conducted in populations of European ancestry. We demonstrate that these heritability estimates for LOAD vary considerably. The variation reflects not only differences in study design and methodological approaches but also the underlying study population characteristics. Our findings indicate that commonly cited heritability estimates, often treated as universal values, should be interpreted within specific population contexts and methodological frameworks.<\/jats:p>","DOI":"10.1371\/journal.pgen.1011701","type":"journal-article","created":{"date-parts":[[2025,9,4]],"date-time":"2025-09-04T17:58:33Z","timestamp":1757008713000},"page":"e1011701","update-policy":"https:\/\/doi.org\/10.1371\/journal.pgen.corrections_policy","source":"Crossref","is-referenced-by-count":7,"title":["Alzheimer disease is (sometimes) highly heritable: Drivers of variation in heritability estimates for binary traits, a systematic review"],"prefix":"10.1371","volume":"21","author":[{"given":"Shiying","family":"Liu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9729-6519","authenticated-orcid":true,"given":"William S.","family":"Bush","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rufus O.","family":"Akinyemi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1057-0261","authenticated-orcid":true,"given":"Goldie S.","family":"Byrd","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5393-9116","authenticated-orcid":true,"given":"Allison Mercedes","family":"Caban-Holt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Farid","family":"Rajabli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christiane","family":"Reitz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9515-5157","authenticated-orcid":true,"given":"Brian W.","family":"Kunkle","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuseppe","family":"Tosto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffery M.","family":"Vance","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Margaret","family":"Pericak-Vance","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan L.","family":"Haines","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4835-9544","authenticated-orcid":true,"given":"Scott M.","family":"Williams","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dana C.","family":"Crawford","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2025,9,4]]},"reference":[{"key":"pgen.1011701.ref001","volume-title":"Genetics and analysis of quantitative traits","author":"M Lynch","year":"1998"},{"issue":"2","key":"pgen.1011701.ref002","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1017\/S0080456800012163","article-title":"XV\u2014The Correlation between Relatives on the Supposition of Mendelian Inheritance","volume":"52","author":"RA Fisher","year":"1919","journal-title":"Trans R Soc Edinb"},{"issue":"4","key":"pgen.1011701.ref003","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1038\/nrg2322","article-title":"Heritability in the genomics era--concepts and misconceptions","volume":"9","author":"PM Visscher","year":"2008","journal-title":"Nat Rev Genet"},{"key":"pgen.1011701.ref004","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1007\/s10709-022-00149-7","article-title":"Heritability: What\u2019s the point? 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