{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,27]],"date-time":"2026-06-27T07:45:22Z","timestamp":1782546322262,"version":"3.54.5"},"reference-count":42,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2026,2,8]],"date-time":"2026-02-08T00:00:00Z","timestamp":1770508800000},"content-version":"vor","delay-in-days":7,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,2,1]],"date-time":"2026-02-01T00:00:00Z","timestamp":1769904000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100000049","name":"National Institute on Aging","doi-asserted-by":"publisher","award":["RF1AG060472"],"award-info":[{"award-number":["RF1AG060472"]}],"id":[{"id":"10.13039\/100000049","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000049","name":"National Institute on Aging","doi-asserted-by":"publisher","award":["UO1AG032984"],"award-info":[{"award-number":["UO1AG032984"]}],"id":[{"id":"10.13039\/100000049","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["alz-journals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Alzheimer's &amp;amp; Dementia"],"published-print":{"date-parts":[[2026,2]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>INTRODUCTION<\/jats:title>\n                    <jats:p>Knowledge of modifiable factors influencing age at onset (AAO) of Alzheimer's disease (AD) remains limited. This study utilizes genetic information to uncover such factors.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS<\/jats:title>\n                    <jats:p>Using 43 exposure genome\u2010wide association studies (GWAS) summary statistics, we calculated corresponding polygenic scores (PGS) for 9219 AD cases and 10,345 controls from the Alzheimer's Disease Genetic Consortium (ADGC). Linear mixed model and survival analyses were performed to identify exposure\u2010PGS associated with AAO. Top exposures were cross\u2010evaluated using PGS from the PGS Catalog and Mendelian randomization (MR) for causal relationships.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS<\/jats:title>\n                    <jats:p>Eight exposures showed significant exposure\u2010PGS associations with AAO of AD. Higher educational attainment, better cognitive performance, and greater relative fat intake were associated with later AAO; whereas the remaining were linked to earlier onset. MR analysis indicated a causal relationship between AAO and educational attainment, cardiovascular disease, and type 2 diabetes (T2D).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>DISCUSSION<\/jats:title>\n                    <jats:p>The eight modifiable factors, particularly educational attainment, cardiovascular disease, and T2D, may facilitate early intervention to delay the onset of AD.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Highlights<\/jats:title>\n                    <jats:p>\n                      <jats:list list-type=\"bullet\">\n                        <jats:list-item>\n                          <jats:p>We screened 43 modifiable factors for their association with the age at onset (AAO) of Alzheimer's disease (AD) using polygenic scores (PGS) as the proxy for the exposure.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Higher educational attainment, better cognitive performance, and greater relative fat intake were linked to later AAO, suggesting an enhanced resilience against AD.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Type 2 diabetes, cardiovascular disease, major coronary heart disease, and increased low\u2010density lipoprotein (LDL) \u2010cholesterol and total cholesterol are associated with earlier AAO.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Mendelian randomization analysis revealed causal effects of educational attainment, type 2 diabetes, and cardiovascular disease on AAO of AD.<\/jats:p>\n                        <\/jats:list-item>\n                      <\/jats:list>\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/alz.71111","type":"journal-article","created":{"date-parts":[[2026,2,9]],"date-time":"2026-02-09T03:22:05Z","timestamp":1770607325000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Leveraging genetic propensity to identify modifiable factors for the age at onset of Alzheimer's disease"],"prefix":"10.1002","volume":"22","author":[{"given":"Yi\u2010Ju","family":"Li","sequence":"first","affiliation":[{"name":"Department of Biostatistics and Bioinformatics Duke University School of Medicine  Durham North Carolina USA"},{"name":"Duke Molecular Physiology Institute Duke University School of Medicine  Durham North Carolina USA"},{"name":"Centre for Biomedical Data Science Duke\u2010NUS Medical School  Singapore Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jong Ok","family":"La","sequence":"additional","affiliation":[{"name":"Duke Molecular Physiology Institute Duke University School of Medicine  Durham North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adam","family":"Naj","sequence":"additional","affiliation":[{"name":"Department of Biostatistics Epidemiology, and Informatics University of Pennsylvania Perelman School of Medicine  Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eden R.","family":"Martin","sequence":"additional","affiliation":[{"name":"John P. Hussman Institute for Human Genomics University of Miami Miller School of Medicine  Miami Florida USA"},{"name":"John T. MacDonald Foundation Department of Human Genetics University of Miami, Miller School of Medicine  Miami Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,2,8]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1002\/alz.13016"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.14283\/jpad.2021.15"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1474\u20104422(06)70537\u20103"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0086141"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12916\u2010016\u20100549\u2010y"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1136\/bmjment\u20102023\u2010300719"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.43657"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.25918"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1002\/alz.12927"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1001\/jamaneurol.2014.1491"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41588\u2010017\u20100009\u20104"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btq340"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41588\u2010018\u20100133\u20109"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41588\u2010018\u20100144\u20106"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467\u2010019\u201013690\u20105"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41588\u2010021\u201000931\u2010x"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586\u2010022\u201005477\u20104"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41380\u2010020\u20100697\u20105"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41588\u2010019\u20100361\u20107"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41366\u2010018\u20100120\u20103"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586\u2010022\u201005275\u2010y"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41588\u2010020\u201000713\u2010x"},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3977"},{"key":"e_1_2_8_25_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pbio.3001547"},{"key":"e_1_2_8_26_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1009025"},{"key":"e_1_2_8_27_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41588\u2010018\u20100147\u20103"},{"key":"e_1_2_8_28_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41593\u2010018\u20100326\u20107"},{"key":"e_1_2_8_29_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41588\u2010022\u201001016\u2010z"},{"key":"e_1_2_8_30_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467\u2010018\u201004930\u20101"},{"key":"e_1_2_8_31_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467\u2010018\u201004951\u2010w"},{"key":"e_1_2_8_32_1","doi-asserted-by":"publisher","DOI":"10.1002\/gepi.22354"},{"key":"e_1_2_8_33_1","doi-asserted-by":"publisher","DOI":"10.1002\/gepi.21758"},{"key":"e_1_2_8_34_1","doi-asserted-by":"publisher","DOI":"10.1002\/gepi.21965"},{"key":"e_1_2_8_35_1","doi-asserted-by":"publisher","DOI":"10.1093\/ije\/dyx102"},{"key":"e_1_2_8_36_1","doi-asserted-by":"publisher","DOI":"10.1093\/ije\/dyv080"},{"key":"e_1_2_8_37_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41588\u2010018\u20100099\u20107"},{"key":"e_1_2_8_38_1","doi-asserted-by":"publisher","DOI":"10.1093\/ije\/dyt093"},{"key":"e_1_2_8_39_1","doi-asserted-by":"publisher","DOI":"10.1002\/sim.6835"},{"key":"e_1_2_8_40_1","doi-asserted-by":"publisher","DOI":"10.1093\/aje\/154.7.635"},{"key":"e_1_2_8_41_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41398\u2010022\u201002067\u2010w"},{"key":"e_1_2_8_42_1","doi-asserted-by":"publisher","DOI":"10.1001\/archneur.60.2.194"},{"key":"e_1_2_8_43_1","doi-asserted-by":"publisher","DOI":"10.29219\/fnr.v66.8629"}],"container-title":["Alzheimer's &amp; 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