{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,6,20]],"date-time":"2026-06-20T03:51:54Z","timestamp":1781927514224,"version":"3.54.5"},"posted":{"date-parts":[[2026,6,17]]},"group-title":"Health Informatics","reference-count":32,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T00:00:00Z","timestamp":1781654400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"name":"NIH","award":["1R15HL172198"],"award-info":[{"award-number":["1R15HL172198"]}]},{"name":"NIH","award":["1R15HL173852"],"award-info":[{"award-number":["1R15HL173852"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,6,17]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>\n                    The heart\u2013brain axis links cardiovascular and neurodegenerative disease through shared vascular and inflammatory mechanisms. Although low-density lipoprotein cholesterol\n                    <jats:bold>(<\/jats:bold>\n                    LDL-C) is an established causal factor in atherosclerotic cardiovascular disease (ASCVD), its relationship with dementia remains uncertain, with midlife elevations associated with increased risk but late-life associations often appearing null or inverse. To address this cholesterol paradox, we integrated mendelian randomization (MR) with an active-comparator new-user target trial emulation.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>We applied a triangulated causal inference framework integrating two-sample MR with observational target trial emulation. Genetic variants associated with LDL-C were used as instrumental variables to evaluate Alzheimer\u2019s disease (AD), Dementia with Lewy bodies (DLB), Frontotemporal dementia (FTD), and any dementia (AnyDem), with causal estimates derived using inverse-variance weighted models and sensitivity analyses for heterogeneity and pleiotropy. In parallel, an active-comparator new-user design compared statin versus ezetimibe initiation among adults aged \u226560 years using propensity score (PS) overlap weighting and Cox proportional hazards models to evaluate cardiovascular and dementia outcomes.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>Genetically predicted LDL-C was associated with increased risk of DLB (OR 1.65, 95% CI 1.30\u20132.10; p&lt;0.001), but not AD or AnyDem; FTD estimates were inconsistent. Sensitivity analyses suggested heterogeneity and possible pleiotropy for DLB. In the observational analysis (n=6,977), statin initiation was associated with higher risks of ASCVD (HR 1.26, 95% CI 1.11\u20131.45) and AnyDem (HR 1.66, 95% CI 1.16\u20132.38), although estimates attenuated after lipid adjustment and lagged analyses, suggesting residual confounding, treatment selection, and reverse causation in late-life observational associations.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>These findings suggest that LDL-C reflects accumulated vascular and metabolic risk rather than a direct causal driver of AD or overall dementia, although a subtype-specific association was observed for DLB. Late-life associations appeared influenced by timing, reverse causation, and treatment selection, warranting cautious interpretation.<\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2026.06.10.26355413","type":"posted-content","created":{"date-parts":[[2026,6,18]],"date-time":"2026-06-18T00:55:16Z","timestamp":1781744116000},"source":"Crossref","is-referenced-by-count":0,"title":["Low-Density Lipoprotein Cholesterol and Dementia Risk: Integrating Mendelian Randomization and Target Trial Emulation Within the Heart\u2013Brain Axis"],"prefix":"10.64898","author":[{"given":"Kudakwashe","family":"Mukumbi","sequence":"first","affiliation":[{"name":"Department of Applied Computing, Michigan Technological University, 1400 Townsend Dr, Houghton, MI, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanrong","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Mathematical Sciences, Michigan Technological University, Houghton, MI, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-2552-2971","authenticated-orcid":false,"given":"Zixin","family":"Shi","sequence":"additional","affiliation":[{"name":"Department of Applied Computing, Michigan Technological University, 1400 Townsend Dr, Houghton, MI, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edward","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Biology, Michigan Technological University, Houghton, MI, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aili","family":"Toyli","sequence":"additional","affiliation":[{"name":"Department of Mathematical Sciences, Michigan Technological University, Houghton, MI, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guang-Uei","family":"Hung","sequence":"additional","affiliation":[{"name":"Department of Nuclear Medicine, Chang Bing Show Chwan Memorial Hospital, Changhua, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qing-Hui","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Kinesiology and Integrative Physiology, Michigan Technological University, Houghton, MI, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiuying","family":"Sha","sequence":"additional","affiliation":[{"name":"Department of Mathematical Sciences, Michigan Technological University, Houghton, MI, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pai-Yi","family":"Chiu","sequence":"additional","affiliation":[{"name":"Department of Neurology, Show Chwan Memorial Hospital, Changhua, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6039-959X","authenticated-orcid":false,"given":"Weihua","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Applied Computing, Michigan Technological University, 1400 Townsend Dr, Houghton, MI, USA"},{"name":"Center for Biocomputing and Digital Health, Institute of Computing and Cybersystems, and Health Research Institute, Michigan Technological University, Houghton, MI, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026061920151422000_2026.06.10.26355413v1.1","unstructured":"World Health Organization. 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