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This study aimed to investigate interrelationships between PRS for type 2 diabetes, Life\u2019s Essential 8 (LE8) metrics, and dementia. Methods: We included 437,732 UK Biobank participants aged \u226540 years between 2006 and 2010. PRS for type 2 diabetes was calculated by summing weighted genetic variant effects. Incident all-cause and cause-specific dementias were identified using registry records up to December 2022. LE8 scores were classified as low vs. moderate-to-high levels. Cox regression and restricted cubic splines were applied. Results: Over an average follow-up of 13.27 years (SD = 2.27), 9425 participants developed dementia. A dose\u2013response relationship was observed between PRS and vascular dementia, with risk rising sharply beyond the 95th percentile. Individuals with low LE8 constantly showed a higher risk of all-cause dementia than those with moderate-to-high LE8 across all values of PRS for type 2 diabetes. APOE \u03b54 accounted for more than 35% of the population-attributable risk of dementia, whereas the PRS for type 2 diabetes contributed only 1%. The population-attributable risk of all-cause dementia could be further reduced by 5.91% to 10.46% through maintaining moderate-to-high LE8 behavioral components, even after considering APOE \u03b54. Conclusions: A dose\u2013response relationship exists between PRS for type 2 diabetes and dementia, particularly vascular dementia. Adherence to optimal LE8 metrics, particularly behavioral components, may contribute to dementia prevention across genetic strata. These findings highlight the importance of multidomain lifestyle interventions in dementia prevention.<\/jats:p>","DOI":"10.3390\/nu18132080","type":"journal-article","created":{"date-parts":[[2026,6,25]],"date-time":"2026-06-25T12:37:55Z","timestamp":1782391075000},"page":"2080","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Life\u2019s Essential 8, Polygenic Risk for Type 2 Diabetes, and Dementia: Evidence from the UK Biobank"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1525-5538","authenticated-orcid":false,"given":"Yuanjing","family":"Li","sequence":"first","affiliation":[{"name":"Department of Health Sciences, The Swedish School of Sport and Health Sciences, 11486 Stockholm, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6058-4982","authenticated-orcid":false,"given":"\u00d6rjan","family":"Ekblom","sequence":"additional","affiliation":[{"name":"Department of Health Sciences, The Swedish School of Sport and Health Sciences, 11486 Stockholm, Sweden"},{"name":"Division of Nursing, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, 14157 Huddinge, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bikram","family":"Bucha","sequence":"additional","affiliation":[{"name":"Department of Health Sciences, The Swedish School of Sport and Health Sciences, 11486 Stockholm, Sweden"},{"name":"Master\u2019s Programme in Nutrition Science, Karolinska Institutet, 14157 Huddinge, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ariana","family":"Cojocari","sequence":"additional","affiliation":[{"name":"Department of Health Sciences, The Swedish School of Sport and Health Sciences, 11486 Stockholm, Sweden"},{"name":"Master\u2019s Programme in Nutrition Science, Karolinska Institutet, 14157 Huddinge, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5051-4929","authenticated-orcid":false,"given":"Hui-Xin","family":"Wang","sequence":"additional","affiliation":[{"name":"Stress Research Institute, Department of Psychology, Stockholm University, 11419 Stockholm, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7209-741X","authenticated-orcid":false,"given":"Rui","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Health Sciences, The Swedish School of Sport and Health Sciences, 11486 Stockholm, Sweden"},{"name":"Division of Clinical Geriatrics, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, 17164 Solna, Sweden"},{"name":"Wisconsin Alzheimer\u2019s Disease Research Center, School of Medicine and Public Health, University of Wisconsin, Madison, WI 53705, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2313","DOI":"10.2337\/db20-0895","article-title":"Relationship Between Glycemia and Cognitive Function, Structural Brain Outcomes, and Dementia: A Mendelian Randomization Study in the UK Biobank","volume":"70","author":"Garfield","year":"2021","journal-title":"Diabetes"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"4915","DOI":"10.1111\/dom.70677","article-title":"Dementia Risk in Type 1 and 2 Diabetes: A Nationwide Population-Based Comparison","volume":"28","author":"Jun","year":"2026","journal-title":"Diabetes Obes. 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