Life’s Essential 8, Polygenic Risk for Type 2 Diabetes, and Dementia: Evidence from the UK Biobank

Background/Objectives: It is unclear if adherence to healthy guidelines can modify the association between polygenic risk score (PRS) for type 2 diabetes and dementia. This study aimed to investigate interrelationships between PRS for type 2 diabetes, Life’s Essential 8 (LE8) metrics, and dementia. Methods: We included 437,732 UK Biobank participants aged ≥40 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–response 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 ε4 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 ε4. Conclusions: A dose–response 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.