Two major population studies reveal how cardiovascular health and inherited dementia risk intersect to shape cognitive outcomes in people with diabetes.
Study: The Joint Effects of Life’s Essential 8 and Genetics on Mild Cognitive Impairment and Dementia Risk in People With Diabetes: Findings From the UK Biobank and All of Us. Image Credit: Crystal Light / Shutterstock
A recent study in the journal Diabetes Care evaluated the joint associations of cardiovascular health and genetic risk with the development of mild cognitive impairment and dementia among people with diabetes.
Interplay of Hyperglycemia, Cardiovascular Health, and Genetic Susceptibility in Dementia
Chronic hyperglycemia and insulin resistance are important contributors to cognitive dysfunction and dementia. Currently, one in three adults aged 65 or older has diabetes, and this prevalence continues to increase.
Diabetes doubles the risk of developing dementia compared to normoglycemic individuals. This elevated risk is particularly concerning due to the absence of effective dementia prevention strategies for the aging diabetic population.
Life’s Essential 8 (LE8) defines eight modifiable cardiovascular health (CVH) factors: diet, physical activity, nicotine exposure, sleep, body mass index, lipids, blood glucose, and blood pressure. Adherence to LE8 is associated with reduced risk of cardiovascular and neurodegenerative diseases.
Maintaining optimal CVH metrics may attenuate genetic risk for diseases such as dementia. Individuals who quit smoking, exercise regularly, maintain a healthy diet, and consume alcohol in moderation have been reported to have up to a one-third lower dementia risk, even among those with high genetic susceptibility.
However, the extent to which adherence to LE8 can offset genetic risk for mild cognitive impairment (MCI) or dementia, or which CVH components confer the greatest protective benefit in people with diabetes, remains unexamined.
Assessing the Cognitive Impacts of LE8 Adherence and Genetic Risk in People With Diabetes
This study examined how adherence to the American Heart Association’s Life’s Essential 8 (LE8) cardiovascular health metrics and genetic risk factors are associated with cognitive outcomes in individuals with diabetes.
Two extensive and diverse cohorts were examined: the UK Biobank (UKB), a large-scale prospective study of over 500,000 adults in the United Kingdom, and All of Us (AoU), a nationwide U.S. research initiative aiming to enroll more than 1 million participants. Both cohorts provided rich phenotypic, genetic, and health-outcome data, and the analyses focused exclusively on participants identified as having diabetes.
In UKB, LE8 adherence was evaluated using eight standardized health components, whereas the AoU cardiovascular health score included five components: blood pressure, cholesterol, blood glucose, BMI, and nicotine exposure. Genetic risk was determined using polygenic risk scores (PRS) for Alzheimer's disease (AD) and the APOE ε4 genotype.
Primary outcomes included mild cognitive impairment (MCI) and dementia as defined by ICD-10 codes. In UKB, secondary outcomes encompassed magnetic resonance imaging (MRI)-derived brain structure measures and results from multiple cognitive tests.
Analyses adjusted for demographic and clinical covariates, assessing both the independent and combined effects of LE8 and genetic risk. Statistical methods included Cox proportional hazards models, competing-risk analyses, and subgroup analyses by sex, ethnicity, diabetes type, and medication use.
Better Cardiovascular Health Linked to Lower MCI Risk in Diabetes After Accounting for Genetics
Among 41,374 UKB participants with diabetes and no dementia, those with low LE8 scores were younger, more likely to be men, had lower socioeconomic status, and were diagnosed at a younger age with longer diabetes duration. Their average LE8 score was 42.7.
Brain volumes were generally similar, but higher LE8 scores were associated with greater gray matter and less white matter hyperintensity. Higher LE8 scores were not significantly associated with performance across the cognitive domains tested. In the AoU cohort, low LE8 was also associated with younger age at diagnosis, a higher proportion of men, less frequent use of diabetes medication, and lower average LE8 scores. The AoU group had greater racial and ethnic diversity and a higher rate of MCI.
Each five-point increase in LE8 score was associated with a 5% lower risk of mild cognitive impairment in UKB. Having moderate or high LE8 scores was also associated with lower MCI risk, but not with a significant reduction in overall all-cause dementia risk, even after accounting for genetic risk. The relationships with MCI and dementia were generally stronger in those with lower or moderate genetic risk, while they were attenuated at high genetic risk. Overall, links with dementia were also not statistically significant in AoU.
Age and genetic susceptibility were among the strongest contributors to cognitive risk, while lipids, BMI, sleep, and glucose ranked among the most important LE8 components. Several LE8 components showed significant additive interactions with genetic risk for dementia and MCI in UKB, with lipids and glucose showing the strongest and most consistent interactions, although no significant interactions were detected in AoU.
Moderate or high LE8 scores were not associated with reduced Alzheimer’s or vascular dementia risk in UKB, but in AoU, higher LE8 was linked to lower vascular dementia risk. Subgroup analyses in UKB found significant associations with lower MCI risk among men, White participants, and people with longer diabetes duration, while moderate or high LE8 was associated with lower MCI and dementia risk among those with type 1 diabetes. Associations were not statistically significant among women or among those with shorter diabetes duration. Among metformin or insulin users in AoU, associations with MCI or dementia were also not significant, although some subgroup analyses had limited statistical power.
Conclusions
Better CVH was consistently associated with a lower risk of MCI in individuals with diabetes after accounting for genetic predisposition. Associations with dementia appeared more dependent on genetic risk, with stronger associations among those with low or moderate genetic susceptibility and attenuated associations among those at high genetic risk. Additionally, higher LE8 scores were associated with more favorable brain MRI markers, underscoring the importance of comprehensive vascular and metabolic management for brain health in this vulnerable population.
Several limitations should be considered when interpreting these findings. Dementia diagnoses in the UKB cohort were based on ICD-10 codes from electronic health records, which may have introduced misclassification. The Alzheimer’s disease PRS used as a proxy for genetic risk may not fully capture susceptibility to other dementia subtypes. Differences in participant demographics, data collection methods, follow-up duration, and outcome case counts between cohorts may have contributed to heterogeneity and reduced the precision of replication analyses. In addition, relatively few participants had high LE8 scores, so the moderate and high groups were combined for the main association analyses.
In the future, longitudinal and interventional research is warranted to clarify the causal role of CVH in dementia risk among people with diabetes.
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