Midlife Cardiometabolic Profiles Predict Early- and Late-Onset Dementia

Distinct midlife cardiometabolic profiles are differentially associated with risks for early-onset and late-onset dementia regardless of genetic predisposition, according to study results published in Diabetes, Obesity and Metabolism.

To investigate the role of genetic risk (apolipoprotein E [APOE] ε4 status) in the associations between midlife cardiometabolic profile patterns and the risk for early-onset and late-onset dementia, researchers conducted a population-based cohort study. UK Biobank data comprised 289,494 adults aged 37 to 73 years.

After exclusion of individuals with dementia at baseline and those on cardiometabolic medications, the researchers identified 5 distinct cardiometabolic profiles with unsupervised clustering of 12 cardiometabolic markers (eg, body mass index [BMI], blood pressure, lipids, liver enzymes, inflammation markers). Incident dementia cases were identified through linked hospital and death records, classified as early-onset (<65 years) or late-onset (≥65 years).

Among the participants (mean age, 55.0 years; 57.3% women), 279 (0.1%) had early-onset dementia and 3167 (1.7%) had late-onset dementia. The 5 distinct midlife cardiometabolic clusters were:

1. Obesity-dyslipidemia;
2. High blood pressure;
3. High liver enzymes;
4. Inflammation; and,
5. Relatively healthy.

Cluster 2 had the highest systolic blood pressure (SBP; 151.8 mmHg), cluster 4 had markedly elevated C-reactive protein (CRP; 19.8 mg/L), and cluster 3 showed elevated gamma-glutamyl transferase (GGT; 124.5 U/L). Cluster 5 had the most favorable profile across markers.

Compared with cluster 5, cluster 3 had the highest risk for early-onset dementia (hazard ratio [HR], 2.58; 95% CI, 1.61-4.14), while both cluster 3 (HR, 1.36; 95% CI, 1.09-1.71) and cluster 4 (HR, 1.39; 95% CI, 1.13-1.72) were associated with increased late-onset dementia risk.

Cluster 3 was associated with both Alzheimer disease and vascular dementia across age groups, whereas cluster 4 was specifically associated with late-onset vascular dementia. Cluster 1 also showed increased risk for early-onset vascular dementia. These associations were consistent across APOE ε4 carriers and non-carriers, with no significant interaction observed for early-onset (P =.125) or late-onset (P =.356) dementia.

Among participants without the APOE ε4 allele, cluster 3 conferred the highest risk for early-onset dementia (HR, 3.62; 95% CI, 2.09-6.26). For late-onset dementia, those with both APOE ε4 and cluster 4 had the highest risk (HR, 6.13; 95% CI, 4.55-8.24).

MRI analyses showed that cluster 3 was associated with reduced total brain volume (β, -0.13; 95% CI, -0.20 to -0.06) and grey matter volume (β, -0.18; 95% CI, -0.24 to -0.11). Both clusters 3 and 4 were associated with greater white matter hyperintensity volume (β, 0.19 and 0.20, respectively).

Study limitations include potential misclassification of early-onset dementia due to incomplete case capture and limited primary care data, observational design that precludes causal inference, and a lack of generalizability.

The study authors concluded, “These findings may help improve the identification of individuals who are at high risk of developing early-onset or late-onset dementia and underscore the importance of targeting clustered cardiometabolic profiles for dementia prevention, regardless of APOE ε4 status.”

This article originally appeared on Endocrinology Advisor