Cardiometabolic Diseases and Dementia Risk Show Dose-dependent Relationship in Large Twin Study

Risk of dementia may increase by more than 2-fold along with the number of comorbid cardiometabolic diseases an individual develops, according to new research from scientists at the Karolinska Institutet in Sweden.

Further, the Swedish researchers found that the risk may be higher among adults who develop the diseases including type 2 diabetes, heart disease, and stroke, earlier in the life course vs later. Based on their additional analysis of mono- and dizygotic twins in the world’s largest twin registry, the authors also suggest that the association in the dose-dependent multimorbidity-dementia relationship is likely rooted in genetics.

Cardiometabolic multimorbidity, ie, coexistence of ≥2 cardiometabolic diseases, affects an estimated 30% of older adults, study authors write, and as greater numbers of people live longer with these diseases well managed, the proportion stands only to increase.

Individually T2D, heart disease, and stroke are well-established risk factors for dementia, but the authors note little research has explored the relationship between dementia and clusters of the diseases or the temporal impact of cardiometabolic disease development on subsequent dementia. Moreover, a nuanced understanding of the biological and genetic pathways that may underly an association between both conditions remains limited.

Individually T2D, heart disease, and stroke are well-established risk factors for dementia, but the authors note little research has explored the relationship between dementia and clusters of the diseases or the temporal impact of cardiometabolic disease development on subsequent dementia.

The Swedish research team, led by Weili Xu, PhD, associate professor and senior researcher, Aging Research Center, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, took advantage of mining the data available in the Swedish Twin Registry to set a 3-fold aim for this study: 1) to examine the impact of cardiometabolic multimorbidity on the risk of dementia; 2) to assess how the timing of cardiometabolic disease onset over the life-course influences dementia risk; and 3) to explore the role of genetic background in the cardiometabolic disease–dementia association using twin data.

Within the Swedish Twin Registry, investigators identified a cohort of 17 913 individuals (mean age 70.1 years, 55% women) who were registered between March 1998 and December 2002 and free of dementia. Cardiometabolic diseases [including age of onset in mid (60) or late (≥60) life] were obtained from medical records with cardiometabolic multimorbidity defined as having ≥2 diseases.

FINDINGS

Median follow-up was 15.4 years during which the investigators found a total of 3020 (16.9%) participants developed dementia, including 1050 (5.9%) with Alzheimer disease (AD) and 638 (3.6%) with vascular dementia (VaD).

Dose-dependent

Xu et al report that an increasing number of cardiometabolic diseases was associated in a dose-dependent manner with a greater risk of dementia as well as all dementia subtypes. With each additional cardiometabolic disease developed the risk of...

• ...all-cause dementia rose 42% (HR: 1.42, 95% CI: 1.31–1.53)
• ...AD rose 26% (HR: 1.26, 95% CI: 1.10–1.45)
• ...VaD rose 64% (HR: 1.64, 95% CI: 1.42– 1.88)

With and without disease. When Xu and colleagues compared individuals with and without cardiometabolic disease, among those with a single disease the risk of all-cause dementia was increased by 42% (95% CI: 1.27–1.58) and significantly increased risks were seen for both AD, 31% (95% CI: 1.08–1.59) and VaD, 78% (95% CI: 1.44– 2.21).

Multimorbidity. In persons with multiple comorbid cardiometabolic diseases, the risk of dementia was more than doubled (HR: 2.10, 95% CI: 1.73–2.57). This heightened risk, again included a significant risk of AD (HR: 1.49, 95% CI: 1.02–2.20) and VaD (HR: 2.65, 95% CI: 1.83–3.84).

Combinations. The investigators then examined associations between specific constellations of multimorbidity and dementia and found that every possible combination of T2D, HD, and stroke, whether alone or in combination, was associated with a significantly increased risk of either all-cause dementia, AD or VaD.

Age of onset

Results of analysis that accounted for age at the onset of cardiometabolic disease suggest that the risk conferred on dementia grew weaker with time, reduced by 11% for each decade of older age at the development of a first disease (95% CI: 0.86– 0.92), and by 16% for each decade of older age at the development of a second (95% CI: 0.81–0.89). These findings the authors note may indicate that earlier onset of cardiometabolic disease may be more toxic to cognitive health and that perhaps because midlife disease may be more aggressive.

Twin data

In the matched co-twin analysis, the investigators found that the significant association between cardiometabolic disease and dementia found in the classic cohort study design remained among cardiometabolic disease and dementia- discordant dizygotic twin pairs but was attenuated among cardiometabolic disease and dementia-discordant monozygotic twin pairs.

Xu et al say that to their knowledge, theirs is the first study demonstrate that cardiometabolic diseases, particularly when developed in midlife, increase the risk of dementia, including both AD and VaD. “These findings add to the growing evidence of a connection between cardiometabolic multimorbidity and both vascular and neurodegenerative forms of dementia and highlight the need for special monitoring of individuals who develop T2D, HD, or stroke in mid-life in order to reduce their risk of developing dementia in older age.”

“Elucidating the mechanisms by which cardiometabolic multimorbidity impacts dementia will require future studies integrating longitudinal measures of cognitive function with neuropathological, genetic, and biomarker data,” they conclude.