Metabolic Syndrome Is Associated With Poor Cognition: A Population-Based Study of 70-Year-Old Adults Without Dementia

Abstract Background Individual conditions of metabolic syndrome (MetS) have been related to dementia; however, their combined impact on the preclinical stage is unknown. We investigated the associations between MetS and domain-specific cognitive function as well as the role of sociodemographic, cardiovascular, and genetic factors. Methods Within the Gothenburg H70 Birth Cohort Study-Birth cohort 1944, 1131 dementia-free participants (aged 70 years) were examined during 2014–2016. MetS (central obesity plus at least 2 factors [reduced HDL-cholesterol, elevated triglycerides, blood pressure, or blood glucose]) was identified according to the International Diabetes Federation criteria. Five cognitive domains (memory, attention/perceptual speed, executive function, verbal fluency, visuospatial abilities) were generated after z-standardizing raw scores from 10 neuropsychological tests. Education, heart disease, claudication (indicating peripheral atherosclerosis), and apolipoprotein genotype were ascertained by trained staff. Data were analyzed with linear regression models. Results Overall, 618 participants (55%) had MetS. In multiadjusted linear regressions, MetS was related to poorer performance in attention/perceptual speed (β −0.14 [95% CI −0.25, −0.02]), executive function (β −0.12 [95% CI −0.23, −0.01]), and verbal fluency (β −0.19 [95% CI −0.30, −0.08]). These associations were present only among individuals who did not carry any APOE-ε4 allele or were highly educated. However, among those with MetS, high education was related to better cognitive performance. MetS together with comorbid heart disease or claudication was associated with even worse cognitive performance than each alone. Conclusions MetS is associated with poor attention/perceptual speed, executive function, and verbal fluency performance. Education, apolipoprotein E-ε4 allele, and comorbid cardiovascular disease influenced the observed associations.


APPENDIX A. Assessment of cardio-and cerebro-vascular diseases and claudication.
CVD included myocardial infarction, angina pectoris, heart failure, atrial fibrillation, and stroke/transient ischemic attack (TIA).Specifically, a standard 12-lead electrocardiogram (ECG) was coded, according to the Minnesota Code, by a biomedical analyst working at the cardiac laboratory at Sahlgrenska University Hospital (Rydberg Sterner et al. 2019).Myocardial infarction was identified based on self-reported history or the presence of moderate or major Q-waves on ECG (Minnesota Codes: 1-1-X or 1-2-X, excluding 1-2-6 and 1-2-8).Angina pectoris was based on self-reported history or the standard criteria (Rose GA.The diagnosis of ischaemic heart pain and intermittent claudication in field surveys.Bull World Health Organ 1962;27:645-658).Heart failure was based on self-reported history.Atrial fibrillation was based on self-reported history or ECG (Minnesota Code: 8-3).Stroke and TIA-defined as sudden onset of focal symptoms or aphasia lasting for more than 24 hours (stroke) or less than 24 hours (TIA)-were identified based on self-report, key informants interview, or the Swedish National Patient register (ICD-10 codes: I60, I61, I629, I630-I635, I638-I639, I64, I690-I691, and I693-I694).
The ) proposed an alternative definition of MetS that emphasize the role of insulin-resistance as a major underlying mechanisms.Thus, according to the abovementioned criteria, MetS was defined as the presence of at least three of the following five factors: central adiposity, raised triglycerides, reduced high-density lipoprotein cholesterol, raised blood pressure, and raised blood glucose.We repeated all the analyses in the manuscript using this definition.Results were substantially unchanged.
Stratified analyses by education replicated the negative associations of MetS with global cognition, attention/perceptual speed, and verbal fluency among participants with higher education, but not with a lower educational attainment.Similarly, stratified analyses by APOE-ε4 (carriers vs. non-carriers of any ε4 allele) showed that the independent negative relationships of MetS with global cognition and the domains of attention/perceptual speed, executive function, and verbal fluency were present in participants who did not carry an ɛ4 allele.

eTable 1 .
Cognitive characteristics of dementia-free participants (n=1131) by presence/absence of metabolic syndrome.

APPENDIX B. Sensitivity analysis.
presence of intermittent claudication was assessed based on the criteria proposed by Rose in 1962 (Rose GA.The diagnosis of ischaemic heart pain and intermittent claudication in field surveys.Bull World Health Organ 1962;27:645-658) with two questions (no vs. yes): 1) Do you usually get pain in the calves when you walk uphill, in stairs or on the level?; 2) Does the pain disappear within a few minutes if you stop to rest without sitting down?. Participants who answered "yes" to both questions were categorized as having claudication.

Associations between metabolic syndrome (Mets) and cognitive function from stratified analyses by heart disease.
Note: Data are presented as means ± standard of the raw test scores.Abbreviations: APOE-ɛ4.apolipoprotein ɛ4 allele; HDL.High-density lipoprotein; LDL.Low-density lipoprotein.eTable 2.

Joint association between metabolic syndrome (MetS) and education, MetS and heart diseases, and MetS and apolipoprotein status in relation to cognitive function.
Linear regression models, separate for each cognitive outcome, were adjusted for sex, education, physical activity, smoking, alcohol risk consumption, heart disease, stroke/TIA, and APOE-ε4.Abbreviations: APOE-ε4, apolipoprotein E gene-ε4 allele; CI, confidence intervals; TIA, transient ischemic attack.