Adiposity impacts cognitive function in Asian populations: an epidemiological and Mendelian Randomization study

Abstract

Background: Obesity and related metabolic disturbances including diabetes, hypertension and hyperlipidemia predict future cognitive decline. Asia has a high prevalence of both obesity and metabolic disease, potentially amplifying the future burden of dementia in the region. We aimed to investigate the impact of adiposity and metabolic risk on cognitive function in Asian populations, using an epidemiological analysis and a two-sample Mendelian Randomization (MR) study.

Methods: The Health for Life in Singapore (HELIOS) Study is a population-based cohort of South-East-Asian men and women in Singapore, aged 30-84 years. We analyzed 8769 participants with metabolic and cognitive data collected between 2018 and 2021. Whole-body fat mass was quantified with Dual X-Ray Absorptiometry (DEXA). Cognition was assessed using a computerized cognitive battery. An index of general cognition ' g ' was derived through factor analysis. We tested the relationship of fat mass indices and metabolic measures with ' g ' using regression approaches. We then performed inverse-variance-weighted MR of adiposity and metabolic risk factors on ' g ', using summary statistics for genome-wide association studies of BMI, visceral adipose tissue (VAT), waist-hip-ratio (WHR), blood pressure, HDL cholesterol, triglycerides, fasting glucose, HbA1c, and general cognition.

Findings: Participants were 58.9% female, and aged 51.4 (11.3) years. In univariate analysis, all 29 adiposity and metabolic measures assessed were associated with ' g ' at P < 0.05. In multivariable analyses, reduced ' g ' was consistently associated with increased visceral fat mass index and lower HDL cholesterol (P < 0.001), but not with blood pressure, triglycerides, or glycemic indices. The reduction in ' g ' associated with 1SD higher visceral fat, or 1SD lower HDL cholesterol, was equivalent to a 0.7 and 0.9-year increase in chronological age respectively (P < 0.001). Inverse variance MR analyses showed that reduced ' g ' is associated with genetically determined elevation of VAT, BMI and WHR (all P < 0.001). In contrast, MR did not support a causal role for blood pressure, lipid, or glycemic indices on cognition.

Interpretation: We show an independent relationship between adiposity and cognition in a multi-ethnic Asian population. MR analyses suggest that both visceral adiposity and raised BMI are likely to be causally linked to cognition. Our findings have important implications for preservation of cognitive health, including further motivation for action to reverse the rising burden of obesity in the Asia-Pacific region.

Funding: The Nanyang Technological University-the Lee Kong Chian School of Medicine, National Healthcare Group, National Medical Research Council, Ministry of Education, Singapore.

Keywords: Adiposity; Aging; Asia; Cardiovascular risk factors; Cognitive function; DEXA; General cognition; Mendelian Randomization; Metabolic syndrome; Visceral adiposity.

Fig. 1

Univariate and multivariate associations of visceral adiposity and metabolic phenotypes to general cognition. All variables were z-normalized, and all associations were adjusted for sex, age, and ethnicity. A) A volcano plot summarizing multiple univariate associations. X-axis = standardized beta of z-scores; Y-axis = −¹⁰log(p). Dotted horizontal lines were to signify p ≤ 0.05 and p ≤ 10⁻¹⁰. FMI = Fat Mass Index; MetS_status = status of metabolic syndrome (having 3 or more out of 5 symptoms); MetS_sum = metabolic syndrome severity index based on counts of symptoms ranging from 0 to 5. MetS_continuous = metabolic syndrome continuous scores. SBP and DBP = systolic and diastolic blood pressure, respectively. TC = total cholesterol. LDL and HDL = Low- and High-density lipoproteins, respectively. B) A heatmap depicting 4 multivariate regression models comparing i) visceral BMI with alternative adiposity indices ii) BMI-adjusted waist circumference; iii) BMI-adjusted waist-hip-ratio; and iv) BMI. The number within each cell indicates beta coefficient. White NA cell indicates excluded factors. ∗∗p ≤ 0.001; ∗p ≤ 0.05, >0.001. In model iv), the p value for BMI = 0.08. C) A forest plot summarizing cognitive aging of adiposity and metabolic risk factors calculated from the multivariate regression models in sub-Figure B), and a replication of the same multivariate regression models using the UK Biobank dataset (n = 48,135). Cognitive aging = β of a risk factor to ‘g’/β of 1 year of increased age to ‘g’.

Fig. 2

Two-sample Mendelian Randomization reveals causal evidence for visceral adiposity in influencing general cognition. The forest plots illustrate standardized beta (95% Confidence Interval) for each two-sample MR in inverse variance weighted, MR Egger and weighted median. BMI = Body Mass Index; waist_BMI = Waist Circumference adjusted for BMI; WHR_BMI = Waist Hip Circumference adjusted for BMI; VAT = Visceral Adipose Tissue; SBP = Systolic Blood Pressure; DBP = Diastolic Blood Pressure; Trig = Triglycerides; HDL = High-density lipoproteins; Educ.Lvl = Education levels. VAT_no_BMI refers to two-sample MR performed without SNPs that are also genetic variants for BMI.