Association Between Midlife Obesity and Its Metabolic Consequences, Cerebrovascular Disease, and Cognitive Decline

Abstract

Context: Chronic obesity is associated with several complications, including cognitive impairment and dementia. However, we have only piecemeal knowledge of the mechanisms linking obesity to central nervous system damage. Among candidate mechanisms are other elements of obesity-associated metabolic syndrome, such as hypertension, dyslipidemia, and diabetes, but also systemic inflammation. While there have been several neuroimaging studies linking adiposity to changes in brain morphometry, a comprehensive investigation of the relationship has so far not been done.

Objective: To identify links between adiposity and cognitive dysfunction.

Methods: This observational cohort study (UK Biobank), with an 8-year follow-up, included more than 20 000 participants from the general community, with a mean age of 63 years. Only participants with data available on both baseline and follow-up timepoints were included. The main outcome measures were cognitive performance and mediator variables: hypertension, diabetes, systemic inflammation, dyslipidemia, gray matter measures, and cerebrovascular disease (volume of white matter hyperintensities on magnetic resonance imaging).

Results: Using structural equation modeling, we found that body mass index, waist-to-hip ratio, and body fat percentage were positively related to higher plasma C-reactive protein, dyslipidemia, hypertension, and diabetes. In turn, hypertension and diabetes were related to cerebrovascular disease. Finally, cerebrovascular disease was associated with lower cortical thickness and volume and higher subcortical volumes, but also cognitive deficits (largest significant pcorrected = 0.02).

Conclusions: We show that adiposity is related to poor cognition, with metabolic consequences of obesity and cerebrovascular disease as potential mediators. The outcomes have clinical implications, supporting a role for the management of adiposity in the prevention of late-life dementia and cognitive decline.

Keywords: cerebrovascular disease; cognition; gray matter; obesity; white matter hyperintensities.

Figure 1.

Schematic representation of the structural equation model. Dashed lines represent nonsignificant associations. Note that not all measured variables contributing to cortical thickness, cortical volume, and subcortical volume are depicted in this graph. Age and sex were added to each of the associations between variables as covariates of no interest and are not depicted here. Education was added in each regression with cognition as outcome variable and is not depicted here. Abbreviations: CbVD, cerebrovascular disease; CRP, C-reactive protein; DBP, diastolic blood pressure; EF, executive function; FI, fluid intelligence; HbA1c, hemoglobin A1c; HDL, high-density lipoprotein; HT, hypertension; PM, prospective memory; RT, reaction time; SBP, systolic blood pressure; subc., subcortical; TG, triglycerides, VM, visuospatial memory; WM, working memory; WMH, white matter hyperintensities.

Figure 2.

Associations between: a, body mass index and cortical thickness; b, waist-to-hip ratio and cortical thickness; c, body fat percentage and cortical thickness; d, body mass index and cortical volume; e, waist-to-hip ratio and cortical volume; f, body fat percentage and cortical volume; g, body mass index and subcortical volume; h, waist-to-hip ratio and subcortical volume; i, body fat percentage and subcortical volume. Figures depict T-values of significant associations. Warm colors depict positive associations, while cold colors depict negative associations. T-value cutoff for a significant association: +-2.1294. Associations were corrected for multiple comparisons using Benjamini-Hochberg correction. Abbreviations: BF%, body fat percentage; BMI, body mass index; CT, cortical thickness; VOL, cortical volume; WHR, waist-to-hip-ratio.

Figure 3.

Proportion of relationships mediated by white matter hyperintensities between a, body mass index and cortical thickness; b, waist-to-hip ratio and cortical thickness; c, body fat percentage and cortical thickness; d, body mass index and cortical volume; e, waist-to-hip ratio and cortical volume; f, body fat percentage and cortical volume; g, body mass index and subcortical volume; h, waist-to-hip ratio and subcortical volume; i, body fat percentage and subcortical volume. Figures depict only significant consistent mediations. Associations were corrected for multiple comparisons using Benjamini-Hochberg correction. Abbreviations: BF%, body fat percentage; BMI, body mass index; CT, cortical thickness; VOL, cortical volume; WHR, waist-to-hip-ratio.