Phenotypic heterogeneity of obesity‐related brain vulnerability: one‐size interventions will not fit all

Abstract

Intact memory and problem solving are key to functional independence and quality of life in older age. Considering the unprecedented demographic shift toward a greater number of older adults than children in the United States in the next few decades, it is critically important for older adults to maintain work productivity and functional independence for as long as possible. Implementing early interventions focused on modifiable risk factors for cognitive decline at midlife is a strategy with the highest chance of success at present, bearing in mind the current lack of dementia cures. We present a selective, narrative review of evidence linking nutrition, body composition, vascular health, and brain function in midlife to highlight the phenotypic heterogeneity of obesity-related brain vulnerability and to endorse the development of individually tailored lifestyle modification plans for primary prevention of cognitive decline.

Associations between vascular risk factors and brain MRI indices in UK Biobank

“…Though there is some tendency for VRFs to co-occur, our simultaneous modelling indicated that smoking, hypertension, pulse pressure, diabetes, and WHR each made unique statistical contributions to lower global brain and higher WMH volumes. Whereas it is possible that associations between obesity and brain structure are partly attributable to the findings that obesity promotes arterial stiffness, it is possible that the unique statistical contributions identified herein could pertain to other mechanisms through which body composition is linked to negative brain and cognitive endpoints, including metabolic and endocrine routes, which may have independent neurovascular consequences 17 , 26 , 48 . Similarly, the unique contributions to brain structure made by hypertension and smoking may indicate that the deleterious effects of smoking on the brain extend beyond putative alterations in hypertension 49 .…”

Associations between vascular risk factors and brain MRI indices in UK Biobank

“…Though there is some tendency for VRFs to co-occur, our simultaneous modelling indicated that smoking, hypertension, pulse pressure, diabetes and WHR each made unique statistical contributions to lower global brain and higher WMH volumes. Whereas it is possible that associations between obesity and brain structure are partly attributable to the findings that obesity promotes arterial stiffness, it is possible that the unique statistical contributions identified herein could pertain to other mechanisms through which body composition is linked to negative brain and cognitive endpoints, including metabolic and endocrine routes, which may have independent neurovascular consequences 17,24,45 . Similarly, the unique contributions to brain structure made by hypertension and smoking may indicate that the deleterious effects of smoking on the brain extend beyond putative alterations in hypertension 46 .…”

“…Cerebral small vessel disease (CSVD; a constellation of clinical and imaging findings of presumed vascular aetiology 13 ) causes ~45% of dementia and 20% of stroke worldwide 14 , though its pathophysiology and the interplay among its many possible determinants are not well understood 13 . Though the specific mechanisms by which these determinants, often known as vascular risk factors (VRFs), remain to be fully elucidated, anthropometric indices (waist:hip ratio and body mass index; WHR and BMI), blood glucose, elevated pulse pressure, chronic hypertension, diabetes and hypercholesterolaemia are all putative VRFs that have been associated with cerebrovascular complications [15][16][17][18] . The resultant damage to cerebral vasculature and increased vascular resistance are thought to deregulate cerebral blood flow, alongside blood brain barrier dysfunction, and could further lead to abnormal protein synthesis and formation of Alzheimer's disease-typical plaques and tangles 15,18,19 .…”

Epigenetic predictors of lifestyle traits applied to the blood and brain

“…One of the discussed studies was able to show that smoking had unique statistical contributions to brain morphology when modelling against many other vascular risk factors (VRFs) in a large population (N=9,722) (Cox et al ., 2019); these findings indicate that there some brain areas may be more susceptible to smoking. As VRFs (such as smoking) associate with various adverse outcomes including cognitive ageing and dementia (Haley et al ., 2018; Pasha et al ., 2018; Sweeney et al ., 2018; Cheng et al ., 2020), areas such as BA46 may be more susceptible to ageing and effects that underpin cognitive function, as they show the strongest VRF-related coupling in blood and brain. A larger sample with more detailed regional sampling across the brain will be required to investigate this.…”