Systemic inflammation as a predictor of brain aging: Contributions of physical activity, metabolic risk, and genetic risk

Abstract

Inflammatory processes may contribute to risk for Alzheimer's disease (AD) and age-related brain degeneration. Metabolic and genetic risk factors, and physical activity may, in turn, influence these inflammatory processes. Some of these risk factors are modifiable, and interact with each other. Understanding how these processes together relate to brain aging will help to inform future interventions to treat or prevent cognitive decline. We used brain magnetic resonance imaging (MRI) to scan 335 older adult humans (mean age 77.3 ± 3.4 years) who remained non-demented for the duration of the 9-year longitudinal study. We used structural equation modeling (SEM) in a subset of 226 adults to evaluate whether measures of baseline peripheral inflammation (serum C-reactive protein levels; CRP), mediated the baseline contributions of genetic and metabolic risk, and physical activity, to regional cortical thickness in AD-relevant brain regions at study year 9. We found that both baseline metabolic risk and AD risk variant apolipoprotein E ε4 (APOE4), modulated baseline serum CRP. Higher baseline CRP levels, in turn, predicted thinner regional cortex at year 9, and mediated an effect between higher metabolic risk and thinner cortex in those regions. A higher polygenic risk score composed of variants in immune-associated AD risk genes (other than APOE) was associated with thinner regional cortex. However, CRP levels did not mediate this effect, suggesting that other mechanisms may be responsible for the elevated AD risk. We found interactions between genetic and environmental factors and structural brain health. Our findings support the role of metabolic risk and peripheral inflammation in age-related brain decline.

Associations between rare microglia‐linked Alzheimer's disease risk variants and subcortical brain volumes in young individuals

“…Our observations should be interpreted with several considerations. First, as these three variants considered in this analysis are uncommon (minor allele frequency ,1%), these sample sizes for the respective minor alleles were small (N RANGE: [14][15][16][17][18][19][20][21][22][23]. However, as our observations are consistent with prior associations [7,11,32], we suggest that this work may add important insight into rare AD variants across the lifespan.…”

“…From this data set, 1141 subjects were genotyped, and 1,580,642 single‐nucleotide polymorphism (SNPs) passed initial quality control. Quality control was implemented in PLINK v1.9 [16]. Briefly, SNPs were excluded if the call rate was less than 98%, or if the χ 2 test for Hardy‐Weinberg equilibrium had a P value less than 1 × 10 −4 .…”

Neuroanatomical correlates of food addiction symptoms and body mass index in the general population

“…First evidence suggests that individual differences in OFC thickness partly mediate the genetic risk for obesity (Opel et al, 2017), possibly by provoking, or failing to inhibit, impulsive and compulsive (eating) behavior. Subsequent intake of high fat diet, weight gain and adverse metabolic consequences of obesity, such as increased low-grade inflammation or progressive insulin resistance, might further harm brain tissue (Corlier et al, 2018;Dingess, Darling, Kurt Dolence, Culver, & Brown, 2017;Shaw, Nettersheim, Sachdev, Anstey, & Cherbuin, 2017;Thompson et al, 2017). In this vicious cycle, structural damage to frontal brain regions would contribute to more impulsive and compulsive eating behavior, and lead to even more weight gain or reduced dieting success (DelParigi et al, 2007;Schmidt et al, 2018).…”

Neuroanatomical correlates of food addiction and obesity in the general population

“…Meanwhile, we find strong evidence for an association of BMI and lower cortical thickness in the OFC which might result from the adverse metabolic consequences of obesity (Cazettes et al, 2011;Dingess et al, 2017), and thus not be causally related to food addiction (Marqués-Iturria et al, 2013;Kharabian Masouleh et al, 2016;Thompson et al, 2017). Obesity, and especially visceral fat accumulation, is known to coincide with adverse metabolic responses, such as increased low-grade inflammation or progressive insulin resistance (Van Gaal et al, 2006), that enhance the vulnerability of the brain tissue (Corlier et al, 2018). Therefore, even though an association of reduced OFC thickness and addictive-like eating behavior seems plausible and is somewhat supported by the data, the current cross-sectional study provides evidence for a negative association of obesity and (orbito)frontal cortex thickness, largely independent of food addiction.…”