Sex modifies the associations of regional fat with cognitive functioning and AD‐related brain volumes, in Israeli middle‐aged adults at high AD risk

Abstract

AbstractBackgroundHigh body mass index (BMI) has been consistently linked to poorer cognition and higher dementia risk, with different associations in males and females. However, BMI does not represent well specific fat depots. We examined in middle‐aged adults at high Alzheimer’s dementia (AD) risk, whether regional abdominal adiposity is associated with cognitive functioning and brain indices and whether sex modifies these associations.Methods204 healthy Israeli middle‐aged AD offspring (59.44 [SD = 7.60] years old, 60% females) underwent abdominal Magnetic Resonance Imaging (MRI) to quantify hepatic, pancreatic, and peripheral fat %‐visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT). A broad cognitive battery defined global cognition and specific cognitive domains (episodic memory, working memory, executive functions, and language). A subsample of 142 participants had brain MRI to assess regional brain volumes (total gray matter [GM], hippocampus, and inferior, middle, and superior frontal gyrus [IFG, MFG, and SFG, respectively]). Partial correlations examined associations of regional abdominal adiposity with cognitive functioning, and brain indices, adjusting for age, sex, education, BMI, and time interval between abdominal MRI and the dependent variable. Fisher‐z transformation compared partial correlations between males and females.ResultsIn the whole sample, the only significant association was of higher hepatic fat % with lower GM volume (r = ‐264, p = 0.003), with similar associations in males and females. Only in males, higher pancreatic fat % was associated with lower global cognitive functioning (Males: r = ‐.276, p = .028; Females: r = 0.009, p = 0.93), executive functioning (Males: r = ‐0.267, p = 0.034; Females: r = 0.015, p = 0.87) and episodic memory (Males: r = ‐0.278, p = 0.027; Females: r = 0.068, p = 0.484) as well as with lower IFG volume (Males: r = ‐0.343, p = .017; Females: r = 0.117; p = 0.326). Also only in males, higher VAT% was associated with SFG volume (Males: r = .261, p = .045; Females: r = ‐0.198; p = 0.091).ConclusionIn middle‐aged males, but not in females, at high AD risk, regional abdominal adiposity, primarily pancreatic fat, was associated with lower cognitive functioning and lower AD‐related brain volumes. Results suggest sex differences in the contributions of fat to brain and cognitive aging. Since fat % is modifiable, these results may suggest that interventions to decrease distinct fats for the advancement of brain health must be sex‐specific.