Background Advanced glycations end products increase oxidant stress, inflammation, and neurotoxicity. Serum levels are increased in diabetes and aging. We examined the relationship between serum methylglyoxal derivatives (sMG), and cognitive decline, in 267 non-demented elderly. Methods Tobit mixed regression models assessed the association of baseline sMG with cognitive decline in the Mini Mental State Exam (MMSE) over time, controlling for sociodemographic factors (age, sex, and years of education), cardiovascular risk factors (diabetes and presence of an APOE4 allele), and kidney function. sMG was assessed by ELISA. Results The fully adjusted model showed an annual decline of 0.26 MMSE points per unit increase in baseline sMG (p=0.03). Significance was unchanged as additional risk factors were added to the model. The interactions of sMG with diabetes, sex, age, kidney function, and APOE4 genotype were not significant. Conclusions Higher levels of baseline sMG were associated with a faster rate of cognitive decline, after adjusting for several sociodemographic and clinical characteristics. This relationship did not differ by sex, APOE4 genotype, or diabetes status suggesting its generality. Since subjects were cognitively normal at the beginning of the study, elevated sMG may be indicative of brain cell injury initiated before clinically evident cognitive compromise.

Introduction: The female advantage in brain metabolic function may confer cognitive resilience against Alzheimer's disease (AD). Methods: A total of 1259 participants (44% women; 52% mild cognitive impairment; 18% AD) aged 55 to 90 from the Alzheimer's Disease Neuroimaging Initiative (ANDI) completed tests of global cognition, verbal memory, and executive function, and neuroimaging assessments of regional glucose metabolism, hippocampal volume (HV), and amyloid beta (Aβ). We examined sex differences in brain metabolism and cognition by AD biomarker quartiles (Aβ, HV). We then examined if metabolism mediates sex differences in cognition. Results: Metabolism was higher in women versus men when pathology was mild‐to‐moderate (quartiles 2 to 3). Women outperformed men on all cognitive outcomes at ≥1 biomarker quartile, reflecting minimal‐to‐moderate pathology; however, these differences were eliminated/attenuated after adjusting for metabolism. The female advantage in verbal memory was also observed at minimal pathology quartiles but was unchanged after metabolism adjustment. Discussion: Women's greater brain metabolism may confer cognitive resilience against early AD.

Background Cognitively normal women have consistently shown higher brain glucose metabolism than men across the adult life span in key Alzheimer’s disease (AD) related regions. The goal of our work was to examine whether these sex differences provide resilience to the effect of AD pathologies on cognition. Method 1259 participants (44% women; aged 55‐90) from the Alzheimer’s Disease Neuroimaging Initiative completed the Mini Mental Status Exam (MMSE), the Clinical Dementia Rating‐Sum of Boxes (CDR‐SOB) and neuroimaging assessments of glucose metabolism (FDG‐PET) in regions of interest (posterior cingulate, angular gyrus, inferior/middle temporal gyrus), brain volumes (T1 MRI) and cortical amyloid‐β burden (AV45‐PET). First, we examined whether sex moderates the relationship between brain glucose metabolism in the grey matter and whole brain gray matter volume (WBV) in the overall sample and within cognitively normal (CN), amnestic mild cognitive impairment (aMCI) and AD diagnostic groups. Second, we divided the AD pathological markers of cortical amyloid‐β burden and hippocampal volume (HV) into quartiles and examined sex differences in MMSE and CDR‐SOB scores within biomarker quartiles before and after adjusting for brain metabolism and the covariates of age, education, APOE4 and WBV. Result In the overall sample and within aMCI, metabolism was higher in women versus men per unit of WBV when WBV was moderate/large but showed a steeper decrease as WBV diminished. Women showed better MMSE and CDR‐SOB scores than men (ps<.05) at mild/moderate levels of AD brain pathology (quartiles 1‐3), particularly after adjustment for sex differences in brain volume. In contrast, men and women showed similarly poor MMSE and CDR‐SOB scores within the highest quartile of severe AD brain pathology (ps>.05). The female cognitive advantage at mild/moderate quartiles of AD pathological markers was eliminated or markedly attenuated (41‐94%) after adjusting for brain metabolism Conclusion More efficient neural function in women versus men may provide women greater resilience against the effects of early AD pathological changes and serve as a mechanism underlying better clinical profiles in women in early disease process and faster decline thereafter. These sex‐based mechanistic differences will have important implications for disease identification and treatment.