Prediabetes Is Associated With Brain Hypometabolism and Cognitive Decline in a Sex-Dependent Manner: A Longitudinal Study of Nondemented Older Adults

Although type 2 diabetes is a well-known risk factor for Alzheimer's disease (AD), little is known about how its precursor—prediabetes—impacts neuropsychological function and brain health. Thus, we examined the relationship between prediabetes and AD-related biological and cognitive/clinical markers in a well-characterized sample drawn from the Alzheimer's Disease Neuroimaging Initiative. Additionally, because women show higher rates of AD and generally more atherogenic lipid profiles than men, particularly in the context of diabetes, we examined whether sex moderates any observed associations. The total sample of 911 nondemented and non-diabetic participants [normal control = 540; mild cognitive impairment (MCI) = 371] included 391 prediabetic (fasting blood glucose: 100–125 mg/dL) and 520 normoglycemic individuals (age range: 55–91). Linear mixed effects models, adjusted for demographics and vascular and AD risk factors, examined the independent and interactive effects of prediabetes and sex on 2–6 year trajectories of FDG-PET measured cerebral metabolic glucose rate (CMRglu), hippocampal/intracranial volume ratio (HV/IV), cerebrospinal fluid phosphorylated tau-(181)/amyloid-β(1−42) ratio (p-tau(181)/Aβ(1−42)), cognitive function (executive function, language, and episodic memory) and the development of dementia. Analyses were repeated in the MCI subsample. In the total sample, prediabetic status had an adverse effect on CMRglu across time regardless of sex, whereas prediabetes had an adverse effect on executive function across time in women only. Within the MCI subsample, prediabetic status was associated with lower CMRglu and poorer executive function and language performance across time within women, whereas these associations were not seen within men. In the total sample and MCI subsample, prediabetes did not relate to HV/IV, p-tau(181)/Aβ(1−42), memory function or dementia risk regardless of sex; however, among incident dementia cases, prediabetic status related to earlier age of dementia onset in women but not in men. Results suggest that prediabetes may affect cognition through altered brain metabolism, and that women may be more vulnerable to the negative effects of glucose intolerance.