Association of Insulin Resistance With Cerebral Glucose Uptake in Late Middle–Aged Adults at Risk for Alzheimer Disease

Abstract

IMPORTANCE Converging evidence suggests that Alzheimer disease (AD) involves insulin signaling impairment. Patients with AD and individuals at risk for AD show reduced glucose metabolism, as indexed by fludeoxyglucose F 18-labeled positron emission tomography (FDG-PET).OBJECTIVES To determine whether insulin resistance predicts AD-like global and regional glucose metabolism deficits in late middle-aged participants at risk for AD and to examine whether insulin resistance-predicted variation in regional glucose metabolism is associated with worse cognitive performance. DESIGN, SETTING, AND PARTICIPANTSThis population-based, cross-sectional study included 150 cognitively normal, late middle-aged (mean [SD] age, 60.7 [5.8] years) adults from the Wisconsin Registry for Alzheimer's Prevention (WRAP) study, a general community sample enriched for AD parental history. Participants underwent cognitive testing, fasting blood draw, and FDG-PET at baseline. We used the homeostatic model assessment of peripheral insulin resistance (HOMA-IR). Regression analysis tested the statistical effect of HOMA-IR on global glucose metabolism. We used a voxelwise analysis to determine whether HOMA-IR predicted regional glucose metabolism. Finally, predicted variation in regional glucose metabolism was regressed against cognitive factors. Covariates included age, sex, body mass index, apolipoprotein E ε4 genotype, AD parental history status, and a reference region used to normalize regional uptake.MAIN OUTCOMES AND MEASURES Regional glucose uptake determined using FDG-PET and neuropsychological factors. RESULTS Higher HOMA-IR was associated with lower global glucose metabolism (β = −0.29; P < .01) and lower regional glucose metabolism across large portions of the frontal, lateral parietal, lateral temporal, and medial temporal lobes (P < .001). The association was especially robust in the left medial temporal lobe (R 2 = 0.178). Lower glucose metabolism in the left medial temporal lobe predicted by HOMA-IR was significantly related to worse performance on the immediate memory (β = 0.317; t 148 = 4.08; P < .001) and delayed memory (β = 0.305; t 148 = 3.895; P < .001) factor scores. CONCLUSIONS AND RELEVANCEOur results show that insulin resistance, a prevalent and increasingly common condition in developed countries, is associated with significantly lower regional cerebral glucose metabolism, which in turn may predict worse memory performance. Midlife may be a critical period for initiating treatments to lower peripheral insulin resistance to maintain neural metabolism and cognitive function.

A Key Role of Insulin Receptors in Memory

“…Impaired insulin sensitivity has been linked to cognitive deficits and structural and functional brain abnormalities in the elderly (15,16). Furthermore, lower levels of insulin and insulin receptors and altered levels of different components of the insulin signaling pathways were described in AD hippocampi, indicating that a scenario of brain insulin resistance develops in AD (17).…”

The human-specificCASP4gene product contributes to Alzheimer-related synaptic and behavioural deficits

“…Since animal blood contains low level of LPS, derived from intestinal microbiota, as well as oxidatively modified lipids, we consider that loss of BBB integrity might cause extravasation of blood LPS and/or oxidatively modified lipids into the brain parenchyma and trigger caspase-4 activation and inflammatory responses in microglial cells. From this perspective, it is also interesting to consider metabolic risk associated with AD, for example as hyperinsulinemia (79), which leads to altered glucose metabolism in the brain (80). Consumption of high-fat diet has been shown to induce an increase in the level of blood LPS in mice and humans (and likely endogenous oxidatively modified lipids as well), leading to metabolic endotoxemia, and insulin resistance (81)(82)(83)(84).…”

The diabetic brain and cognition

“…Third, chronic exposure to hyperglycemia in DM also induces abnormalities in the cerebral capillaries (termed ''vasculopenia'') (Serlin et al 2011). Recent human study in asymptomatic, late middle-aged adults (N = 186) from the Registry for Alzheimer's Prevention who underwent [C-11]Pittsburgh compound B (PiB) position emission tomography as an indicator of amyloid deposition in the brain tested the interaction between insulin resistance and glycemic status on PiB distribution volume in the cerebral cortex (Willette et al 2015a). The results of that study demonstrated that in normoglycemia, higher peripheral insulin resistance corresponded to higher PiB uptake in frontal and temporal areas, indicating that in individuals at risk for AD, peripheral insulin resistance may contribute to and predicts brain amyloid deposition in brain regions affected by AD.…”

“…Insulin resistance predicts medial temporal hypermetabolism in Mild Cognitive Impairment (MCI) conversion to AD (Willette et al 2015b). In addition, changes in glucose uptake in medial temporal regions in AD predict worse memory performance (Willette et al 2015a). Moreover, DM facilitates cognitive decline in patients with mild AD compared to those without comorbid DM (Jellinger 2015a;Ascher-Svanum et al 2015).…”