Association of Insulin Resistance With Cerebral Glucose Uptake in Late Middle–Aged Adults at Risk for Alzheimer Disease
Open accessAbstract
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 PARTICIPANTS: This 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 < .05, familywise error corrected). The association was especially robust in the left medial temporal lobe (R2 = 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; t148 = 4.08; P < .001) and delayed memory (β = 0.305; t148 = 3.895; P < .001) factor scores. CONCLUSIONS AND RELEVANCE: Our 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.
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IN insulin may support impaired brain glucose turnover in patients with AD and at-risk individuals.
“In addition to improvements in insulin signalling, IN insulin may support impaired brain glucose turnover in patients with AD and at-risk individuals.143,144”
From Intranasal insulin (2021) · cites this paper as [143]
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- Authors
- Willette, A. A., Bendlin, B. B., Starks, E. J., Birdsill, A. C., Johnson, S. C., Christian, B. T., Okonkwo, O. C., La Rue, A., Hermann, B. P., Koscik, R. L., Jonaitis, E. M., Sager, M. A., & Asthana, S.
- Affiliations
- Iowa State University (US)
- University of Wisconsin–Madison (US)
- Wisconsin Alzheimer’s Institute, University of Wisconsin School of Medicine and Public Health, Madison
- Corresponding author
- Bendlin, Barbara B.
- ORCID
- Venue
- JAMA Neurology
- Publisher
- American Medical Association (AMA)
- Published
- 2015-09-01
- Volume
- 72
- Issue
- 9
- Pages
- 1013
- ISSN
- 2168-6149 (ISSN-L)
- PMC
- PMC4570876
- OpenAlex
- W1895530546
- Cited by
- 418
- References
- 69
- Citations by year
- 2026: 37 · 2025: 36 · 2024: 35 · 2023: 38 · 2022: 36 · 2021: 46 · 2020: 42 · 2019: 34 · 2018: 26 · 2017: 41 · 2016: 36 · 2015: 11
- FWCI
- 30.67
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- JAMA Neurology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (UL1TR000427)
- National Institute on Aging (R01AG037639, P50AG033514, R01AG021155, R01AG027161)
- National Institute of General Medical Sciences (T32GM008692)
- National Center for Research Resources (UL1RR025011)
- National Center for Advancing Translational Sciences
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (P30HD003352)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
- Keywords
- insulin resistance, Alzheimer's disease risk, brain glucose metabolism, HOMA-IR, FDG-PET, medial temporal lobe, memory performance, insulin signaling, middle-aged adults, cognitive aging, Wisconsin Registry for Alzheimer's Prevention, APOE ε4
- MeSH terms
- Aged, Alzheimer Disease, Cerebral Cortex, Cognition Disorders, Cross-Sectional Studies, Diabetes Mellitus, Female, Glucose, Humans, Insulin Resistance, Male, Middle Aged, Statistics as Topic, Fluorodeoxyglucose F18, Positron-Emission Tomography, Ideal Body Weight
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