Insulin resistance predicts brain amyloid deposition in late middle‐aged adults

Willette, Auriel A.; Johnson, Sterling C.; Birdsill, Alex C.; Sager, Mark A.; Christian, Bradley T.; Baker, Laura D.; Craft, Suzanne; Oh, Jennifer M.; Statz, E. H.; Hermann, Bruce P.; Jonaitis, Erin M.; Koscik, Rebecca L.; Rue, Asenath La; Asthana, Sanjay; Bendlin, Barbara B.

doi:10.1016/j.jalz.2014.03.011

Cited by 220 publications

(178 citation statements)

References 36 publications

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“…increased sAPPβ) and thus Aβ42 formation. Whilst associations between HOMA-IR and neocortical Aβ burden were not assessed in the latter study, the findings were suggestive of being consistent with that previously observed 18 . There are number of factors that may account for the differences in the findings in our cohort and the Wisconsin cohorts.…”

Section: Discussionsupporting

confidence: 89%

“…Age may have a major role in determining where in the progression of AD pathology, IR has the greatest impact. The participants in the Wisconsin studies were younger (57.7 yrs 49 , and 60 yrs 18 ) compared to our study cohort (CN average age 70 yrs.) and other cohorts where no associations with Aβ-amyloid was reported (~75 yrs.…”

Section: Discussionmentioning

confidence: 62%

“…Two recent studies have shown increases in HOMA-IR associated with increases in Aβ 18,48 . The study by Willette et al 18 , showed that higher HOMA-IR was associated with higher amyloid load (as assessed by PiB-PET) in normoglycaemic participants recruited from the Wisconsin Registry for Alzheimer's disease Prevention (WRAP).…”

Section: Discussionmentioning

confidence: 97%

“…The study by Willette et al 18 , showed that higher HOMA-IR was associated with higher amyloid load (as assessed by PiB-PET) in normoglycaemic participants recruited from the Wisconsin Registry for Alzheimer's disease Prevention (WRAP). The study performed analysis of HOMA-IR with PiB-PET and did not include CSF Aβ42, or CSF T-tau/P-tau levels.…”

Section: Discussionmentioning

confidence: 99%

“…Together, these findings suggest that IR/T2D is not associated with cerebral accumulation of Aβ but with other hallmarks of the disease. However, in a recent cross-sectional study, Aβ deposition was associated with a higher Homeostatic Model Assessment of IR (HOMA-IR) in late-middle aged, normoglycaemic cognitively normal participants 18 . The conflicting results in the current literature may be in part due to demographic differences in populations (e.g.…”

Section: Growing Evidence Supports the Hypothesis That Type 2 Diabetementioning

confidence: 91%

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[P4–134]: Insulin Resistance Is Associated With Reductions in Specific Cognitive Domains and Increases in CSF Tau in Cognitively Normal Adults

Laws

Gaskin

Woodfield

et al. 2017

Alzheimer's & Dementia

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Growing evidence supports the hypothesis that type 2 diabetes (T2D) increases the risk of developing dementia. Experimental evidence from mouse models demonstratesEpidemiological studies indicate that Type 2 diabetes (T2D) is associated with an increased risk of dementia [1][2][3][4][5] . Clinical studies using cross-sectional designs support this association by showing that cognition is worse in patients with T2D as compared to matched controls without T2D 6,7 . Furthermore, studies of structural magnetic resonance imaging (MRI) show that in T2D cognitive impairment is associated with greater levels of vascular

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Section: Discussionsupporting

confidence: 89%

Section: Discussionmentioning

confidence: 62%

Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

Section: Growing Evidence Supports the Hypothesis That Type 2 Diabetementioning

confidence: 91%

See 3 more Smart Citations

[P4–134]: Insulin Resistance Is Associated With Reductions in Specific Cognitive Domains and Increases in CSF Tau in Cognitively Normal Adults

Laws

Gaskin

Woodfield

et al. 2017

Alzheimer's & Dementia

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

et al. 2015

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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.

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Evaluation of Amyloid Protective Factors and Alzheimer Disease Neurodegeneration Protective Factors in Elderly Individuals

et al. 2017

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IMPORTANCE While amyloid and neurodegeneration are viewed together as Alzheimer disease pathophysiology (ADP), the factors that influence amyloid and AD-pattern neurodegeneration may be considerably different. Protection from these ADP factors may be important for aging without significant ADP. OBJECTIVE To identify the combined and independent protective factors for amyloid and AD-pattern neurodegeneration in a population-based sample and to test the hypothesis that "exceptional agers" with advanced ages do not have significant ADP because they have protective factors for amyloid and neurodegeneration. DESIGN, SETTING, AND PARTICIPANTS This cohort study conducted a prospective analysis of 942 elderly individuals (70-Ն90 years) with magnetic resonance imaging and Pittsburgh compound B-positron emission tomography scans enrolled in the Mayo Clinic Study of Aging, a longitudinal population-based study of cognitive aging in Olmsted County, Minnesota. We operationalized "exceptional aging" without ADP by considering individuals 85 years or older to be without significant evidence of ADP. MAIN OUTCOMES AND MEASURES We evaluated predictors including demographics, APOE, intellectual enrichment, midlife risk factors (physical inactivity, obesity, smoking, diabetes, hypertension, and dyslipidemia), and the total number of late-life cardiac and metabolic conditions. We used multivariate linear regression models to identify the combined and independent protective factors for amyloid and AD-pattern neurodegeneration. Using a subsample of the cohort 85 years of age or older, we computed Cohen d-based effect size estimations to compare the quantitative strength of each predictor variable in their contribution with exceptional aging without ADP. RESULTS The study participants included 423 (45%) women and the average age of participants was 79.7 (5.9) years. Apart from demographics and the APOE genotype, only midlife dyslipidemia was associated with amyloid deposition. Obesity, smoking, diabetes, hypertension, and cardiac and metabolic conditions, but not intellectual enrichment, were associated with greater AD-pattern neurodegeneration. In the 85 years or older cohort, the Cohen d results showed small to moderate effects (effect sizes > 0.2) of several variables except job score and midlife hypertension in predicting exceptional aging without ADP. CONCLUSIONS AND RELEVANCE The protective factors that influence amyloid and AD-pattern neurodegeneration are different. "Exceptional aging" without ADP may be possible with a greater number of protective factors across the lifespan but warrants further investigation.

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Insulin resistance predicts brain amyloid deposition in late middle‐aged adults

Cited by 220 publications

References 36 publications

[P4–134]: Insulin Resistance Is Associated With Reductions in Specific Cognitive Domains and Increases in CSF Tau in Cognitively Normal Adults

[P4–134]: Insulin Resistance Is Associated With Reductions in Specific Cognitive Domains and Increases in CSF Tau in Cognitively Normal Adults

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

Evaluation of Amyloid Protective Factors and Alzheimer Disease Neurodegeneration Protective Factors in Elderly Individuals

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