Pre-Diabetes, but not Type 2 Diabetes, Is Related to Brain Amyloid in Late Middle-Age

Luchsinger, José A.; Palta, Priya; Rippon, Brady; Sherwood, Greysi; Soto, Luisa M. Solis; Ceballos, Fernando; Laing, Krystal K; Igwe, Kay C.; He, Hengda; Razlighi, Qolamreza R.; Teresi, Jeanne A.; Moreno, Herman; Brickman, Adam M.

doi:10.3233/jad-200232

Cited by 20 publications

(13 citation statements)

References 35 publications

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“…The pattern of results also persisted after excluding participants with T2DM, indicating that even pre-diabetes levels of FBG may negatively impact CBF, especially in the context of an additional AD risk factor (i.e., intrusion errors). These findings are consistent with evidence that pre-diabetes can accelerate cognitive decline (Marseglia et al, 2019) and be associated with greater Aβ on PET (Luchsinger et al, 2020) and more severe MTL neurofibrillary tangle pathology among those at genetic risk for AD (Bangen et al, 2016). Finally, the absence of any main effect of FBG or interaction of FBG and intrusion errors on regional gray matter volumes suggests that these regional CBF patterns may be altered earlier and precede the ultimate downstream structural changes of gray matter degeneration that likely would not be observed until significant tau accumulation, supporting CBF/neurovascular dysfunction as an early biomarker of risk for decline.…”

Section: Discussionsupporting

confidence: 90%

Intrusion errors moderate the relationship between blood glucose and regional cerebral blood flow in cognitively unimpaired older adults

Thomas

Weigand

Cota

et al. 2021

Brain Imaging and Behavior

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Regional cerebral blood flow (CBF) has a complex relationship with cognitive functioning such that cognitively unimpaired individuals at risk for Alzheimer’s disease (AD) may show regional hyperperfusion, while those with cognitive impairment typically show hypoperfusion. Diabetes and word-list intrusion errors are both linked to greater risk of cognitive decline and dementia. Our study examined associations between fasting blood glucose, word-list intrusion errors, and regional CBF. 113 cognitively unimpaired older adults had arterial spin labeling MRI to measure CBF in a priori AD vulnerable regions: medial temporal lobe (MTL), inferior parietal lobe (IPL), precuneus, medial orbitofrontal cortex (mOFC), and pericalcarine (control region). Hierarchical linear regressions, adjusting for demographics, vascular risk, and reference CBF region, examined the main effect of blood glucose on regional CBF as well as whether intrusions moderated this relationship. Higher glucose was associated with higher CBF in the precuneus (β = .134, 95% CI = .007 to .261, p = .039), IPL (β = .173, 95% CI = .072 to .276, p = .001), and mOFC (β = .182, 95% CI = .047 to .320, p = .009). There was no main effect of intrusions on CBF across regions. However, the glucose x intrusions interaction was significant such that having higher glucose levels and more intrusion errors was associated with reduced CBF in the MTL (β = -.186, 95% CI = -.334 to -.040, p = .013) and precuneus (β = -.146, 95% CI = -.273 to -.022, p = .022). These findings may reflect early neurovascular dysregulation, whereby higher CBF is needed to maintain unimpaired cognition in individuals with higher glucose levels. However, lower regional CBF in unimpaired participants with both higher glucose and more intrusions suggests a failure in this early compensatory mechanism that may signal a decrease in neural activity in AD vulnerable regions.

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Section: Discussionsupporting

confidence: 90%

Intrusion errors moderate the relationship between blood glucose and regional cerebral blood flow in cognitively unimpaired older adults

Thomas

Weigand

Cota

et al. 2021

Brain Imaging and Behavior

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“…This was a cross-sectional analysis of a community-based cohort of 333 late middle-aged Hispanic adults without dementia and with functional connectivity data out of 350 recruited between 03/01/2016 and 07/31/2019 in New York City as part of a study of Alzheimer's disease biomarkers ( 14 ). We targeted Hispanics because they are the most common ethnic group in the community surrounding CUIMC ( 15 ) and because there is a paucity of AD biomarkers studies in Non-Whites ( 13 ).…”

Section: Methodsmentioning

confidence: 99%

Brain Amyloid Burden and Resting-State Functional Connectivity in Late Middle-Aged Hispanics

et al. 2020

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Non-linear relations of brain amyloid beta (Aβ) with task- based functional connectivity (tbFC) measured with functional magnetic resonance imaging (fMRI) have been reported in late middle age. Our objective was to examine the association between brain Aβ and resting-state functional connectivity (rsFC) in late middle-aged adults. Global brain Aβ burden was ascertained with 18 F-Florbetaben Positron Emission Tomography (PET); rsFC was ascertained on 3T Magnetic Resonance Imaging (MRI) among 333 late middle-aged Hispanics adults without dementia in four major brain functional connectivity networks: default mode network (DMN), fronto-parietal control network (FPC), salience network (SAL) and dorsal attention network (DAN). We examined the relationship of global brain Aβ with rsFC using multivariable linear regression adjusted for age, sex, education, and APOE-ε4 genotype. We quantified the non-linear associations both with quadratic terms and by categorizing Aβ into three groups: low Aβ, intermediate Aβ, and positive Aβ. We found no significant linear or non-linear associations between Aβ, measured either continuously or categorically, with rsFC in the examined networks. Our null findings may be explained by the younger age of our participants in whom amyloid burden is relatively low. It is also possible that the recently reported non-linear relationship is exclusive to task fMRI and not rsfMRI.

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“…demonstrate the strong predictive relationship between APOE Ɛ4 genotype and Aβ burden; carriers of the allele were more likely to possess intermediate and high levels of Aβ compared to non‐carriers. 43 Future treatments for individuals with T2DM should target physiological processes implicated in increased Aβ generation within the brain. As a result, the progression of the AD pathology may be hindered or stopped altogether.…”

Section: Discussionmentioning

confidence: 99%

Is diabetes associated with increased pathological burden in Alzheimer's disease?

Sadrolashrafi

Craft

Decourt

et al. 2021

Alz & Dem Diag Ass & Dis Mo

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Introduction:We examined the association between Alzheimer's disease (AD) and type 2 diabetes mellitus (DM) and hypothesized that diabetes is associated with an increased pathological burden in clinically and pathologically diagnosed AD. Methods: All data were obtained from the Uniform Data Set (UDS) v3, the Neuropathology Data Set, and the Researcher's Data Dictionary-Genetic Data from the National Alzheimer's Coordinating Center. The dataset (37 cases with diabetes and 1158 cases without) relies on autopsy-confirmed data in clinically diagnosed AD patients who were assessed for diabetes type in form A5 or D2 during at least one visit. Differences in scores were explored using a general linear model. Effect sizes were calculated using sample means and standard deviations (Cohen's d). Results: The presence of diabetes was associated with a lower Thal phase of amyloid plaques (A score; 4.6 ± 0.79 vs. 4.3 ± 0.85, P < .05) and lower Braak stage for neurofibrillary degeneration (B score; 5.58 ± 0.72 vs. 5.16 ± 0.96, P < 0.05) but not for density of neocortical neuritic plaques (CERAD score-C score). The National Institute on Aging-Alzheimer's Association Alzheimer's disease neuropathologic change (ABC score) was not different between AD+DM and AD-DM. Discussion: This pilot study found a significantly lower Thal phase of amyloid plaques and Braak stage for neurofibrillary degeneration in AD-confirmed individuals with diabetes compared to those without. Thus type 2 DM is not associated with increased AD pathology in clinically and pathologically confirmed cases of AD.

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Pre-Diabetes, but not Type 2 Diabetes, Is Related to Brain Amyloid in Late Middle-Age

Cited by 20 publications

References 35 publications

Intrusion errors moderate the relationship between blood glucose and regional cerebral blood flow in cognitively unimpaired older adults

Intrusion errors moderate the relationship between blood glucose and regional cerebral blood flow in cognitively unimpaired older adults

Brain Amyloid Burden and Resting-State Functional Connectivity in Late Middle-Aged Hispanics

Is diabetes associated with increased pathological burden in Alzheimer's disease?

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