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

Sadrolashrafi, Kaviyon; Craft, Suzanne; Decourt, Boris; Adem, Abdu; Wilson, Jeffrey R.; Miller, Justin; Sabbagh, Marwan N.

doi:10.1002/dad2.12248

Cited by 9 publications

(11 citation statements)

References 44 publications

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“…Thus, the cases of all-cause dementia among APOE ε4 noncarriers may include a greater number of vascular dementia, whereas APOE ε4 is associated with bona fide “pure” AD. Studies in which AD diagnosis is limited to neuropathologically confirmed cases have consistently found no association with type-2 diabetes or metabolic syndrome (Abner et al, 2016; Groeneveld et al, 2019; Hassing et al, 2002; Heyman et al, 1984; Peila et al, 2002; Sadrolashrafi et al, 2021; Thambisetty et al, 2013). Likewise, we find disparate effects of type-2 diabetes and AD on cerebral glucose transporters (manuscript in preparation).…”

Section: Discussionmentioning

confidence: 99%

Amyloid β-peptide impacts on glucose regulation are dependent on apolipoprotein E genotype

Sung

Barger

2022

Preprint

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The apolipoprotein E gene (APOE) constitutes the greatest genetic risk factor for Alzheimer's disease, wherein the ϵ4 allele confers a dramatically elevated risk compared to the more common ϵ3 allele. Biological mechanisms that differ across these alleles have been explored in mouse models wherein the murine Apoe gene has undergone targeted replacement with sequences encoding human ApoE3 or -4 (ApoE-TR mice). Results with such models have indicated that the two variants of ApoE produce differential effects on energy metabolism, including metabolic syndrome. However, glucose regulation has not been compared in ApoE-TR mice with and without Aβ accumulation. We crossed ApoE3- and ApoE4-TR mice with a transgenic line that accumulates human Aβ(1-42). In male ApoE3-TR mice, introduction of Aβ caused aberrations in glucose tolerance and membrane translocation of astrocytic glucose transporter 1. Phosphorylation of Tau at AD-relevant sites was correlated with glucose intolerance. These effects appeared independent of insulin dysregulation and were not observed in females. In ApoE4-TR mice, the addition of Aβ had no significant effects due to a trend toward perturbation of the baselines. Thus, metabolic changes may have a larger interaction with AD pathology and its consequences in individuals who do not carry an APOE ϵ4 allele. The fact that ApoE4 generally failed to exacerbate the effects of Aβ on glucose further highlights the growing distinction between the glycemic effects of Aβ versus those of peripheral insulin resistance.

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Section: Discussionmentioning

confidence: 99%

Amyloid β-peptide impacts on glucose regulation are dependent on apolipoprotein E genotype

Sung

Barger

2022

Preprint

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“…RAGE activation regulates βand γ-secretase cleavage of amyloid precursor protein, to generate Aβ [67]. Membrane-bound RAGE has also been shown to transport Aβ into the brain [68] by mediating amyloid transport across the blood-brain barrier [69,70]. A mouse transgenic model of AD showed that Aβ binds to RAGE, resulting in transport of Aβ from the bloodstream across the blood-brain barrier [70].…”

Section: Ages In Neurocognitive and Mental Disorders: Mechanisms Of A...mentioning

confidence: 99%

The Effects of Dietary Advanced Glycation End-Products on Neurocognitive and Mental Disorders

et al. 2022

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Advanced glycation end products (AGEs) are glycated proteins or lipids formed endogenously in the human body or consumed through diet. Ultra-processed foods and some culinary techniques, such as dry cooking methods, represent the main sources and drivers of dietary AGEs. Tissue accumulation of AGEs has been associated with cellular aging and implicated in various age-related diseases, including type-2 diabetes and cardiovascular disease. The current review summarizes the literature examining the associations between AGEs and neurocognitive and mental health disorders. Studies indicate that elevated circulating AGEs are cross-sectionally associated with poorer cognitive function and longitudinally increase the risk of developing dementia. Additionally, preliminary studies show that higher skin AGE accumulation may be associated with mental disorders, particularly depression and schizophrenia. Potential mechanisms underpinning the effects of AGEs include elevated oxidative stress and neuroinflammation, which are both key pathogenetic mechanisms underlying neurodegeneration and mental disorders. Decreasing dietary intake of AGEs may improve neurological and mental disorder outcomes. However, more sophisticated prospective studies and analytical approaches are required to verify directionality and the extent to which AGEs represent a mediator linking unhealthy dietary patterns with cognitive and mental disorders.

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“…95 However, others failed to show a correlation between type II diabetes and AD pathology. 96,97 Furthermore, in several diabetic mouse models of AD, increased tau phosphorylation is observed. 98 Indeed, defects in insulin receptor function, induced in rats by intracerebroventricular injection of streptozotocin, led to impaired learning, memory and cognition, along with decreased glucose uptake and oxidative glucose metabolism.…”

Section: Does a Loss Of Insulin Signalling Reduce Glucose Uptake In N...mentioning

confidence: 99%

Potential mechanisms to modify impaired glucose metabolism in neurodegenerative disorders

McDonald

Lerskiatiphanich

Woodruff

et al. 2022

J Cereb Blood Flow Metab

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Neurodegeneration refers to the selective and progressive loss-of-function and atrophy of neurons, and is present in disorders such as Alzheimer’s, Huntington’s, and Parkinson’s disease. Although each disease presents with a unique pattern of neurodegeneration, and subsequent disease phenotype, increasing evidence implicates alterations in energy usage as a shared and core feature in the onset and progression of these disorders. Indeed, disturbances in energy metabolism may contribute to the vulnerability of neurons to apoptosis. In this review we will outline these disturbances in glucose metabolism, and how fatty acids are able to compensate for this impairment in energy production in neurodegenerative disorders. We will also highlight underlying mechanisms that could contribute to these alterations in energy metabolism. A greater understanding of these metabolism-neurodegeneration processes could lead to improved treatment options for neurodegenerative disease patients.

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

Cited by 9 publications

References 44 publications

Amyloid β-peptide impacts on glucose regulation are dependent on apolipoprotein E genotype

Amyloid β-peptide impacts on glucose regulation are dependent on apolipoprotein E genotype

The Effects of Dietary Advanced Glycation End-Products on Neurocognitive and Mental Disorders

Potential mechanisms to modify impaired glucose metabolism in neurodegenerative disorders

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