Abstract
Epidemiological studies suggest that individuals with type 2 diabetes (T2D) have a twofold to fourfold increased risk for developing Alzheimer’s disease (AD), however, the exact mechanisms linking the two diseases are unknown. In both conditions, the majority of pathophysiological changes, including glucose and insulin dysregulation, insulin resistance, and AD-related changes in Aβ and tau, occur decades before the onset of clinical symptoms and diagnosis. In this study, we investigated the relationship between metabolic biomarkers associated with T2D and amyloid pathology including Aβ levels, from cerebrospinal fluid (CSF) and fasting plasma of healthy, pre-diabetic (PreD), and T2D vervet monkeys (Chlorocebus aethiops sabaeus). Consistent with the human disease, T2D monkeys have increased plasma and CSF glucose levels as they transition from normoglycemia to PreD and diabetic states. Although plasma levels of acylcarnitines and amino acids remained largely unchanged, peripheral hyperglycemia correlated with decreased CSF acylcarnitines and CSF amino acids, including branched chain amino acid (BCAA) concentrations, suggesting profound changes in cerebral metabolism coincident with systemic glucose dysregulation. Moreover, CSF Aβ40 and CSF Aβ42 levels decreased in T2D monkeys, a phenomenon observed in the human course of AD which coincides with increased amyloid deposition within the brain. In agreement with previous studies in mice, CSF Aβ40 and CSF Aβ42 were highly correlated with CSF glucose levels, suggesting that glucose levels in the brain are associated with changes in Aβ metabolism. Interestingly, CSF Aβ40 and CSF Aβ42 levels were also highly correlated with plasma but not CSF lactate levels, suggesting that plasma lactate might serve as a potential biomarker of disease progression in AD. Moreover, CSF glucose and plasma lactate levels were correlated with CSF amino acid and acylcarnitine levels, demonstrating alterations in cerebral metabolism occurring with the onset of T2D. Together, these data suggest that peripheral metabolic changes associated with the development of T2D produce alterations in brain metabolism that lead to early changes in the amyloid cascade, similar to those observed in pre-symptomatic AD.
Highlights
Rates of type 2 diabetes (T2D) and Alzheimer’s disease (AD) are reaching epidemic proportions and are expected to continue to rise over the several decades (Holtzman et al, 2011)
Preclinical studies in mouse models of cerebral amyloidosis suggest that systemic hyperglycemia increases amyloid β (Aβ) levels within the hippocampal interstitial fluid (ISF) by 25%; an effect that is amplified when plaques are already present in the brain during the hyperglycemia challenge (Macauley et al, 2015; Stanley et al, 2016)
PreD and T2D monkeys had elevated fasting blood glucose levels compared to normoglycemic controls [Table 1; p < 0.0001, F(2,9) = 39.17], but there were no differences in fasting insulin levels (Table 1)
Summary
Rates of type 2 diabetes (T2D) and Alzheimer’s disease (AD) are reaching epidemic proportions and are expected to continue to rise over the several decades (Holtzman et al, 2011). Pathological hallmarks of AD, including the extracellular aggregation of amyloid β (Aβ) into amyloid plaques and the intracellular accumulation of the tau protein into neurofibrillary tangles (NFTs), begin decades before cognitive decline and clinical diagnosis (Hardy and Selkoe, 2002; Bateman et al, 2012; Musiek and Holtzman, 2015) While both are considered diseases of aging and mechanisms linking the two conditions remain elusive, epidemiological and cross-sectional studies suggest that individuals with T2D have a twofold to fourfold increased risk for developing AD and dementia and show increased AD pathology (Ott et al, 1999; Crane et al, 2013; Huang et al, 2014). Many non-human primate species develop T2D and amyloid pathology with age (Wagner et al, 2006; Latimer et al, 2019), and represent an important translational tool for examining the metabolic relationship between the two conditions
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