Insulin signalling in Alzheimer′s disease and diabetes: from epidemiology to molecular links

Ribé, Elena M.; Lovestone, Simon

doi:10.1111/joim.12534

Cited by 67 publications

(60 citation statements)

References 111 publications

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“…Previous research has shown many correlations between inflammation in the brain and neuronal damage [32]. Obesity and insulin resistance are also associated with higher levels of inflammatory biomarkers [33]. …”

Section: Discussionmentioning

confidence: 99%

Peripheral versus Central Index of Metabolic Dysfunction and Associations with Clinical and Pathological Outcomes in Alzheimer’s Disease

McLimans

Webb

Anantharam

et al. 2017

JAD

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Background/Objective Insulin-like growth factor binding protein 2 (IGFBP-2) regulates blood glucose levels, facilitates hippocampal synaptic plasticity and may have a predictive value for Alzheimer’s disease (AD) diagnosis. Methods IGFBP-2 levels were studied in plasma in 566 subjects and in cerebrospinal fluid (CSF) in 245 subjects across the AD spectrum from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Variants in the IGFBP-2 gene were examined. Linear mixed modeling in SPSS tested main effects of IGFBP-2 and interactions with APOE4 on neurocognitive indices and biomarkers. Voxel-wise regression was used to gauge IGFBP-2 and regional gray matter and glucose metabolism associations. Results Each point increase in IGFBP-2 corresponded to a 3 times greater likelihood of having mild cognitive impairment (MCI) or AD. IGFBP-2 showed beneficial associations with respect to cognitive scores in individuals with two APOE4 alleles. Higher IGFBP-2 predicted higher insulin resistance, but not CSF amyloid or tau. Voxel-wise analyses showed that plasma IGFBP-2 predicted lower grey matter volume and FDG metabolism in a large area spanning the frontal, temporal, and occipital lobes. CSF IGFBP-2 levels showed similar voxel-wise analysis results, but were uniquely associated with CSF amyloid and tau. Analysis of single nucleotide polymorphisms (SNPs) in IGFBP-2 showed that subjects carrying risk alleles versus common alleles had increased risk of AD and lower memory scores. Voxel-wise analyses of these SNPs also implicated the hippocampus and prefrontal cortex. Conclusions IGFBP-2 is associated with AD risk and outcomes; plasma IGFBP-2 provides stronger predictive power for brain outcomes, while CSF IGFBP-2 provides improved predictive accuracy for AD CSF biomarkers.

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Section: Discussionmentioning

confidence: 99%

Peripheral versus Central Index of Metabolic Dysfunction and Associations with Clinical and Pathological Outcomes in Alzheimer’s Disease

McLimans

Webb

Anantharam

et al. 2017

JAD

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“…Members of the bone morphogenetic protein family of growth factors have been implicated as crucial modulators of neurogenesis in the adult hippocampus [25, 26] and have been demonstrated to affect amyloid-β-induced neurotoxicity [27, 28] and amyloid plaque burden [29]. In addition, available evidence indicates involvement of insulin and insulin-like growth factor-1 [30] and STAT3 [31] signaling in AD.…”

Section: Discussionmentioning

confidence: 99%

Genetically-Predicted Adult Height and Alzheimer’s Disease

Larsson

Traylor

Burgess

et al. 2017

JAD

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Background Observational studies have linked increased adult height with better cognitive performance and reduced risk of Alzheimer’s disease (AD). It is unclear whether the associations are due to shared biological processes that influence height and AD or due to confounding by early life exposures or environmental factors. Objective To use a genetic approach to investigate the association between adult height and AD. Methods We selected 682 single nucleotide polymorphisms (SNPs) associated with height at genome-wide significance (p < 5 × 10−8) in the Genetic Investigation of ANthropometric Traits (GIANT) consortium. Summary statistics for each of these SNPs on AD were obtained from the International Genomics of Alzheimer’s Project (IGAP) of 17,008 individuals with AD and 37,154 controls. The estimate of the association between genetically predicted height and AD was calculated using the inverse-variance weighted method. Results The odds ratio of AD was 0.91 (95% confidence interval, 0.86–0.95; p = 9.8 × 10−5) per one standard deviation increase (about 6.5 cm) in genetically predicted height based on 682 SNPs, which were clustered in 419 loci. In an analysis restricted to one SNP from each height-associated locus (n = 419 SNPs), the corresponding OR was 0.92 (95% confidence interval, 0.86–0.97; p = 4.8 × 10−3). Conclusion This finding suggests that biological processes that influence adult height may have a role in the etiology of AD.

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“…This has led to increased interest in the role that insulin might play in the nervous system and it is becoming very clear that there is a strong link between diabetes and Alzheimer's disease (Ribe and Lovestone, 2016). Many of the CNS changes associated with diabetes are similar to those observed in Alzheimer's disease, including increased beta amyloid and tau phosphorylation (Akter et al, 2011).…”

Section: Insulin and The Nervous Systemmentioning

confidence: 99%

A Role for Insulin in Diabetic Neuropathy

Grote

Wright

2016

Front. Neurosci.

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The peripheral nervous system is one of several organ systems that are profoundly affected in diabetes. The longstanding view is that insulin does not have a major role in modulating neuronal function in both central and peripheral nervous systems is now being challenged. In the setting of insulin deficiency or excess insulin, it is logical to propose that insulin dysregulation can contribute to neuropathic changes in sensory neurons. This is particularly important as sensory nerve damage associated with prediabetes, type 1 and type 2 diabetes is so prevalent. Here, we discuss the current experimental literature related to insulin's role as a potential neurotrophic factor in peripheral nerve function, as well as the possibility that insulin deficiency plays a role in diabetic neuropathy. In addition, we discuss how sensory neurons in the peripheral nervous system respond to insulin similar to other insulin-sensitive tissues. Moreover, studies now suggest that sensory neurons can also become insulin resistant like other tissues. Collectively, emerging studies are revealing that insulin signaling pathways are active contributors to sensory nerve modulation, and this review highlights this novel activity and should provide new insight into insulin's role in both peripheral and central nervous system diseases.

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Insulin signalling in Alzheimer′s disease and diabetes: from epidemiology to molecular links

Cited by 67 publications

References 111 publications

Peripheral versus Central Index of Metabolic Dysfunction and Associations with Clinical and Pathological Outcomes in Alzheimer’s Disease

Peripheral versus Central Index of Metabolic Dysfunction and Associations with Clinical and Pathological Outcomes in Alzheimer’s Disease

Genetically-Predicted Adult Height and Alzheimer’s Disease

A Role for Insulin in Diabetic Neuropathy

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