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Alzheimer’s Disease and Diabetes: Insulin Signaling as the Bridge Linking Two Pathologies

ByCrossFitJanuary 13, 2020

This 2019 review summarizes potential mechanisms linking Alzheimer’s disease and diabetes.

Neurodegeneration will develop in 29% of diabetics at some point in their lives (1). Brain insulin resistance is associated with Alzheimer’s disease and cognitive impairment, and the regions of the brain most closely associated with Alzheimer’s pathology — the hippocampus, hypothalamus, and cortex — are also the regions richest in insulin receptors (2). The review authors argue these associations may be causal and explore ways hyperglycemia and impaired brain insulin signaling may directly contribute to cognitive decline and Alzheimer’s disease.

Insulin signaling in the brain triggers neuronal development and synaptic plasticity, while impaired insulin signaling is associated with reduced vascular development (3). Decreased vascular development can itself lead to neuronal inflammation and synapse loss by impairing nutrient transport to and from brain cells (4). Broadly, insufficient insulin activity in the brain and hippocampus specifically has been associated with neurodegeneration, cognitive impairment, and impairments in memory formation (5).

As summarized in the figure below, impairments in the insulin signaling cascade — which involves activation of IRS-1, PI3K, Akt and a variety of other proteins and enzymes — can also be directly linked to multiple elements of Alzheimer’s pathology, including the accumulation of amyloid beta (AB) plaques and hyperphosphorylated tau neurofibrillary tangles (NFTs).

Dysfunctional insulin signaling directly contributes to amyloid beta accumulation. When amyloid precursor protein (APP, the primary function of which is not completely understood) is cleaved in the context of high insulin signaling, it produces a soluble remnant the cell can eliminate. When insulin signaling is deficient, this cleavage instead forms an insoluble amyloid-beta protein fragment, which over time leads to amyloid plaque formation. One of the consequences of these amyloid plaques is impaired insulin receptor functionality. Thus, insulin resistance and amyloid plaque development form a vicious cycle in which initial insulin resistance leads to plaque development, which leads to further insulin resistance (6).

Insulin signaling similarly activates GSK3B, a protein that decreases hyperphosphorylation of tau (the first step toward development of pathological neurofibrillary tangles); thus, impaired insulin signaling allows NFT accumulation (7).

The authors briefly explore additional mechanisms, noting advanced glycation endproducts (AGEs) and decreased sirtuin activity may lead to insulin resistance and increased tau accumulation (8). Increased AGE activity and decreased sirtuin activity are known consequences of diabetes and insulin resistance.

Notably, ApoE4, the strongest genetic risk factor for Alzheimer’s, leads to insulin resistance by decreasing the availability of insulin receptors at the cellular level (9).

The majority of the data supporting these mechanisms has been drawn from animal and in vitro models, thus reflecting the preliminary nature of the hypothesis. Taken together, this early research nonetheless illustrates a variety of mechanisms by which diabetes and/or insulin resistance could directly contribute to the development of Alzheimer’s disease.

Takeaway: Research on the link between insulin resistance and Alzheimer’s disease remains promising but preliminary. However, given the lack of viable alternatives to prevent or treat Alzheimer’s disease and the failure of other theoretical frameworks to deliver clinical improvements, the hypothesis that Alzheimer’s is at least partially the result of insulin resistance, hyperglycemia, or the downstream consequences thereof deserves further exploration.


Notes

  1. Bridging type 2 diabetes and Alzheimer’s disease: Assembling the puzzle pieces in the quest for the molecules with therapeutic potential
  2. Aberrant insulin signaling in Alzheimer’s disease: Current knowledge; Demonstrated brain insulin resistance in Alzheimer’s disease patients is associated with IGF-1 resistance, IRS-1 dysregulation and cognitive decline; Role for neuronal insulin resistance in neurodegenerative diseases; Insulin deficiency exacerbates cerebral amyloidosis and behavioral deficits in an Alzheimer transgenic mouse model; Dysregulation of insulin signaling, glucose transporters, O-GlcNAcylation, and phosphorylation of tau and neurofilaments in the brain: Implication for Alzheimer’s disease
  3. Glucose-induced oxidative stress and programmed cell death in diabetic neuropathy; Synergistic effects of beta-amyloid and ceramide-induced insulin resistance on mitochondrial metabolism in neuronal cells; Insulin resistance and the effects of insulin on the cholesterol synthesis pathway and A-beta secretion in neural cells
  4. Insulin resistance and Alzheimer-like reductions in regional cerebral glucose metabolism for cognitively normal adults with prediabetes or early type 2 diabetes
  5. Diabetes mellitus induces Alzheimer’s disease pathology: Histopathological evidence from animal models; Abnormal glucose metabolism in Alzheimer’s disease: Relation to autophagy/mitophagy and therapeutic approaches; Evidence for altered insulin receptor signaling in Alzheimer’s disease; Aberrant insulin signaling in Alzheimer’s disease: Current knowledge; Alzheimer’s disease and insulin resistance: Translating basic science into clinical applications; Alzheimer’s beta-amyloid peptides compete for insulin binding to the insulin receptor; Insulin resistance and Alzheimer-like reductions in regional cerebral glucose metabolism for cognitively normal adults with prediabetes or early type 2 diabetes; Tau in Alzheimer disease and related tauopathies
  6. Role for neuronal insulin resistance in neurodegenerative diseases; Amyloid beta oligomers induce impairment of neuronal insulin receptors.; Synergistic effects of beta-amyloid and ceramide-induced insulin resistance on mitochondrial metabolism in neuronal cells
  7. Amyloid-beta plaques enhance Alzheimer’s brain tau-seeded pathologies by facilitating neuritic plaque tau aggregation
  8. Advanced glycation end products, dementia, and diabetes; Regulation of SIRT6 protein levels by nutrient availability
  9. APOE genotype influences insulin resistance, apolipoprotein CII and CIII according to plasma fatty acid profile in the Metabolic Syndrome.

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