Patients with classic Alzheimer’s disease have senile plaques in the brain that are thought to be responsible for the neuro-degenerative process. Plaques are mainly composed of the beta-amyloid (A-beta) peptide. Diabetes is accompanied by defects in microcirculation, which induce numerous anomalies also in red blood cells and platelets, including an increase in aggregation, a lesser membrane deformability and viscosity and a greater tendency to adhere to the endothelium. Previous studies show that senile dementia is more common in patients with type 2 diabetes (DM2) and who, in time, may develop overt dementia. Additionally, patients with hyperglycemia are more prone to develop mild cognitive impairment. Finally, DM2-related conditions, including obesity, hyperinsulinemia, and metabolic syndrome, can all be risk factors for Alzheimer’s. Beta amyloid has been shown to cause insulin receptor disturbances, a sign that it is present in diabetes with insulin resistance.
As if that weren’t enough, high plasma insulin levels in patients with insulin resistance may be responsible for inhibiting the insulin-degrading enzyme (ICE). This event alters, in turn, the degradation of A-beta favoring its toxicity. Plasma from diabetic patients may contain high levels of oxidized lipids and toxic aldehydes, which promote the vascular defects reported in diabetic patients. Lipid oxidation levels have also been reported to correlate with levels of glycated hemoglobin (HbA1c), an important marker of disease progression. Both the red blood cells and platelets of patients with Alzheimer’s disease, on the other hand, have physical surface variations and an alteration in the composition of the plasma membrane. In patients with Alzheimer’s, there is a characteristic reduction in brain perfusion and metabolism. This can depend both on these characteristics of the red blood cells, and on their lower hemoglobin content which obviously carries less oxygen to the brain cells.
It has long been known that with aging bioenergetic variations occur that affect the entire body, but more so the brain, with its high energy requirement. Because late-onset Alzheimer’s is an age-related disease, many physiological changes with age can contribute to the risk for the disease, including changes in bioenergetics and metabolism. But what is the root of this metabolism imbalance? Some research teams pointed finger toward intrinsic blood defects. For example, anemia is readily found in people with diabetes and contributes to the pathogenesis of its complications, especially in cases of kidney failure. Chronic kidney failure associated with low hemoglobin levels could cause cerebral hypoxia, through a mechanism that involves erythropoietin. In addition, the low hemoglobin levels expose the red blood cells to greater fragility. It has also been reported that lower hemoglobin levels are correlated with the cognitive impairment that happens in Alzheimer disease.
This distinctive feature also appears in chronic kidney failure (CKD), where anemia secondary to the condition can lead to the onset of cognitive impairment that can simulate Alzheimer’s-type dementia. There are already proofs (suspects started 30 years ago) that brains with dementia (senile, vascular, diabetic, etc.) have a frank defect in glucose metabolism either in its utilization (glycolysis) and committment toward mitochondria, our cellular powerplants. This concept has been confirmed very recently as well (Huang YC et al. 2022). A particular focus has been given to molecules that are important in energy production, such as nicotinamide adenine dinucleotide (NAD). Along with coenzyme Q10, this cofactor is pivotal for the normal cellular energetics as well as for protection against oxidative stress. On the other hand, it is also known that oxidative stress may happens under high cellular glucose load, like in diabetes itself.
Paradoxically, diabetes and brain dementia share the reactive oxygen specie over-production as driving force, though there always has been the dilemma “who came first, the egg or the chicken”, since initial hypotheses speculated that was oxidative stress itself in causing the initial damage. Actually this could be the truth for diabetes, since high blood glucose falls always into higher production of oxidant intermediates. Together with data showing that insulin dysfunction in diabetes drives the hyper-phosphorilation of Tau protein (a cellular hallmark for neuronal dysfunction in dementia), and that almost overlaps the pattern seen in Alzhimers’, has led researchers to a more awareness of what could be possible common roots of either senile dementia and diabetes. And there are also accumulating evidences (either experimental and clinical) that antidiabetic treatment with metformin may reduce Tau hyper-phosphorylation, leading to think that glucose homoestasis may be the undelying root for these two widespread morbilities that represent a global sanitary burden of unprecedented proportions.
- Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
Huang YC et al. PLoS One 2022; 17(1):e0260966.
Hobday AL, Parmar MS. Cureus 2021; 13(9):e18362.
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Dott. Gianfrancesco Cormaci
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