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| title | chunk | source | category | tags | date_saved | instance |
|---|---|---|---|---|---|---|
| Biochemistry of Alzheimer's disease | 3/5 | https://en.wikipedia.org/wiki/Biochemistry_of_Alzheimer's_disease | reference | science, encyclopedia | 2026-05-05T11:04:17.929946+00:00 | kb-cron |
=== Historical cholinergic hypothesis === The cholinergic hypothesis of AD development was first proposed in 1976 by Peter Davies and A.J.F Maloney. It claimed that Alzheimer's begins as a deficiency in the production of acetylcholine, a vital neurotransmitter. Much early therapeutic research was based on this hypothesis, including restoration of the "cholinergic nuclei". The possibility of cell-replacement therapy was investigated on the basis of this hypothesis. All of the first-generation anti-Alzheimer's medications are based on this hypothesis and work to preserve acetylcholine by inhibiting acetylcholinesterases (enzymes that break down acetylcholine). These medications, though sometimes beneficial, have not led to a cure. In all cases, they have served to only treat symptoms of the disease and have neither halted nor reversed it. These results and other research have led to the conclusion that acetylcholine deficiencies may not be directly causal, but are a result of widespread brain tissue damage, damage so widespread that cell-replacement therapies are likely to be impractical. More recent findings center on the effects of the misfolded and aggregated proteins, amyloid beta and tau: tau protein abnormalities may initiate the disease cascade, then beta amyloid deposits progress the disease.
=== Glucose consumption === The human brain is one of the most metabolically active organs in the body and metabolizes a large amount of glucose to produce cellular energy in the form of adenosine triphosphate (ATP). Despite its high energy demands, the brain is relatively inflexible in its ability to utilize substrates for energy production and relies almost entirely on circulating glucose for its energy needs. This dependence on glucose puts the brain at risk if the supply of glucose is interrupted, or if its ability to metabolize glucose becomes defective. If the brain is not able to produce ATP, synapses cannot be maintained and cells cannot function, ultimately leading to impaired cognition. Imaging studies have shown decreased utilization of glucose in the brains of Alzheimer's disease patients early in the disease, before clinical signs of cognitive impairment occur. This decrease in glucose metabolism worsens as clinical symptoms develop and the disease progresses. Studies have found a 17%-24% decline in cerebral glucose metabolism in patients with Alzheimer's disease, compared with age-matched controls. Numerous imaging studies have since confirmed this observation. Abnormally low rates of cerebral glucose metabolism are found in a characteristic pattern in the Alzheimer's disease brain, particularly in the posterior cingulate, parietal, temporal, and prefrontal cortices. These brain regions are believed to control multiple aspects of memory and cognition. This metabolic pattern is reproducible and has even been proposed as a diagnostic tool for Alzheimer's disease. Moreover, diminished cerebral glucose metabolism (DCGM) correlates with plaque density and cognitive deficits in patients with more advanced disease. Diminished cerebral glucose metabolism (DCGM) may not be solely an artifact of brain cell loss since it occurs in asymptomatic patients at risk for Alzheimer's disease, such as patients homozygous for the epsilon 4 variant of the apolipoprotein E gene (APOE4, a genetic risk factor for Alzheimer's disease), as well as in inherited forms of Alzheimer's disease. Given that DCGM occurs before other clinical and pathological changes occur, it is unlikely to be due to the gross cell loss observed in Alzheimer's disease. In imaging studies involving young adult APOE4 carriers, where there were no signs of cognitive impairment, diminished cerebral glucose metabolism (DCGM) was detected in the same areas of the brain as older subjects with Alzheimer's disease. However, DCGM is not exclusive to APOE4 carriers. By the time Alzheimer's has been diagnosed, DCGM occurs in genotypes APOE3/E4, APOE3/E3, and APOE4/E4. Thus, DCGM is a metabolic biomarker for the disease state.
=== Insulin signaling === A connection has been established between Alzheimer's disease and diabetes during the past decade, as insulin resistance, which is a characteristic hallmark of diabetes, has also been observed in brains of subjects with Alzheimer's disease. Neurotoxic oligomeric amyloid-β species decrease the expression of insulin receptors on the neuronal cell surface and abolish neuronal insulin signaling. It has been suggested that neuronal gangliosides, which take part in the formation of membrane lipid microdomains, facilitate amyloid-β-induced removal of the insulin receptors from the neuronal surface. In Alzheimer's disease, oligomeric amyloid-β species trigger TNF-α signaling. c-Jun N-terminal kinase activation by TNF-α in turn activates stress-related kinases and results in IRS-1 serine phosphorylation, which subsequently blocks downstream insulin signaling. The resulting insulin resistance contributes to cognitive impairment. Consequently, increasing neuronal insulin sensitivity and signaling may constitute a novel therapeutic approach to treat Alzheimer's disease.