The biochemistry of Alzheimer's disease, one of the most common causes of dementia in old age, is still not fully understood. Alzheimer's disease is thought to be a disease of protein misfolding resulting from the accumulation of the abnormally folded protein amyloid beta in the brains of those affected by the disease. Amyloid beta, a short peptide, is an abnormal protein by-product of the nucleoprotein amyloid, a membrane protein, whose function is unclear, but it is thought to play a role in neuronal development. Presenilins are components of the proteolytic complexes involved in the processing and degradation of amyloid precursor proteins. Amyloid beta monomers are normally soluble, and contain short regions of beta sheets and a polypropylene dimer structure in solution, although they are large alpha helices in tissues. At high concentrations they undergo a dramatic conformational change to form a tertiary structure rich in beta sheets that aggregate to form amyloid fibrils, which are deposited outside neurons in formations Dense, known as senile plaques or neuritic plaques. Less dense deposits are diffuse occlusions and sometimes in the walls of small blood vessels in the brain in a process called vascular amyloid dysfunction. Alzheimer's disease is also considered a tau-related disease, resulting from abnormal aggregation of this protein, a microtubule-associated protein expressed in neuronal cells that normally stabilizes microtubules in the cytoskeleton. Like most microtubule-associated proteins, tau is controlled by phosphorylation, but in Alzheimer's patients, highly phosphorylated tau aggregates into double helices, which in turn aggregate into clumps within the cell body, known as amyloid plaque-associated neurofibrillary tangles. Although little is known about the process of fimbriae assembly, it has recently been identified that prolyl isomerase—a protein in the parafilin family—accelerates the aggregation of abnormal tau. Neuroinflammation is also involved in the complex cascade that causes Alzheimer's disease and its symptoms. With medical evidence The pathophysiological analysis of the immunological changes in Alzheimer's disease documents increased concentrations of inflammatory cytokines in the blood and cerebrospinal fluid. Whether this inflammation is a cause or a consequence of Alzheimer's disease is not fully understood, but inflammation in the brain, including increased susceptibility of resident microglia to amyloid deposits, is implicated in the pathological progression of Alzheimer's disease. At the macroscopic level, Alzheimer's disease is characterized by a loss of neurons and synapses in the cerebral cortex and some subcortical regions, leading to gross atrophy in the affected areas, including degeneration in the temporal and parietal lobes, parts of the frontal cortex, and the cingulate gyrus. Both amyloid deposits and neurofibrillary tangles are clearly visible under microscopic examination in the brains of people with Alzheimer's disease. These deposits are dense, insoluble deposits of protein and cellular material outside and around neurons. Tangles are insoluble, twisted fibers that accumulate inside the cell. Although many older adults develop some tangles, the brains of Alzheimer’s patients have significantly higher levels of these tangles and at different locations in the brain. The biochemical events that lead to the accumulation of amyloid-beta and tau are fundamental to understanding Alzheimer’s disease. A delicate balance of production enzymes regulates the accumulation of amyloid-beta. The activity of alpha-proteinase inhibits the aggregation of amyloid-beta. Recently, the relationship between cholinergic neuronal activity and alpha-proteinase activity, which can inhibit amyloid-beta, has been highlighted in the brains of Alzheimer’s patients. Alzheimer’s disease has been defined as a proteinaceous or protopathic disease due to the accumulation of abnormally folded amyloid-beta proteins in the brains of patients. Abnormal amyloid-beta accumulation can be detected using cerebrospinal fluid analysis and subsequently using positron emission tomography. Although Alzheimer’s shares pathophysiological mechanisms with prion diseases, it does not Amyloid-beta is a short peptide, a secondary protein of the membrane protein amyloid of unclear function but thought to be involved in neuronal development. Prenicillin is a component of a protein complex involved in the processing and degradation of secondary membrane amyloid. Although beta-amyloid monomers are harmless, they undergo a dramatic conformational change at high enough concentrations to form a tertiary structure rich in beta sheets that aggregate to form amyloid fibrils that deposit outside neurons in dense formations known as senile plaques or neuritic plaques, in less dense clumps such as diffuse plaques, and sometimes in the walls of small blood vessels in the brain in a process called amyloid angiopathy or cerebral angiopathy. Alzheimer's disease is also considered a tau-related disease, resulting from abnormal aggregation of this protein, a microtubule-associated protein expressed in neurons that normally stabilizes microtubules in the cytoskeleton. Like most microtubule-associated proteins, tau is controlled by Phosphorylation, however, in Alzheimer's patients, the highly phosphorylated tau protein aggregates into double helices, which in turn aggregate into clumps within the cell body, known as neurofibrillary tangles associated with amyloid plaques. Levels of the neurotransmitter acetylcholine are decreased. Levels of other neurotransmitters, such as serotonin, norepinephrine, and somatostatin, are also frequently decreased. Replenishment of acetylcholine with its antagonists is an FDA-approved treatment. An alternative approach to stimulating M1-M3 acetylcholine receptors has been proposed, through the development of slower dissociation agonists, as next-generation cholinergics in Alzheimer's disease. Although the overall histopathological features of Alzheimer's disease in the brain are well characterized, three main hypotheses have been advanced regarding the underlying cause. The oldest hypothesis suggests that a deficiency in cholinergic signaling initiates the development of the disease. Alternatively, two alternative hypotheses suggest that either tau or beta-amyloid initiates the disease. In sequence. While researchers have not identified a clear causative pathway resulting from any of the three molecular hypotheses to explain the gross anatomical changes observed in advanced Alzheimer's disease, variants of the beta-amyloid hypothesis of molecular initiation have become dominant among the three possibilities: The oldest hypothesis for the etiology of Alzheimer's disease is the "cholinergic hypothesis." It states that Alzheimer's disease begins as a deficiency in the production of acetylcholine, a vital neurotransmitter. Early therapeutic research was based on this hypothesis, including the restoration of "cholinergic nuclei." The possibility of cell replacement therapy has been investigated on the basis of this hypothesis. All first-generation anti-Alzheimer's drugs are based on this hypothesis and work to preserve acetylcholine by inhibiting acetylcholinesterase. These drugs, while sometimes helpful, have not led to a cure. In all cases, they have only treated the symptoms of the disease and have not stopped or reversed it. These findings and other research have led to the conclusion that acetylcholine deficiency may not be a cause Directly, it is the result of extensive brain tissue damage, and the damage is so widespread that cell-replacement therapies are likely to be impractical. More recently, cholinergic effects have been proposed as a possible causative factor for the formation of plaques and tangles that lead to generalized neuroinflammation. Newer hypotheses focus on the effects of the enveloped and aggregated proteins, amyloid beta and tau. Two positions were described slightly as the B and Tau views in one scientific publication. In it, it was suggested that Tauians believe that tau protein abnormalities initiate the disease cascade, while Bists believe that beta-amyloid deposits are the causative agent. The hypothesis that tau is the primary causative agent was long rejected because of the observation that amyloid plaque deposition does not correlate well with neuronal loss. A mechanism for neurotoxicity has been proposed based on loss of tau protein that helps to inhibit the cytoskeleton. However, no consensus has been reached on whether tau is phosphorylated or caused by the formation of abnormal helical filament aggregates. Support for The tau hypothesis also derives from the existence of other diseases known as tauopathies in which the same protein is misfolded. However, the majority of researchers support the alternative hypothesis that amyloid is the primary causative factor. The amyloid hypothesis is initially compelling because the gene for the beta-amyloid precursor APP is located on chromosome 21, and patients with trisomy 21—commonly known as Down syndrome—who have an extra gene copy commonly show Alzheimer’s-like disorders by age 40. The traditional formulation of the amyloid hypothesis points to the cytotoxicity of mature aggregated fibroins, which are thought to be the toxic form of the protein responsible for disrupting the calcium ion balance in the cell and thus inducing apoptosis. This hypothesis is supported by the observation that higher levels of amyloid beta, which is known to form fibrils more rapidly in vitro, are associated with earlier onset and greater cognitive impairment in mouse models and with the diagnosis of Alzheimer’s in humans. However, the mechanisms of calcium influx, or proposals for alternative cytotoxic mechanisms, by mature fibrils are not clear. A 1994 study showed that isoprenoid changes in Alzheimer’s disease are different from those occurring during normal aging, and therefore do not This disease can be considered a consequence of premature aging. During aging the human brain shows a gradual increase in dodehol levels, a decrease in ubiquinone levels, but relatively unchanged concentrations of cholesterol and dodehyde phosphate. In Alzheimer's disease, the situation is reversed with decreased dodehyde levels and increased ubiquinone levels. Dodehyde phosphate concentrations are also increased, while cholesterol remains unchanged. The increase in the sugar carrier dodecyl phosphate may reflect increased glycosylation rate in the affected brain and an increase in the endogenous antioxidant oxynone in an attempt to protect the brain from oxidative stress, for example caused by lipid peroxidation. Rubrin, previously identified in Russia, is neuroprotective in a rat model of Alzheimer's disease. Oxidative stress appears to be a major factor in the pathogenesis of Alzheimer's disease. Excessive oxidative stress is thought to play a critical role in the accumulation and deposition of beta-amyloid in the disease. Alzheimer's patients have elevated levels of oxidative DNA damage in both nuclear and mitochondrial DNA, but mitochondrial DNA has approximately 10 times more strands than nuclear DNA. Aged mitochondria may be a critical factor in the origin of neurodegeneration in Alzheimer's disease. Even individuals with mild cognitive impairment, the stage between normal aging and early dementia, have increased oxidative damage in both nuclear and mitochondrial DNA in the brain.