Abstract
Alzheimer's disease (AD), a common neurodegenerative disease in the elderly and the most prevalent cause of dementia, is characterized by progressive cognitive impairment. The prevalence of AD continues to increase worldwide, becoming a great healthcare challenge of the twenty-first century. In the more than 110 years since AD was discovered, many related pathogenic mechanisms have been proposed, and the most recognized hypotheses are the amyloid and tau hypotheses. However, almost all clinical trials targeting these mechanisms have not identified any effective methods to treat AD. Scientists are gradually moving away from the simple assumption, as proposed in the original amyloid hypothesis, to new theories of pathogenesis, including gamma oscillations, prion transmission, cerebral vasoconstriction, growth hormone secretagogue receptor 1α (GHSR1α)-mediated mechanism, and infection. To place these findings in context, we first reviewed the neuropathology of AD and further discussed new insights in the pathogenesis of AD.
Highlights
Alzheimer’s disease (AD), which was first described by German Bavarian psychiatrist and neurologist Alois Alzheimer in 1907 [1], is the most common degenerative central nervous system disease in the elderly
The second pathway is the amyloidogenic pathological pathway in which Aβ precursor protein (APP) is cleaved to C-terminal fragment (CTF)-β by β-secretase and different lengths of Aβ peptides by γ-secretase, including Aβ42 which is more prone to aggregation and plaque formation than Aβ40 and has stronger neurotoxicity [22, 23]
The activity of tau prion was inversely proportional to age, which means compared with the AD patients with the greatest longevity, patients who died at younger ages due to AD had lower concentrations of both prion-like Aβ and prion-like tau at the time of death, neurofibrillary tangles (NFTs) increased
Summary
Alzheimer’s disease (AD), which was first described by German Bavarian psychiatrist and neurologist Alois Alzheimer in 1907 [1], is the most common degenerative central nervous system disease in the elderly. FAD is mainly associated with mutations in the Aβ precursor protein (APP) and presenilin genes PSEN1 and PSEN2, whereas SAD has a complex etiology, involving genetic, environmental, metabolic, viral, and other factors [5]. 40–50% of EOAD and 80% of LOAD are associated with APOE. Researchers are beginning to explore new theories of the pathogenesis of AD from different perspectives, such as gamma oscillations, prion transmission, cerebral vasoconstriction, growth hormone secretagogue receptor 1α (GHSR1α)-mediated mechanism, and infection. Discoveries in these areas make it possible to reasonably explain the pathological mechanisms of AD and suggest potential effective treatments for AD.
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