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Genes of high and low penetrance, as well as epigenetic and environmental factors are participating in AD pathogenesis. Brain traumas, vascular problems (cerebral hypoperfusion, hypoxia, hypoglycemia), declining amyloid degradation and clearance with aging are involved in ER- and mitochondrial dysfunction and protein dyshomeostasis. Amyloid accumulation leads to neuroinflammation, synaptic failure, neuronal dysfunction and death.
