The amyloid hypothesis of Alzheimer's disease at 25years

Despite continuing debate about the amyloid -protein (or A hypothesis, new lines of evidence from laboratories and clinics worldwide support the concept that an imbalance between production and clearance of A42 and related A peptides is a very early, often initiating factor in Alzheimer's disease (AD). Confirmation that presenilin is the catalytic site of -secretase has provided a linchpin: all dominant mutations causing early-onset AD occur either in the substrate (amyloid precursor protein, APP) or the protease (presenilin) of the reaction that generates A. Duplication of the wild-type APP gene in Down's syndrome leads to A deposits in the teens, followed by microgliosis, astrocytosis, and neurofibrillary tangles typical of AD. Apolipoprotein E4, which predisposes to AD in >40% of cases, has been found to impair A clearance from the brain. Soluble oligomers of A42 isolated from AD patients' brains can decrease synapse number, inhibit long-term potentiation, and enhance long-term synaptic depression in rodent hippocampus, and injecting them into healthy rats impairs memory. The human oligomers also induce hyperphosphorylation of tau at AD-relevant epitopes and cause neuritic dystrophy in cultured neurons. Crossing human APP with human tau transgenic mice enhances tau-positive neurotoxicity. In humans, new studies show that low cerebrospinal fluid (CSF) A42 and amyloid-PET positivity precede other AD manifestations by many years. Most importantly, recent trials of three different A antibodies (solanezumab, crenezumab, and aducanumab) have suggested a slowing of cognitive decline in post hoc analyses of mild AD subjects. Although many factors contribute to AD pathogenesis, A dyshomeostasis has emerged as the most extensively validated and compelling therapeutic target.