The amyloid hypothesis of Alzheimer's disease at 25 years
Despite continuing debate about the amyloid b protein (or Ab hypothesis, new lines of evidence from laboratories and clinics worldwide support the concept that an imbalance between production and clearance of Ab42 and related Ab peptides is a very early, often initiating factor in Alzheimer's disease (AD) Confirmation that presenilin is the catalytic site of g 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 Ab. Duplication of the wild type APP gene in Down's syndrome leads to Ab 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 Ab clearance from the brain. Soluble oligomers of Ab42 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) Ab42 and amyloid PET positivity precede other AD manifestations by many years. Most importantly, recent trials of three different Ab 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, Ab dyshomeostasis has emerged as the most extensively validated and compelling therapeutic target.
EMBO molecular medicine