Despite continuing debate about the amyloid β-protein (or Aβ hypothesis, new 
lines of evidence from laboratories and clinics worldwide support the concept 
that an imbalance between production and clearance of Aβ42 and related Aβ 
peptides is a very early, often initiating factor in Alzheimer's disease (AD). 
Confirmation that presenilin is the catalytic site of γ-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 Aβ. Duplication of the wild-type APP gene in Down's 
syndrome leads to Aβ 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 Aβ clearance from 
the brain. Soluble oligomers of Aβ42 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) Aβ42 and amyloid-PET 
positivity precede other AD manifestations by many years. Most importantly, 
recent trials of three different Aβ 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, Aβ 
dyshomeostasis has emerged as the most extensively validated and compelling 
therapeutic target.