Abstract
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.
Highlights
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)
We summarize the salient findings over three decades that undergird the amyloid hypothesis (Box 1), and we discuss several alternative concepts or concerns that have been counterposed to it (Table 1)
Human genetics proves that Ab-elevating APP mutations lead to downstream alteration and aggregation of wild-type tau, whereas tau mutations do not lead to Ab deposition and amyloid-related dementia
Summary
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). Based on many human biomarker studies, low CSF Ab42 and positive amyloid-PET scans precede other AD-related changes (increased CSF tau, decreased cerebral glucose metabolism, brain atrophy, clinical dementia) by years.
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