The amyloid hypothesis of Alzheimer's disease at 25 years

Dennis J Selkoe, John Hardy, Dennis J Selkoe, John Hardy

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.

Keywords: Alzheimer; Aβ; cell biology; genetics; treatment.

© 2016 The Authors. Published under the terms of the CC BY 4.0 license.

Figures

Figure 1. The sequence of major pathogenic…
Figure 1. The sequence of major pathogenic events leading to AD proposed by the amyloid cascade hypothesis
The curved blue arrow indicates that Aβ oligomers may directly injure the synapses and neurites of brain neurons, in addition to activating microglia and astrocytes.
Figure 2. Progressive cleavages of the APP…
Figure 2. Progressive cleavages of the APP transmembrane domain by the Presenilin/γ‐secretase complex
Figure 3. A hypothetical temporal model integrating…
Figure 3. A hypothetical temporal model integrating Alzheimer's disease biomarkers
The threshold for the first detection of biomarkers associated with pathophysiological changes is denoted by the black horizontal line. The gray area denotes the zone in which abnormal pathophysiological changes lie below this biomarker detection threshold. In this model, the occurrence of tau pathology can precede Aβ deposition in time, but only early on at a sub‐threshold biomarker detection level. Aβ deposition occurs independently and rises above the biomarker detection threshold (purple and red arrows). This induces acceleration of tauopathy, and CSF tau then rises above the detection threshold (light blue arrow). Later still, changes in FDG PET and MRI (dark blue arrow) rise above the detection threshold. Finally, cognitive impairment becomes evident (green arrow), with a wide range of cognitive responses that depend on the individual's risk profile (light green‐filled area). Note that while CSF Aβ42 alteration is plotted as a biomarker (purple), this represents a decrease in CSF Aβ42 levels and is a surrogate for an increase in parenchymal Aβ42 and changes in other Aβ peptides in the brain tissue. Aβ, amyloid β‐protein; FDG, fluorodeoxyglucose; MCI, mild cognitive impairment. (Adapted from Fig 6 of Jack et al, 2013.)

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