The amyloid hypothesis of Alzheimer's disease at 25 years

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.

Decreased plasma C‐reactive protein levels in APOE ε4 allele carriers

“…Inflammation is centrally involved in AD pathogenesis, as denoted by the presence of activated microglia and astrocytes as well as the increased levels of inflammatory molecules in the brain. A β 42 is the key neurotoxic and pro‐inflammatory component in AD,7, 8 but recent studies have also pointed toward a potential anti‐inflammatory role for A β 42 under certain conditions 13, 14. Since ApoE is the major mediator of A β clearance from the brain,44 we wanted to address potential changes in the plasma concentration of A β among different APOE groups.…”

“…In particular, A β peptides of 42 amino acids in length (A β 42) are considered the key mediators of synaptotoxicity and neurotoxicity in AD 7. According to the prevailing amyloid‐cascade hypothesis, A β deposition in the brain triggers the hyperphosphorylation of tau and its accumulation as neurofibrillary tangles, activation of inflammatory cells and pathways, initiation of oxidative stress, and decline in synaptic and neuronal health and finally neurodegeneration 8. This view recently gained further support from the identification of a protective APP variant (A673T), which was later shown to reduce A β levels and protect against cognitive decline 9, 10.…”

BACE inhibition-dependent repair of Alzheimer’s pathophysiology

“…Therefore, the prevention and treatment of AD is a major unmet medical need. The amyloid hypothesis posits that the abnormal accumulation of amyloid-β (Aβ) peptides in the brain, and their aggregation, is an essential feature of AD (2,3); however, results from clinical studies using several Aβ-targeting compounds have called into question the existence of a direct link between a reduction in Aβ and improvement of brain function, particularly in more advanced disease stages (4)(5)(6). In addition, recent evidence obtained in mouse models carrying genetic mutations that cause AD in humans revealed that immunotherapy with antibodies against Aβ worsened rather than reversed neuronal dysfunction (7).…”

Protein homeostasis of a metastable subproteome associated with Alzheimer’s disease

“…N eurodegenerative diseases are highly complex disorders characterized by extensive neuronal dysfunction, which is typically associated with protein misfolding and aggregation (1)(2)(3)(4)(5)(6)(7)(8)(9). A feature common to essentially all of these conditions is the presence of abnormal protein deposits, including amyloid plaques and neurofibrillary tangles in Alzheimer's disease (AD) and Lewy bodies in Parkinson's disease (PD) (1)(2)(3)(4)(5)(6)(7)(8)(9).…”

“…A feature common to essentially all of these conditions is the presence of abnormal protein deposits, including amyloid plaques and neurofibrillary tangles in Alzheimer's disease (AD) and Lewy bodies in Parkinson's disease (PD) (1)(2)(3)(4)(5)(6)(7)(8)(9). It is increasingly recognized that the formation of such deposits, rather than being an unusual process involving only a small number of proteins, may represent a widespread phenomenon (1), with hundreds of different proteins found to aggregate under stress conditions, in aging, or in disease (5,(10)(11)(12)(13)(14)(15).…”