Journal of Alzheimer's Disease - Volume 64, issue s1

Authors: Cline, Erika N. | Bicca, Maíra Assunção | Viola, Kirsten L. | Klein, William L.

Article Type: Review Article

Abstract: The amyloid-β oligomer (AβO) hypothesis was introduced in 1998. It proposed that the brain damage leading to Alzheimer’s disease (AD) was instigated by soluble, ligand-like AβOs. This hypothesis was based on the discovery that fibril-free synthetic preparations of AβOs were potent CNS neurotoxins that rapidly inhibited long-term potentiation and, with time, caused selective nerve cell death (Lambert et al., 1998). The mechanism was attributed to disrupted signaling involving the tyrosine-protein kinase Fyn, mediated by an unknown toxin receptor. Over 4,000 articles concerning AβOs have been published since then, including more than 400 reviews. AβOs have been shown to accumulate in …an AD-dependent manner in human and animal model brain tissue and, experimentally, to impair learning and memory and instigate major facets of AD neuropathology, including tau pathology, synapse deterioration and loss, inflammation, and oxidative damage. As reviewed by Hayden and Teplow in 2013, the AβO hypothesis “has all but supplanted the amyloid cascade.” Despite the emerging understanding of the role played by AβOs in AD pathogenesis, AβOs have not yet received the clinical attention given to amyloid plaques, which have been at the core of major attempts at therapeutics and diagnostics but are no longer regarded as the most pathogenic form of Aβ. However, if the momentum of AβO research continues, particularly efforts to elucidate key aspects of structure, a clear path to a successful disease modifying therapy can be envisioned. Ensuring that lessons learned from recent, late-stage clinical failures are applied appropriately throughout therapeutic development will further enable the likelihood of a successful therapy in the near-term. Show more

Keywords: Alzheimer’s disease, amyloid-β peptide, diagnostics, etiology, model systems, oligomers, prions, receptors, structure-function, tau, therapeutics

DOI: 10.3233/JAD-179941

Citation: Journal of Alzheimer's Disease, vol. 64, no. s1, pp. S567-S610, 2018

Authors: Gulisano, Walter | Maugeri, Daniele | Baltrons, Marian A. | Fà, Mauro | Amato, Arianna | Palmeri, Agostino | D’Adamio, Luciano | Grassi, Claudio | Devanand, D.P. | Honig, Lawrence S. | Puzzo, Daniela | Arancio, Ottavio

Article Type: Review Article

Abstract: The “Amyloid Cascade Hypothesis” has dominated the Alzheimer’s disease (AD) field in the last 25 years. It posits that the increase of amyloid-β (Aβ) is the key event in AD that triggers tau pathology followed by neuronal death and eventually, the disease. However, therapeutic approaches aimed at decreasing Aβ levels have so far failed, and tau-based clinical trials have not yet produced positive findings. This begs the question of whether the hypothesis is correct. Here we have examined literature on the role of Aβ and tau in synaptic dysfunction, memory loss, and seeding and spreading of AD, highlighting important parallelisms …between the two proteins in all of these phenomena. We discuss novel findings showing binding of both Aβ and tau oligomers to amyloid-β protein precursor (AβPP), and the requirement for the presence of this protein for both Aβ and tau to enter neurons and induce abnormal synaptic function and memory. Most importantly, we propose a novel view of AD pathogenesis in which extracellular oligomers of Aβ and tau act in parallel and upstream of AβPP. Such a view will call for a reconsideration of therapeutic approaches directed against Aβ and tau, paving the way to an increased interest toward AβPP, both for understanding the pathogenesis of the disease and elaborating new therapeutic strategies. Show more

Keywords: Amyloid-β peptide, amyloid-β protein precursor, oligomers, synaptic dysfunction, tau

DOI: 10.3233/JAD-179935

Citation: Journal of Alzheimer's Disease, vol. 64, no. s1, pp. S611-S631, 2018

Authors: Mormino, Elizabeth C. | Papp, Kathryn V.

Article Type: Review Article

Abstract:  The aberrant accumulation of the amyloid protein is a critical and early event in the Alzheimer’s disease (AD) cascade. Given the early involvement of this pathological process, it is not surprising that many clinically normal (CN) older individuals demonstrate evidence of abnormal Aβ at postmortem examination and in vivo using either CSF or PET imaging. Converging evidence across multiple research groups suggests that the presence of abnormal Aβ among CN individuals is associated with elevated risk of future clinical impairment and cognitive decline. Amyloid positivity in conjunction with biomarkers of neuronal injury offers further insight into which CN are …most at risk for short-term decline. Although in its infancy, tau PET has demonstrated early increases among Aβ+ that will likely be an important indicator of risk among CN. Overall, the detection of early Aβ among CN individuals has provided an important opportunity to understand the contributions of this pathology to age-related cognitive decline and to explore early intervention with disease modifying strategies. Show more

Keywords: Aging, amyloid, biomarkers, cognitive decline, early detection, memory, PET

DOI: 10.3233/JAD-179928

Citation: Journal of Alzheimer's Disease, vol. 64, no. s1, pp. S633-S646, 2018

Authors: Santana, Isabel | Baldeiras, Inês | Santiago, Beatriz | Duro, Diana | Freitas, Sandra | Pereira, Miguel Tábuas | Almeida, Maria Rosário | Oliveira, Catarina Resende

Article Type: Research Article

Abstract: The amyloid cascade hypothesis proposes amyloid-β (Aβ) as the earliest and key pathological hallmark of Alzheimer’s disease (AD), but this mandatory “amyloid-first pathway” has been contested. Longitudinal studies of mild cognitive impairment (MCI) patients represent an opportunity to investigate the intensity of underlying biological processes (amyloidosis versus neurodegeneration) and their relevance for progression to AD. We re-examined our cohort of amnestic MCI, grouped according to cerebrospinal fluid (CSF) biomarkers, aiming at establishing their prognostic value for Alzheimer-type dementia and testing the hypothetical model of biomarkers sequence, based on the amyloid cascade. Our baseline population consisted of 217 MCI patients, 63% …with neurodegeneration markers and 47% with amyloidosis. Within the longitudinal study-group (n  = 165), 85 progressed to AD and 80 remained cognitively stable. Age, CSF Aβ42 , and t-Tau were identified as the best single predictors of conversion to AD. Regarding MCI classification according to the NIA-AA criteria, the high-AD-likelihood group (HL-both amyloid and neurodegeneration markers) was the most frequent (42%); followed by the Suspected Non-Alzheimer Pathophysiology group (SNAP-26%), the low-AD-likelihood group (LL-negative biomarkers-22%), and the Isolated Amyloid Pathology group (IAP-10%). Risk of progression to AD was higher in HL in relation to the LL group (HR = 6.1, 95% CI = 2.1–18.0, p  = 0.001). SNAP and IAP groups were equivalent in terms of risk of progression to AD (IAP: HR = 2.6, 95% CI = 0.7–9.3, p  = 0.141; SNAP: HR = 3.1, 95% CI = 1.1–9.6; p  = 0.046), but only SNAP was significantly different from the LL group. These results support different neurobiological pathways to AD beyond the amyloid hypothesis, highlighting the alternative “neurodegeneration-first pathway” for further investigation. Show more

Keywords: Alzheimer’s disease, amyloid, cerebrospinal fluid biomarkers, mild cognitive impairment, neurodegeneration

DOI: 10.3233/JAD-179908

Citation: Journal of Alzheimer's Disease, vol. 64, no. s1, pp. S647-S657, 2018

Authors: Nguyen, Phuong H. | del Castillo-Frias, Maria P. | Berthoumieux, Olivia | Faller, Peter | Doig, Andrew J. | Derreumaux, Philippe

Article Type: Research Article

Abstract: Targeting the early oligomers formed by the amyloid-β (Aβ) peptide of 40 and 42 amino acids is considered one promising therapeutic approach for Alzheimer’s disease (AD). In vitro experiments and computer simulations are often used in synergy to reveal the modes of interactions of drugs. In this account, we present our contribution to understanding how small molecules bind to Aβ40 /Aβ42 peptides, based either on extensive coarse-grained and all-atom simulations, or a variety of experimental techniques. We conclude by offering several perspectives on the future of this field to design more efficient drugs.

Keywords: Aβ oligomers, all-atom/coarse-grained models, Alzheimer’s disease, amyloid simulations, cell-based assays, drugs, in vitro studies

DOI: 10.3233/JAD-179902

Citation: Journal of Alzheimer's Disease, vol. 64, no. s1, pp. S659-S672, 2018