Biochemical Clues May Predict Who Develops Alzheimer Disease – and Who Doesn’t
According to New Research Published in The American Journal of Pathology
According to New Research Published in The American Journal of Pathology
Investigators have wondered why the brains of some cognitively-intact elderly individuals have abundant pathology on autopsy or significant amyloid deposition on neuroimaging that are characteristic of Alzheimer disease (AD). Researchers reporting in The American Journal of Pathology investigated biochemical factors and identified differences in proteins from parietal cortex synapses between patients with and those without manifestation of dementia. Specifically, early-stage AD patients had elevated concentrations of synaptic soluble amyloid-β (Aβ) oligomers compared to controls who were not demented but displayed signs of AD pathology. Synapse-associated hyperphosphorylated tau (p-tau) levels did not increase until late-stage AD.
“Our results suggest that effective therapies will need to target synaptic Aβ oligomers, and that anti-amyloid therapies will be much less effective once synaptic p-tau pathology has developed, thus providing a potential explanation for the failure of amyloid-based trials,” explained lead investigator Karen H. Gylys, PhD, of the UCLA School of Nursing and the Mary S. Easton Center for Alzheimer’s Research at UCLA.
The investigators analyzed brain autopsy samples from different regions in the brain (parietal, superior parietal, entorhinal cortex, and hippocampus) from 46 patients who were classified into groups based on clinical and pathologic criteria: four cognitively-normal elderly controls, two patients with spinocerebellar ataxia type II, 15 patients with no clinical history of dementia but with histopathological signs of AD-related pathology (high-pathology controls), and 24 patients who were clinically demented and histopathologically diagnosed with AD. Patients with early-stage AD were distinguished from those in later stages. Flow cytometry analysis of synaptosomes (resealed nerve terminals) was used to measure the concentrations of two of the biochemical hallmarks of AD, Aβ and p-tau, in synaptic terminals.
Investigators examined whether synaptic Aβ levels were associated with neuritic plaque levels in the parietal cortex. They found little or no evidence of Aβ immunolabeling in either of the control groups but observed a rise in synaptic Aβ concentration associated with increasing neuropathologic disease stages. Synaptic Aβ levels highly correlated with the occurrence of plaque.
Next researchers investigated how Aβ levels are related to clinical dementia. They measured synapse-associated soluble oligomers, known as oAβ in the parietal cortex, levels of which did not correlate with Aβ plaque counts. However, levels of synaptic oAβ in early-stage AD, but not late-stage AD, were significantly elevated relative to both the neuropathologically normal and high pathology groups. “The sharp oAβ elevation in early AD cases suggests that the clinical syndrome of AD dementia may emerge once the level of synapse-associated soluble oligomers exceeds a certain threshold,” noted Dr. Gylys.
Investigators studied the timing of the biochemical changes, noting that other investigators have found evidence that the soluble oligomers of Aβ are the primary toxic peptides that initiate downstream tau pathology as part of the “amyloid cascade hypothesis” of AD. They reported synaptic accumulation of Aβ in the earliest plaque stages, prior to the appearance of synaptic p-tau, which was generally absent until late-stage AD. Aβ and tau levels correlated better in samples from the hippocampus and entorhinal cortex, regions of the brain that are affected earlier in AD than the parietal cortex.
In future work, the authors aim to clarify the precise mechanisms by which soluble Aβ oligomers affect tau and lead to synaptic dysfunction in AD. An intriguing question is whether therapies that slow Aβ oligomer accumulation might delay or even prevent the onset of AD-related dementia. “The correspondence between our human and animal data suggests that this and related animal models will be useful for understanding the progress of synaptic pathology and developing therapies to protect synaptic terminals,” commented Dr. Gylys.
Other investigators involved in the study were Tina Bilousova, Carol A. Miller, Wayne W. Poon, Harry V. Vinters, Maria Corrada, Claudia Kawas, Eric Y. Hayden, David B. Teplow, Charles Glabe, Ricardo Albay III, Gregory M. Cole, and Edmond Teng.
Notes for Editors
“Synaptic Aβ oligomers precede p-tau and differentiate high pathology control cases,” by Tina Bilousova, Carol A. Miller, Wayne W. Poon, Harry V. Vinters, Maria Corrada, Claudia Kawas, Eric Y. Hayden, David B. Teplow, Charles Glabe, Ricardo Albay III, Gregory M. Cole, Edmond Teng, Karen Hoppens Gylys (DOI: http://dx.doi.org/10.1016/j.ajpath.2015.09.018). This article appears online ahead of The American Journal of Pathology, Volume 186, Issue 1 (January 2016) published by Elsevier.
Full text of this study is available to credentialed journalists upon request; contact Eileen Leahy at +1 732 238 3628 or firstname.lastname@example.org. Journalists wishing to interview the authors should contact Laura Perry, Director, Communications, UCLA School of Nursing, at +1 818 212 6226 or email@example.com or Karen Hoppens Gylys at firstname.lastname@example.org.
This research was supported by NIH AG27465 (K.H.G.), NIA AG18879 (C.A.M.), and NIA AG34628 (jointly sponsored by the NIA, AFAR, the John A. Hartford Foundation, the Atlantic Philanthropies, the Starr Foundation and an anonymous donor; to E.T.). DBT was supported by NIH NS038328 and AG041295 and the Jim Easton Consortium for Alzheimer’s Drug Discovery and Biomarkers. E.Y.H. was supported by UCLA CTSI UL1TR000124 and UCLA Older Americans Independence Center (P30 AG028748). H.V.V. was supported by the Daljit S. and Elaine Sarkaria Chair in Diagnostic Medicine. Tissue was obtained from the AD Research 2 Center Neuropathology Cores of USC (NIA P50 AG05142), UCLA (NIA P50 AG 16970), and UC Irvine (NIA P50 AG16573). Flow cytometry was performed in the UCLA Jonsson Comprehensive Cancer Center (JCCC) and Center for AIDS Research Flow Cytometry Core Facility supported by NIH CA16042 and AI 28697, and by the JCCC, the UCLA AIDS Institute, the David Geffen School of Medicine, and the Chancellor’s Office at UCLA. Diagnosis, characterization, and follow-up of 90+ Study subjects were supported by NIA R01AG21055.
The American Journal of Pathology
The American Journal of Pathology, official journal of the American Society for Investigative Pathology, seeks to publish high-quality, original papers on the cellular and molecular biology of disease. The editors accept manuscripts that advance basic and translational knowledge of the pathogenesis, classification, diagnosis, and mechanisms of disease, without preference for a specific analytic method. High priority is given to studies on human disease and relevant experimental models using cellular, molecular, animal, biological, chemical, and immunological approaches in conjunction with morphology.
The leading global forum for reporting quality original research on cellular and molecular mechanisms of disease, The American Journal of Pathology is the most highly cited journal in Pathology – close to 40,000 cites in 2014 – with an Impact Factor of 4.591 and Eigenfactor of 0.06689 according to the 2014 Journal Citation Reports®, Thomson Reuters, 2015, and an h-index of 217 according to the 2014 SCImago Journal and Country Rank.
Elsevier is a world-leading provider of information solutions that enhance the performance of science, health, and technology professionals, empowering them to make better decisions, deliver better care, and sometimes make groundbreaking discoveries that advance the boundaries of knowledge and human progress. Elsevier provides web-based, digital solutions — among them ScienceDirect, Scopus, Research Intelligence and ClinicalKey— and publishes over 2,500 journals, including The Lancet and Cell, and more than 35,000 book titles, including a number of iconic reference works. Elsevier is part of RELX Group, a world-leading provider of information and analytics for professional and business customers across industries. www.elsevier.com