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Alzheimer’s disease as a systems network disorder: chronic stress/dyshomeostasis, innate immunity, and genetics

Ineffective results of clinical trials of over 200 anti-Alzheimer's drug candidates, with a 99.6% attrition rate, suggest that the current paradigm of Alzheimer's disease (AD) may be incomplete, necessitating exploration of alternative and complementary frameworks. Using algorithms for hyp...

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Autores principales: Kurakin, Alexei, Bredesen, Dale E.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7585078/
https://www.ncbi.nlm.nih.gov/pubmed/32957083
http://dx.doi.org/10.18632/aging.103883
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author Kurakin, Alexei
Bredesen, Dale E.
author_facet Kurakin, Alexei
Bredesen, Dale E.
author_sort Kurakin, Alexei
collection PubMed
description Ineffective results of clinical trials of over 200 anti-Alzheimer's drug candidates, with a 99.6% attrition rate, suggest that the current paradigm of Alzheimer's disease (AD) may be incomplete, necessitating exploration of alternative and complementary frameworks. Using algorithms for hypothesis independent search and expert-assisted synthesis of heterogeneous data, we attempted to reconcile multimodal clinical profiles of early-stage AD patients and accumulated research data within a parsimonious framework. Results of our analysis suggest that Alzheimer’s may not be a brain disease but a progressive system-level network disorder, which is driven by chronic network stress and dyshomeostasis. The latter can be caused by various endogenous and exogenous factors, such as chronic inflammatory conditions, infections, vascular dysfunction, head trauma, environmental toxicity, and immune disorders. Whether originating in the brain or on the periphery, chronic stress, toxicity, and inflammation are communicated to the central nervous system (CNS) via humoral and neural routes, preferentially targeting high-centrality regulatory nodes and circuits of the nervous system, and eventually manifesting as a neurodegenerative CNS disease. In this report, we outline an alternative perspective on AD as a systems network disorder and discuss biochemical and genetic evidence suggesting the central role of chronic tissue injury/dyshomeostasis, innate immune reactivity, and inflammation in the etiopathobiology of Alzheimer’s disease.
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spelling pubmed-75850782020-11-03 Alzheimer’s disease as a systems network disorder: chronic stress/dyshomeostasis, innate immunity, and genetics Kurakin, Alexei Bredesen, Dale E. Aging (Albany NY) Research Paper Ineffective results of clinical trials of over 200 anti-Alzheimer's drug candidates, with a 99.6% attrition rate, suggest that the current paradigm of Alzheimer's disease (AD) may be incomplete, necessitating exploration of alternative and complementary frameworks. Using algorithms for hypothesis independent search and expert-assisted synthesis of heterogeneous data, we attempted to reconcile multimodal clinical profiles of early-stage AD patients and accumulated research data within a parsimonious framework. Results of our analysis suggest that Alzheimer’s may not be a brain disease but a progressive system-level network disorder, which is driven by chronic network stress and dyshomeostasis. The latter can be caused by various endogenous and exogenous factors, such as chronic inflammatory conditions, infections, vascular dysfunction, head trauma, environmental toxicity, and immune disorders. Whether originating in the brain or on the periphery, chronic stress, toxicity, and inflammation are communicated to the central nervous system (CNS) via humoral and neural routes, preferentially targeting high-centrality regulatory nodes and circuits of the nervous system, and eventually manifesting as a neurodegenerative CNS disease. In this report, we outline an alternative perspective on AD as a systems network disorder and discuss biochemical and genetic evidence suggesting the central role of chronic tissue injury/dyshomeostasis, innate immune reactivity, and inflammation in the etiopathobiology of Alzheimer’s disease. Impact Journals 2020-09-21 /pmc/articles/PMC7585078/ /pubmed/32957083 http://dx.doi.org/10.18632/aging.103883 Text en Copyright: © 2020 Kurakin and Bredesin. https://creativecommons.org/licenses/by/3.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/3.0/) (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Paper
Kurakin, Alexei
Bredesen, Dale E.
Alzheimer’s disease as a systems network disorder: chronic stress/dyshomeostasis, innate immunity, and genetics
title Alzheimer’s disease as a systems network disorder: chronic stress/dyshomeostasis, innate immunity, and genetics
title_full Alzheimer’s disease as a systems network disorder: chronic stress/dyshomeostasis, innate immunity, and genetics
title_fullStr Alzheimer’s disease as a systems network disorder: chronic stress/dyshomeostasis, innate immunity, and genetics
title_full_unstemmed Alzheimer’s disease as a systems network disorder: chronic stress/dyshomeostasis, innate immunity, and genetics
title_short Alzheimer’s disease as a systems network disorder: chronic stress/dyshomeostasis, innate immunity, and genetics
title_sort alzheimer’s disease as a systems network disorder: chronic stress/dyshomeostasis, innate immunity, and genetics
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7585078/
https://www.ncbi.nlm.nih.gov/pubmed/32957083
http://dx.doi.org/10.18632/aging.103883
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