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

Abstract

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.

Deciphering the links between psychological stress, depression, and neurocognitive decline in patients with Down syndrome

“…In this hypothesis, supported by recent well-referenced studies, it has been suggested that stress may be the spark for a decompensation cascade, starting with depression before evolving towards AD ( Dafsari and Jessen, 2020 ; Justice, 2018 ; Kurakin and Bredesen, 2020 ; Sotiropoulos et al, 2019 ).…”

Patient-Derived Fibroblasts With Presenilin-1 Mutations, That Model Aspects of Alzheimer’s Disease Pathology, Constitute a Potential Object for Early Diagnosis

“…Altogether, this result of the enhanced tau phosphorylation on tau residues Thr 231 , Ser 396 , and Ser 404 , confirms early to middle-advance tau PTMs probably associated to the initial steps to develop AD pathology, from the pre-NFT to the beginning of intracellular NFTs generation, since our cell model corresponds to fibroblast cells from FAD patients at a pre-symptomatic step (according to the data available at the Coriell Institute), and this could explain the absence of late-state markers of AD pathology in these cells. Furthermore, phosphorylations of tau protein in non-neuronal cells, such as fibroblasts, may be an indicative of the genesis of AD pathology that is nowadays been considered as a systemic disease instead of a central nervous system (CNS) exclusive disease (Kurakin and Bredesen, 2020). According to the systems biology analysis performed by Kurakin and Bredesen (2020), AD may not be a brain disease but a progressive system-level network disorder, which is driven by chronic network stress and dyshomeostasis in the whole organism.…”

“…Furthermore, phosphorylations of tau protein in non-neuronal cells, such as fibroblasts, may be an indicative of the genesis of AD pathology that is nowadays been considered as a systemic disease instead of a central nervous system (CNS) exclusive disease (Kurakin and Bredesen, 2020). According to the systems biology analysis performed by Kurakin and Bredesen (2020), AD may not be a brain disease but a progressive system-level network disorder, which is driven by chronic network stress and dyshomeostasis in the whole organism. Independently if the chronic stress, toxicity, and inflammation originate in the brain or in the periphery, they are communicated with the (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.…”

Ecosystem coupling: A unifying framework to understand the functioning and recovery of ecosystems

“…The fact that the word disorder is frequently used as a synonym of disease is highly evocative of this parallelism. Supporting this, recent studies have suggested that Alzheimer and other neurodegenerative dementias may not be a brain disease but a progressive system-level network disorder by chronic network stress and dyshomeostasis, 107,108 including the dysregulation of (the biochemical coupling of) transition metals such as Fe, Cu, and Zn. 109 This dysregulation may actually be linked to air pollution and other environmental stresses 110 in a similar way by which air pollution can decouple ecosystems.…”