See discussions, stats, and author profiles for this publication at: https://www.researchgate.net/publication/349942124 Alzheimer’s disease as a syndrome of overloaded amyloidic synaptic tagging in memory networks Preprint · March 2021 DOI: 10.31219/osf.io/7gsaz CITATIONS READS 0 294 1 author: Niall P Murphy University of Florida 89 PUBLICATIONS 2,720 CITATIONS SEE PROFILE Some of the authors of this publication are also working on these related projects: Psychobiology of pain View project Role of aggregating proteins in mnemonic physiology and pathology View project All content following this page was uploaded by Niall P Murphy on 10 March 2021. The user has requested enhancement of the downloaded file. Title: Alzheimer’s disease as a syndrome of overloaded amyloidic synaptic tagging in memory networks Author: Niall P. Murphy Affiliation: Independent researcher, U.K. Corresponding author: Niall P. Murphy Email: [email protected] Highlights: • A hypothetical model of the role of amyloid beta and tau phosphorylation in Alzheimer’s disease is presented • Aggregation of amyloid beta is proposed to write-protect plasticity underlying memory • Buildup of phospho-tau is proposed to form an image of established plasticity as insurance against plasticity-threatening insults • Alzheimer’s disease is postulated to be a syndrome caused by overloading of memory circuits resulting in aggregated amyloid beta reaching neurotoxic levels • Isodendritic neuromodulators such as norepinephrine and acetylcholine governing sleep and cognitive processing are postulated as controlling memory and delivering tau forms for imaging the potentiation state of synapses. Declarations of interest: none Important: This article is provided as a working hypothesis that has not been peer-reviewed. The article should not be regarded as irrefutable, guide preclinical study or clinical practice/health-related behavior, or be reported in news media as established information. Notification of any errors or comments and suggestions are welcomed by the author at the email address above. Version: 8 March 2021 1 Abstract: Alzheimer’s Disease is defined as progressive memory loss coincident with accumulation of aggregated amyloid beta and phosphorylated tau. Identifying the relationship between these features has guided Alzheimer’s Disease research for decades, principally with the view that aggregated proteins drive a neurodegenerative process. Here I propose that amyloid beta and phospho-tau write-protect and tag neuroplastic changes as they form, protecting and insuring established neuroplasticity from corruption. In way of illustration, binding of oligomeric amyloid beta to the prion receptor is presented as an example possible mechanism. The write-protecting process is conjected to occur at least partially under the governance of isodendritic neuromodulators such as norepinephrine and acetylcholine. Coincident with aging, animals are exposed to accumulating amounts of memorable information. Compounded with recent increases in life expectancy and exposure to information-rich environments this causes aggregating proteins to reach unforeseen toxic levels as mnemonic circuits overload. As the brain cannot purposefully delete memories nor protect against overaccumulation of aggregating proteins, the result is catastrophic breakdown on cellular and network levels causing memory loss. Keywords: Alzheimer disease, amyloid beta, tau, memory, prion protein, neuronal plasticity, nerve degeneration, norepinephrine, acetylcholine, synapses, sleep Funding statement: This research did not receive any specific grant from funding agencies in the public, commercial, or not- for-profit sectors. 2 1. Introduction Alzheimer’s Disease (AD) is the most common cause of dementia, representing about 60 to 70% of cases. Among its known risk factors, age is usually cited as the most substantial. Around 4% of AD cases are of the early onset type, usually affecting people in their 40s to early 60s. Early onset AD, known also as familial AD (FAD), is believed to be driven by mutations in genes directly related to the classically understood pathology of AD – buildup of aggregated amyloid beta (Aβ). The remainder of cases, are of the late onset (LOAD) or sporadic type. The etiology of LOAD is less clear and far more loosely genetically linked despite the pathology and symptomology of FAD and LOAD being similar. The statistics surrounding AD are alarming and need little introduction. In 2018, dementia was the most common cause of death on UK death certificates of which AD constituted about a third of cases. Only pooled cases of cancer eclipse this disturbing statistic. In the US, about one in three seniors die of AD or another form of dementia. Current estimates suggest that by the age of 65, 1 in 10 people are clinically diagnosable as AD dementia with probably more going undiagnosed. By 85 years of age, the likelihood of receiving a diagnosis of AD is somewhere between a staggering one in two to one in three. For context, the WHO reported mean life expectancy worldwide in 2019 as 72.6 years. The emotional and financial toll on sufferers, caregivers and healthcare systems is enormous. As aged populations increase, the incidence of AD is predicted to increase accordingly. Yet, of the top 10 causes of death, AD is alone without any method for preventing, curing, or slowing progression. 1.1. The Aβ cascade hypothesis Histologically, the most salient features of AD are synaptic loss, buildup of extracellular aggregates of Aβ and intracellular aggregates of phosphorylated forms of the microtubule-associated protein tau (pTau) (Serrano-Pozo et al., 2011). One of the earliest and most influential hypotheses devised to explain the etiology of the disease is the “Aβ cascade” hypothesis (see Hardy and Allsop, 1991; Hardy and Higgins, 1992; Selkoe, 1991). This hypothesis, held by what are colloquially known as βabtists, originally positioned accrual of Aβ aggregates as driving the disease. Despite increasing concerns over the hypothesis’ validity (e.g. Castellani and Smith, 2011; Chetelat, 2013; Hardy and Mayer, 2011; Harrison and Owen, 2016; Kametani and Hasegawa, 2018; Makin, 2018; Marchesi, 2012; Morris et al., 2018; Saxena, 2010), often roused by the failure of the hypothesis to deliver a successful treatment, that Aβ could be the primum movens is supported by substantial evidence (e.g., Carrillo-Mora et al., 2014; Harrison and Owen, 2016; Lee et al., 2017a; Leong et al., 2020; Palop and Mucke, 2010; Reiss et al., 2018; Sadigh-Eteghad et al., 2015; Selkoe and Hardy, 2016; Smith and Strittmatter, 2017; Verdile et al., 2004; Viola and Klein, 2015). Most notably Aβ plaques are a major histological feature of (and define) the disease, oligomeric Aβ (oAβ) levels increase in AD, gene mutations affecting production and aggregation of Aβ occur in FAD and not least, extensive preclinical research showing toxic potential of Aβ. Furthermore, polymorphisms in genes, particularly apolipoprotein E (ApoE), involved in Aβ clearance are associated with LOAD. This is not to say that the hypothesis is free of issues. For instance, some have suggested Aβ accumulation is not the cause of AD, particularly LOAD, but a response (Castello and Soriano, 2014; Panza et al., 2019b; Petrofes Chapa et al., 2012; Struble et al., 2010). Issues include inconsistencies between the spatiotemporal deposition of Aβ and the progress of cognitive symptoms, criticisms of preclinical experimental approaches and ambiguity over the exact toxic species of Aβ. Unsurprisingly, the amyloid cascade hypothesis has come under increasing fire with some going as far as suggesting it has been misleading and pursuing it a sunk-cost fallacy (Amtul, 2016; Castellani and Smith, 2011; Castello and Soriano, 2014; 2011). 3 Nonetheless, for better or worse, the amyloid cascade hypothesis has undoubtedly been very influential, forming the basis of a large field of research and clinical development. In fact, by 2009 of the top 10 most cited authors in the AD field, the main area of investigation of four of them was Aβ or Aβ production (Sorensen, 2009). Three of the 10 focused on tau. The original conceptualization of the amyloid cascade hypothesis positioned large extracellular Aβ plaques as causing cognitive and behavioral changes. However, as time has passed it has become apparent that Aβ plaques correlate poorly with disease symptoms. This yielded a revised version of the hypothesis whereby much smaller aggregates of Aβ, particularly oligomers of the 42 amino acid isoform (oAβ42) are believed to be the primary cause (Cline et al., 2018). Among evidence supporting this revision are studies showing buildup of oAβ during the disease (see Ferreira et al., 2015; Kayed et al., 2003), stronger correlation of oAβ with cognitive deficits in mouse models and oAβ being more neurotoxic (Ferreira et al., 2015). The sheer magnitude and influence of the amyloid cascade hypothesis cannot be understated. It has funneled immense amounts of research funding and efforts in its direction, often motivated by demonstrating the toxicity of Aβ. This has not only come at the expense of seeking other explanations but has arguably induced an inherent bias in data available upon which alternative explanations can be built. Nonetheless, accumulation of Aβ remains far more than a straw in the wind and as such requires explanation. 1.2. The case for tau For various reasons including some of those mentioned above, attention has shifted away from Aβ to the other key histological feature of AD: