A scoping review of alzheimer’s disease hypotheses: the case for a multi-factorial theory

Introduction There is a common agreement that Alzheimer’s disease (AD) is inherently complex; otherwise, a general disagreement remains on its etiological underpinning, with numerous alternative hypotheses having been proposed. Methods We performed a scoping review of 105 original manuscripts describing hypotheses and theories of AD published in the past decades, characterized them as having a single or multifactorial focus, and tracked their impact. Results Three stages can be discerned in terms of hypotheses generation, with three quarter of studies proposing a hypothesis characterized as being single-focus. The most important theoretical groupings were the Amyloid group, followed by Metabolism and Mitochondrial dysfunction, then Cerebrovascular. Lately, evidence towards Genetics and especially Gut/Brain interactions came to the fore. Discussion When viewed together, these multi-faceted reports reinforce the notion that AD affects multiple sub-cellular, cellular, anatomical, and physiological systems at the same time but at varying degree between individuals. A major impediment remains provide a comprehensive view of all these systems and their interactions to manage its inherent complexity. 1. We propose a scoping review of 105 original manuscripts describing hypotheses and theories of Alzheimer’s disease (AD) that have been published in the past decades, characterized as having a single or multifactorial focus. 2. We found that three quarter of studies proposed a hypothesis characterized as being single-focus (77/105), with the most important theoretical groupings being the Amyloid group, followed by Metabolism and Mitochondrial dysfunction, then Cerebrovascular. Three stages can be discerned in terms of hypotheses generation. The first phase (∼1980-1995) included the establishment of the main thrusts that have endured to this day (Amyloid, Glial, Infection, Inflammation, Metabolism, Oxidative stress, and Proteinopathies hypotheses; multifactorality; and neurotoxicity). In the second phase (1995-2005), the importance of the Cerebrovasculature, Mitochondrial dysfunction, and Neurotransmitters were recognized. Lately (2005-2020), evidence towards Genetics (outside of the autosomal dominant form of AD), and especially Gut/Brain interactions came to the fore. 3. When viewed together, these multi-faceted reports reinforce the notion that AD affects multiple sub-cellular, cellular, anatomical, and physiological systems at the same time but at varying degree between individuals. A major impediment remains provide a comprehensive view of all these systems and their interactions to manage its inherent complexity. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement S.D. would like to acknowledge funding by the Canadian Institute for Health Research (Operating grant #PJT-159778). L.S.R. would like to acknowledge funding from the Fonds de recherche du Quebec Sante (scholarship #271206). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present work are contained in the manuscript