A SCOPING REVIEW OF ALZHEIMER’S DISEASE HYPOTHESES: THE CASE FOR A MULTI-FACTORIAL THEORY
Authors: Duchesne Simon , Rousseau Louis-Simon , Belzile Florence , Welsh Laurie-Ann , Cournoyer Beatrice , Arseneau Marianne , Lapierre Véronick , Poulin Sara-Maude , Potvin Olivier , Hudon Carol 
Published: July 2023

ABSTRACTIntroductionThere 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.MethodsWe 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.ResultsThree 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.DiscussionWhen 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.RESEARCH IN CONTEXTWe 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.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.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.HIGHLIGHTS-We propose a scoping review of hypotheses and theories for Alzheimer’s disease (AD)-Out of over 11,000 abstracts, we reviewed 105 articles, separated as having a single-focus or multi-factorial approach-The diversity of reports calls for an integrative view of AD in order to encompass its inherent complexity