Beyond the amyloid cascade: An update of Alzheimer's disease pathophysiology

The biological systems are organized on different inter-related spatio-temporal scales (i.e., genetic, molecular, cellular, cellular network), which can be impacted by pathological changes at different levels. The hypothesis on Alzheimer's disease (AD) pathophysiology was primarily shaped by the brain biochemical pathway of amyloid production and cascade [1]. However, this has not yet been translated into effective therapeutics. Recent evidence indicates the need to refine this view of AD. First, increasing evidence questions the well-known sequential biomarker-based pathophysiological AD cascade [2]. This contributes to the emergence of new models of AD pathophysiology [3], [4]. Secondly, novel factors that influence the risk of developing AD have recently been discovered in epidemiology and genetics [5], [6]. Thirdly, the relationships of protective and risk factors with the pathophysiological mechanisms of AD are now beginning to be elucidated [7]. Finally, the contribution of other drivers of the neurodegenerative process besides amyloid peptides is increasingly being explored, especially regarding the role of immunity [8]. These advances have several implications regarding the pathophysiological conception of AD. In this review, we discuss these recent advances and their impact on AD therapeutic development.

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