The vascular facet of late-onset Alzheimer's disease: an essential factor in a complex multifactorial disorder

Purpose of review: This article provides a brief overview of relevant cerebrovascular mechanisms implicated in late-onset Alzheimer's disease (LOAD) development, and highlights the main reasons for incorporating novel cerebrovascular biomarkers to the models defining a multifactorial LOAD pathogenesis. We also discuss how novel brain mapping techniques and multifactorial data-driven models are having a critical role on understanding LOAD and may be particularly useful for identifying effective therapeutic agents for this disorder. Recent findings: A growing body of evidence supports that LOAD is a complex disorder, causally associated to a high multiplicity of pathologic mechanisms. New experimental and neuroimaging data, in combination with the recent use of integrative multifactorial data-driven models, support the early role of vascular factors in LOAD genesis and development. Among other relevant roles, the cerebrovascular system has a key modulatory effect on prion-like propagation, deposition and toxicity (e.g. Aβ, tau proteins). The early signs of vascular dysregulation during LOAD progression are notable both at the microscopic and the macroscopic scales. Summary: We emphasize that LOAD should be studied as a complex multifactorial disorder, not dominated by a dominant biological factor (e.g. Aβ), and without disregarding any relevant pathologic factor, such as vascular dysregulation. Cerebrovascular biomarkers are invaluable for defining multifactorial disease progression models as well as for evaluating the effectiveness of different therapeutic strategies.

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