The Characterization of Alzheimer’s Disease and the Development of Early Detection Paradigms: Insights from Nosology, Biomarkers and Machine Learning

Alzheimer’s Disease (AD) is the only condition in the top ten leading causes of death for which we do not have an effective treatment that prevents, slows, or stops its progression. Our ability to design useful interventions relies on (a) increasing our understanding of the pathological process of AD and (b) improving our ability for its early detection. These goals are impeded by our current reliance on the clinical symptoms of AD for its diagnosis. This characterizations of AD often falsely assumes a unified, underlying AD-specific pathology for similar presentations of dementia that leads to inconsistent diagnoses. It also hinges on postmortem verification, and so is not a helpful method for identifying patients and research subjects in the beginning phases of the pathophysiological process. Instead, a new biomarker-based approach provides a more biological understanding of the disease and can detect pathological changes up to 20 years before the clinical symptoms emerge. Subjects are assigned a profile according to their biomarker measures of amyloidosis (A), tauopathy (T) and neurodegeneration (N) that reflects their underlying pathology in vivo. AD is confirmed as the underlying pathology when subjects have abnormal values of both amyloid and tauopathy biomarkers, and so have a biomarker profile of A+T+(N)- or A+T+(N)+. This new biomarker based characterization of AD can be combined with machine learning techniques in multimodal classification studies to shed light on the elements of the AD pathological process and develop early detection paradigms. A guiding research framework is proposed for the development of reliable, biologically-valid and interpretable multimodal classification models

The Amyloid-beta Pathway in Alzheimer's Disease

Breakthroughs in molecular medicine have positioned the amyloid-β (Aβ) pathway at the center of Alzheimer’s disease (AD) pathophysiology. While the detailed molecular mechanisms of the pathway and the spatial-temporal dynamics leading to synaptic failure, neurodegeneration, and clinical onset are still under intense investigation, the established biochemical alterations of the Aβ cycle remain the core biological hallmark of AD and are promising targets for the development of disease-modifying therapies. Here, we systematically review and update the vast state-of-the-art literature of Aβ science with evidence from basic research studies to human genetic and multi-modal biomarker investigations, which supports a crucial role of Aβ pathway dyshomeostasis in AD pathophysiological dynamics. We discuss the evidence highlighting a differentiated interaction of distinct Aβ species with other AD-related biological mechanisms, such as tau-mediated, neuroimmune and inflammatory changes, as well as a neurochemical imbalance. Through the lens of the latest development of multimodal in vivo biomarkers of AD, this cross-disciplinary review examines the compelling hypothesis- and data-driven rationale for Aβ-targeting therapeutic strategies in development for the early treatment of AD