An integrated view of the relationships between amyloid, tau, and inflammatory pathophysiology in Alzheimer's disease

Abstract Alzheimer's disease (AD) research is a large and burgeoning field, where varied methodological approaches are providing multifaceted, but sometimes contradictory, views on the etiology and progression of pathology. The current review aims to summarize and integrate these findings to provide greater coherence to an increasingly splintered field. We provide an overview of the findings from each subfield (neuropathology, positron emission tomography imaging, fluid biomarkers, genetics, transcriptomics/proteomics), highlighting the strengths and weaknesses of each approach and, where possible, trying to resolve discrepancies between subfields. In particular, we address arguments about whether amyloid versus tau initiates pathology, and integrate nanoscale data from aging macaques to improve clarity regarding the earliest pathological stages, as initial phosphorylation events can be lost post mortem in human tissue. We find that Aβ 42 , phosphorylated tau, and inflammation/excessive calcium can all interact in feedforward cycles to drive AD pathology. Increasing cohesion across subdisciplines will strengthen our understanding of this devastating disease. Highlights AD research is an expansive field, where subfields often diverge. The current review integrates across approaches to give a more cohesive view. Many methods cannot detect the earliest changes in brain. The new fluid biomarker pT217Tau shows that soluble tau pathology begins early. Relating amyloid/tau pathologies to inflammation is key for understanding sporadic AD.