Advances in Alzheimer's disease research over the past two decades

The findings substantially altered understanding of the natural history of Alzheimer's disease and have been summarised in a temporal model.4 Amyloid PET becomes abnormal before neocortical tau PET signal appears. β-amyloidosis seems to promote or facilitate the spread of tauopathy. Fluid phosphorylated tau biomarkers become abnormal close-in-time or slightly after onset of abnormal amyloid PET.6 This entire process can extend over 20 or more years.7 An updated model of the temporal evolution of biomarkers and cognitive impairment is shown in the figure.4 Plasma biomarkers have been the most important development in Alzheimer's disease diagnostics in the past several years. [...]over the past two decades, GWAS studies have uncovered many loci associated with increased risk of clinically defined late-onset Alzheimer's disease, but with smaller effect size, lower population prevalence, or both compared with APOE4.15 These studies point to the importance of the immune response, endocytosis, lipid metabolism, and other pathways in addition to amyloid β and tau in the pathogenesis of Alzheimer's disease. Active disease modifying trials include both symptomatic and preclinical19 cohorts and involve biologicals or small molecules.20 In addition to those targeting amyloid β, trials targeting tau phosphorylation, aggregation and propagation, inflammation, neuroprotection, and other facets of the Alzheimer's disease pathway are underway or in the planning stages.20 Defining the optimal roles for different classes of biomarkers (plasma, CSF, and PET) in clinical trials and in clinical practice will continue to be an important research area.