The past, present, and future of disease-modifying therapies for Alzheimer's disease.

The development of disease-modifying therapies for Alzheimer's disease (AD) is an urgent issue. Progress in the understanding of AD pathophysiology based on the amyloid hypothesis has led to the development of numerous candidate disease-modifying therapies over the past 15 years. The therapeutic target, amyloid β (Aβ), starts to accumulate in AD brains long before the onset of cognitive decline. γ-secretase inhibitors, γ-secretase modulators, and β-secretase inhibitors aim to reduce the production of toxic Aβ species by modifying the processing of amyloid precursor protein. Another strategy is to eliminate accumulated Aβ by active or passive immunotherapeutic approaches. Therapeutic strategies targeting tau protein are also currently emerging. Despite these efforts, successful disease-modifying therapies for AD have not yet been developed. Recently, very early interventional trials targeting preclinical stages of AD have begun; the paradigm shift in AD therapies from cure to prevention could be key to the success of disease modification.