Transient pharmacologic lowering of Aβ production prior to deposition results in sustained reduction of amyloid plaque pathology

Background: Alzheimer's disease (AD) is the leading cause of dementia among the elderly. Disease modifying therapies targeting A beta that are in development have been proposed to be more effective if treatment was initiated prior to significant accumulation of A beta in the brain, but optimal timing of treatment initiation has not been clearly established in the clinic. We compared the efficacy of transient pharmacologic reduction of brain A beta with a gamma-secretase inhibitor (GSI) for 1-3 months (M) treatment windows in APP Tg2576 mice and subsequent aging of the mice to either 15M or 18M. Results: These data show that reducing A beta production in a 2-3M windows both initiated and discontinued before detectable A beta deposition has the most significant impact on A beta loads up to 11M after treatment discontinuation. In contrast, initiation of treatment for 3M windows from 7-10M or 12-15M shows progressively decreasing efficacy. Conclusions: These data have major implications for clinical testing of therapeutics aimed at lowering A beta production, indicating that; i) these therapies may have little efficacy unless tested as prophylactics or in the earliest preclinical stage of AD where there is no or minimal A beta accumulation and ii) lowering A beta production transiently during a critical pre-deposition window potentially provides long-lasting efficacy after discontinuation of the treatment.