Pathological increases in neuronal hyperactivity in selective cholinergic and noradrenergic pathways may limit the efficacy of Aβ-based interventions in MCI and Alzheimer’s disease

In spite of compelling evidence linking Aβ disturbances to the pathophysiology of Alzheimer’s disease, Aβ based treatments have consistently failed to produce any beneficial effects both in mild cognitive impairment (MCI) and Alzheimer’s disease (AD) even with successful reductions of toxic aggregated and soluble Aβ species. Before abandoning both the hypothesis and approach, there is a need to examine some overlooked factors that may have contributed to the lack of efficacy, such as the potential druginduced increases in neuronal hyperactivity leading to adverse cognitive effects. In particular, we posit that selective cholinergic and noradrenergic pathways will be especially vulnerable to this adverse effect. If confirmed, this idea could help identify a potentially preventable and treatable obstacle for enhancing the efficacy of therapeutic agents in MCI and AD.