Approaches for Increasing Cerebral Efflux of Amyloid-β in Experimental Systems

Amyloid protein-β (Aβ) concentrations are increased in the brain in both early onset and late onset Alzheimer's disease (AD). In early onset AD, cerebral Aβ production is increased and its clearance is decreased, while increased Aβ burden in late onset AD is due to impaired clearance. Aβ has been the focus of AD therapeutics since development of the amyloid hypothesis, but efforts to slow AD progression by lowering brain Aβ failed until phase 3 trials with the monoclonal antibodies lecanemab and donanemab. In addition to promoting phagocytic clearance of Aβ, antibodies lower cerebral Aβ by efflux of Aβ-antibody complexes across the capillary endothelia, dissolving Aβ aggregates, and a "peripheral sink" mechanism. Although the blood-brain barrier is the main route by which soluble Aβ leaves the brain (facilitated by low-density lipoprotein receptor-related protein-1 and ATP-binding cassette sub-family B member 1), Aβ can also be removed via the blood-cerebrospinal fluid barrier, glymphatic drainage, and intramural periarterial drainage. This review discusses experimental approaches to increase cerebral Aβ efflux via these mechanisms, clinical applications of these approaches, and findings in clinical trials with these approaches in patients with AD or mild cognitive impairment. Based on negative findings in clinical trials with previous approaches targeting monomeric Aβ, increasing the cerebral efflux of soluble Aβ is unlikely to slow AD progression if used as monotherapy. But if used as an adjunct to treatment with lecanemab or donanemab, this approach might allow greater slowing of AD progression than treatment with either antibody alone.