Disease-Modifying Therapies for Alzheimer's Disease: More Questions than Answers

Scientific advances over the last four decades have steadily infused the Alzheimer's disease (AD) field with great optimism that therapies targeting Aβ, amyloid, tau, and innate immune activation states in the brain would provide disease modification. Unfortunately, this optimistic scenario has not yet played out. Though a recent approval of the anti-Aβ aggregate binding antibody, Aduhelm (aducanumab), as a "disease-modifying therapy for AD" is viewed by some as a breakthrough, many remain unconvinced by the data underlying this approval. Collectively, we have not succeeded in changing AD from a largely untreatable, inevitable, and incurable disease to a treatable, preventable, and curable one. Here, I will review the major foci of the AD "disease-modifying" therapeutic pipeline and some of the "open questions" that remain in terms of these therapeutic approaches. I will conclude the review by discussing how we, as a field, might adjust our approach, learning from our past failures to ensure future success.