Alzheimer’s disease research is changing how scientists understand the long path from early brain changes to memory loss. In this program, John Hardy, Ph.D., University College London Institute of Neurology, explains how genetics helps reveal where neurodegenerative disease begins, not only where it ends. Hardy traces how studies of inherited Alzheimer’s disease, amyloid, presenilin, tau, APOE, and other genetic findings have shaped decades of research into what drives disease and how different brain pathologies may connect over time.

Hardy emphasizes that Alzheimer’s disease is not a single, simple chain reaction. The process can unfold over 20 or 30 years, with amyloid deposition, tangles, immune activity, lipid biology, and microglia all playing important roles. He describes genetics as a kind of referee, helping researchers test competing theories about how disease starts. Mutations in amyloid-related genes and presenilin helped support the amyloid hypothesis, while later studies of genes such as TREM2 and ABCA7 pointed researchers toward the role of microglia, phospholipids, and cell membranes.

This broader view also helps explain why treatment is difficult. Hardy discusses amyloid antibodies, including lecanemab and donanemab, and describes them as a meaningful step forward because they remove amyloid and show clinical benefit. At the same time, he is clear that these treatments do not stop disease. The next challenge is understanding the “residual decline” that continues even after amyloid is reduced, including how much tau, inflammation, vascular changes, and other processes may become partly independent once the disease is underway.

Hardy’s message is cautiously hopeful. Alzheimer’s research has reached a point where the field no longer has to ask whether amyloid-based treatment can work at all. Instead, the work ahead is to make treatment better, identify people earlier, and combine approaches that address more than one part of the disease. For a complex condition like Alzheimer’s, Hardy suggests the future may involve multiple therapies working together, guided by genetics, biomarkers, and a clearer understanding of how disease develops across decades.

Watch: Alzheimer’s and Other Neurodegenerative Diseases: From Mechanisms to (Faltering) Therapies

This program is part of the Shiley Endowed Lecture Series in Alzheimer’s disease and related dementias research, an annual invited lecture made possible through a generous donation from the Shiley Foundation. The series brings prominent scholars known for groundbreaking work in the field to San Diego to share their research with scholars, students, and community members.