On July 13, the day before the Alzheimer’s Association International Conference started in Los Angeles, 263 DIAN participants and their partners met in the same location with scientists, clinicians, research funders, and representatives of the association for a pre-meeting. They celebrated a shared commitment to use the scientific opportunities inherent in dominantly inherited Alzheimer’s disease toward a better understanding and clinical trials to prevent the disease. Four stories in this series showcase the resilience of DIAN participants, progress in AD genetics, a first look at emerging RNA-based therapies, and an update on DIAN clinical trials.
Research presented at this year’s AAIC reflected an influx of new money into the field and, with it, a growing diversity of topics. There was new interest in government policy, NIA funding priorities, and underrepresented minorities, along with an even greater emphasis on lifestyle factors and technologies to lessen the impact of a dementia epidemic forecast by demographic change. No large clinical trials presented major data, while a session picking over the ruins of recent BACE inhibitor trials showcased some transparency and shared willingness among pharma companies to learn from failure. Genetics posted news, as did biomarkers, especially blood tests, and much effort being poured into preparing observational cohorts for prevention trials was evident. Imaging continues to light up the field, debuting a new amyloid staging system and offering head-to-head comparisons of tau ligands. Specific tracers for neuroinflammation and other proteinopathies are still out of reach.
Dementia with Lewy bodies is a devastating disorder, combining some of the worst features of Alzheimer’s and Parkinson’s, but it is relatively rare and often goes unrecognized. DLB research has lagged far behind that for AD and PD, but is rapidly gaining ground. At a recent conference in Las Vegas, researchers discussed worldwide progress in building the infrastructure to support large longitudinal studies and clinical trials for DLB. Researchers presented guidelines for improving diagnosis and management of the disease, and scientists discussed how best to identify prodromal cases for research studies.
At a joint Keystone symposia, microglia continued to twist and turn in the limelight, casting a long shadow as central agents of disease, not mere responders. Researchers embraced the complex reality of mixed pathology, dishing out data from animal models in which Aβ, tau, and α-synuclein mingled and sparked each other’s spread. From a gut-initiated model of Parkinson’s disease to chimeric mice harboring human microglia to a startling conversion of astrocytes to newborn dopaminergic neurons within the brain, researchers upped the ante on disease models and proposed new therapeutic strategies.
Held in romantically beautiful Lisbon, this AD/PD was the biggest thus far, drawing 3,982 attendees from 73 countries, according to Abraham Fisher, its longtime lead organizer. But as the field grows, it has little to celebrate, and the mood reflected that. Trialists were appealing for patience and pointing to deepening clinical trials skills as they learn from continuing setbacks on investigational therapies, most recently of lanabecestat, crenezumab, and aducanumab. Trials targeting tau were not yet reading out, but the medical food Souvenaid posted modestly positive results. At the other end of the bench-to-bedside spectrum, basic science is diversifying. Next-gen genetics is spilling out gene variants which, together with RNAseq, are energizing research into glial and lipid biology. Debate about the amyloid hypothesis, a fixture at AD/PD, evolved toward a focus on genetic variability in how a person’s innate immune system responds to amyloid deposition. Aβ itself? Nothing special about it. It aggregates into an irritant as the brain’s ability to degrade it wanes with age. It starts things off, but other factors later dominate the disease. Or so researchers now think. Read Madolyn Rogers and Gabrielle Strobel’s coverage.