PS20C

New Horizons Lecture: The War on Alzheimer's Disease: Neuroimaging, Biomarkers and Genetics on the Front Lines

Monday 1:30-2:45 PM | PS20C | Room: Arie Crown Theater
 
PARTICIPANTS:
Andrew J. Saykin (Presenter)
Disclosure: Research Grant, Eli Lilly and Company Research collaboration, Eli Lilly and Company Investigataor, Arkley BioTek Support, Eli Lilly and Company
Introduction by
Valerie P. Jackson, MD (Presenter)
President, Radiological Society of North America
Disclosure: Nothing to Disclose

CITE THIS ABSTRACT
Abstract
Alzheimer's disease, the most common form of dementia, affects an estimated 5.8 million Americans and many more individuals worldwide. Despite more than a century of increasing knowledge about AD, first observed as plaques and tangles in postmortem brain tissue, we do not yet have a disease-modifying medication. Although rare forms of AD are caused by mutations in one of three genes, most Alzheimer's is "complex" reflecting the involvement of multiple risk genes, biological pathways and interactions with the environment, including lifestyle factors. Many patients have mixed pathologies. Neuroimaging has proven important in the diagnosis and management of AD and related dementias with recent studies demonstrating value for clinical decision making. For research, the impact of neuroimaging has been transformative, beginning with quantitative MRI analysis of atrophy and PET measures of glucose hypometabolism and followed by targeted molecular imaging with PET tracers specific for amyloid beta plaque and tau deposition. Coupled with CSF analysis, imaging has shown that pathophysiological changes begin about twenty years prior to dementia. This provides a long window of therapeutic opportunity. Early detection and robust biomarkers of disease progression are critical for therapeutic development efforts as effective treatment will need to be instituted prior to extensive neurodegeneration. Challenges include heterogeneity of phenotypic presentation and underlying disease. There are other misfolded proteins beyond amyloid beta and tau. PET tracers and other biomarkers are needed for alpha-synuclein, TDP-43 and other biological processes including immune dysregulation. A key issue remains as to what sets the pathophysiological cascade in motion and how the different elements interact. Genetics can provide some clues and large-scale studies have identified about 30 promising candidate genes related to multiple biological pathways. Multi-layer "omics" studies are also bringing the transcriptome, proteome and metabolome into focus. Advances in systems biology and bioinformatics are helping to identify dysregulated networks in AD. Progress is also being made in network analysis of MRI-based connectome changes based on functional and structural brain connectivity as early indicators of prodromal disease. An important goal is to translate new knowledge of disease heterogeneity into a precision medicine framework. Polygenetic risk scores that aggregate risk across many genes are showing promise and recent efforts are aimed at developing precision risk profiles for amyloid, tau, microvascular disease and immune dysregulation, among other pathways. New developments in blood-based biomarkers also appear promising and may prove useful for pointing to specific pathways and identifying those who require more invasive and expensive tests. Personalized pathway-specific risk estimates will hopefully lead to individually tailored treatments. At the same time, research on lifestyle modifications including exercise, diet, cognitive engagement and sleep is very promising. Single or combinatorial pharmacological approaches are likely to be most effective coupled with attention to lifestyle factors. Despite recent setbacks in clinical trials, battles are being won through global collaborative research efforts, and victory lies ahead.