Neurodegenerative Diseases: What Is to Be Done?

Neurodegenerative diseases, including Alzheimer disease, Parkinson disease, and many others, lead to significant morbidity and mortality. As medical care for other disorders (e.g., cardiovascular disease and cancer) has improved and people are living longer, neurodegenerative diseases have become more prevalent because age is a major risk factor for most of them. There have been tremendous advances in our understanding of the scientific underpinnings of neurodegenerative diseases over the last thirty years. Nonetheless, with a few exceptions, very few effective treatments are available to delay the onset or affect the course of these diseases. This Forum brought together leaders in the field of neurodegeneration from different disciplines and tasked them with defining areas in need of more attention—areas where focused work is needed to reveal a better understanding of these disorders. A time frame of 5–20 years was the goal within which to develop more effective diagnostics and treatments. This chapter identifies eight areas to address: Major specific pathologies and circuit dysfunction in neurodegenerative diseases need to be pinpointed over the life span, and dysfunctional circuits require identification. Utilization of genetically well-defined patient populations will likely offer a better chance for therapeutic success. Therapies affecting neurotransmitter systems and signaling pathways should be further explored utilizing defined patient populations and disease-affected nodes. Better ways need to be developed to understand protein aggregation processes, from the formation of misfolded proteins to the critical clearance pathways that regulate their levels and toxicity, including understanding the mechanisms which underlie protein aggregate spreading in the brain as this could lead to novel therapeutics. Better understanding is needed on the role of human apolipoprotein E (apoE), lipoproteins, and lipid biology under normal conditions and in neurodegenerative diseases. To increase understanding of disease and facilitate drug/biological delivery, more information on the blood-brain barrier, the neurovascular unit, and other barriers separating CNS from non-CNS compartments is required. The role of the innate immune system and other immune mechanisms that contribute to progression of neurodegeneration must be better understood. Regardless of the upstream processes, it may be possible to activate neuroprotective mechanisms using defined factors, signaling pathways, or via cell-based methods. With significant progress in each of these eight areas, substantial changes in the diagnosis and treatment of neurodegenerative diseases should be possible over the next twenty years. Given the current cost of these diseases to society and the increase in their prevalence with no additional progress, a major worldwide effort should be made to address these issues immediately, with the highest of priorities.