Pre-Diagnostic Cognitive and Functional Impairment in Multiple Sporadic Neurodegenerative Diseases

Abstract INTRODUCTION The pathophysiological processes of neurodegenerative diseases begin years before diagnosis. However, pre-diagnostic changes in cognition and physical function are poorly understood, especially in sporadic neurodegenerative disease. METHODS UK Biobank data was extracted. Cognitive and functional measures in individuals who subsequently developed Alzheimer’s Disease, Parkinson’s Disease, Frontotemporal Dementia, Progressive Supranuclear Palsy, Dementia with Lewy Bodies, or Multiple System Atrophy, were compared against those without neurodegenerative diagnoses. The same measures were regressed against time to diagnosis, after adjusting for the effects of age. RESULTS There was evidence for pre-diagnostic cognitive impairment and decline with time, particularly in Alzheimer’s. Pre-diagnostic functional impairment and decline was observed in multiple diseases. DISCUSSION The scale and longitudinal follow-up of UK Biobank participants provides evidence for cognitive and functional decline years before symptoms become obvious in multiple neurodegenerative diseases. Identifying pre-diagnostic functional and cognitive changes could improve selection for preventive and early disease-modifying treatment trials. Research in Context Systematic review Studies of genetic dementia cohorts provide evidence for pre-diagnostic changes in disease biomarkers and cognitive function in several genetic neurode-generative diseases. The pre-diagnostic phase of sporadic neurodegenerative disease has been less well-studied. It is unclear whether early functional or cognitive changes are detectable in sporadic neurodegenerative disease. Interpretation We have established an approach to identify cognitive and functional pre-diagnostic markers of neurodegenerative disease years before diagnosis. We found disease-relevant patterns of pre-diagnostic cognitive and functional impairment, and observed a pre-diagnostic linear decline in a number of cognitive and functional measures. Future Directions Our approach can form the basis for pre-diagnostic cognitive and functional screening to recruit into trials of disease prevention and disease modifying therapies for neurodegenerative diseases. A screening panel based on cognition and function could be followed by disease-specific biomarkers to further improve risk stratification.