Grant: Operating Grant: Joint Programme on Neurodegenerative Disease Research (JPND)

For decades, conventional approaches to neurodegenerative research have not paid much attention to the diversity within clinical diagnostic groups when looking at brain-behavior relationships. Analyzing correlations using discrete clinical diagnostic groups is limited as it fails to capture the entirety of an individual's unique genome and risk factor profile. The complex interplay between genetic and other risk factors, including age, sex and cardiovascular risk in relation to the clinical expression of neurodegenerative disease needs to be addressed by large-scale prospective clinical-imaging-biomarker-genetic studies. We will be combining efforts across four countries (Canada, Italy, Sweden, and Czech Republic) contributing mixed cohorts of patients with neurodegenerative diseases, including Alzheimer's disease, Parkinson's/Lewy body disease, frontotemporal dementia-amyotrophic lateral sclersosis, and vascular cognitive impairment. We will also partner with a large 'at risk' aging cohort, the Rotterdam study from the Netherlands. The main goal is to discover novel contributions of genetic variants and other risk factors to cognitive and neuroimaging measures across the mixed neurodegenerative cohorts blinded to clinical diagnosis. MRI and cognitive signatures of neurodegenerative diseases driven by the genomic and risk factor associations will be identified and validated. Another major goal is to see how these signatures map onto neurodegenerative disease risk in the Rotterdam study (i.e., presymptomatic dementia). The results will provide new insights into correlations between genetic markers, aging, sex and cardiovascular risk and areas of brain shrinkage and cognitive dysfunction associated with neurodegenerative diseases. Understanding these patterns may help to improve diagnosis, to customize treatment, and to better monitor disease-modifying therapies currently under investigation should they become applicable to everyday practice.