PROJECT SUMMARY Major Neurocognitive Disorders of Aging, including Alzheimer's Disease (AD) and Alzheimer's Disease Related Dementias (ADRD), produce cognitive declines that substantially affect daily living. To date, the molecular processes underlying the neurodegeneration and cognitive declines that ultimately give rise to AD/ADRD remain poorly understood. Recent developments in genome wide association study (GWAS) provide promising avenues for identifying genetic variants and associated biological pathways of AD/ADRD risk beyond those characterized by polymorphisms within the well-known APOE gene. However, a major challenge to progress in AD/ADRD genomics is that contemporary methods used to diagnose AD/ADRDs for epidemiological research often rely on cognitive assessments or clinical rating at a single point in time, which are confounded by substantial variation in peak levels of cognitive function in early adulthood. Particularly when peak levels of cognitive function are high, cognitive declines may go undetected for decades before individuals present with impaired levels of functioning. Indeed, it has now become clear that by the time AD/ADRD diagnoses are made, the pathophysiology of AD/ADRD and trajectories of accelerated cognitive decline have accumulated extensively, during a so-called “silent period.” These issues both dilute and bias GWAS associations in conventional case-control, time-to-event, age-at-event, and single occasion designs. The primary goal of the current R01 proposal is therefore to conduct the first large-scale consortium-based GWAS of continuous rates of longitudinal aging-related cognitive change prior to dementia onset. This will allow us to identify variants beyond those in the APOE gene that confer risk for rate of cognitive decline leading to eventual AD/ADRD, estimate improved genome-wide polygenic scores that can be used to enhance assessment of AD/ADRD risk, and identify novel biological pathways of AD/ADRD risk that can be targeted by prevention and treatment efforts.

PROJECT NARRATIVE This project will provide the most comprehensive interrogation of the genetics of aging-related cognitive changes during prodromal, so-called “silent,” periods of AD/ADRD progression. Identifying the genetic risk factors and biological mechanisms underlying progression to clinical AD/ADRD is crucial to developing interventions to prevent, delay, or otherwise mitigate AD/ADRD progression.