Neuroimaging Genetic Risk for Alzheimer’s Disease in Preclinical Individuals: From Candidate Genes to Polygenic Approaches

Better characterization of the preclinical phase of Alzheimer’s disease (AD) is needed to develop effective interventions. Neuropathologic changes in AD, including neuronal loss and the formation of proteinaceous deposits, can begin 20 years before the onset of clinical symptoms. As such, the emergence of cognitive impairment should not be the sole basis used to diagnose AD or to evaluate individuals for enrollment in clinical trials for preventive AD treatments. Instead, early preclinical biomarkers of disease and genetic risk should be used to determine the most likely prognosis and to enroll individuals in appropriate clinical trials. Neuroimaging-based biomarkers and genetic analysis together present a powerful system for classifying preclinical pathology in patients. Disease-modifying interventions are more likely to produce positive outcomes when administered early in the course of AD. This review examines the utility of the neuroimaging genetics field as it applies to AD and early detection during the preclinical phase. Neuroimaging studies focused on single genetic risk factors are summarized. Particular focus is on the recent increased interest in polygenic methods, and the benefits and disadvantages of these approaches are discussed. Challenges in the neuroimaging genetics field, including limitations of statistical power arising from small effect sizes and the overuse of cross-sectional designs, are also discussed. Despite the limitations, neuroimaging genetics has already begun to influence clinical trial design and is expected to play a major role in the prevention of AD.