UCLA

Drugs developed to slow, halt or reverse the progression of Alzheimer’s Disease (AD) have failed to alter the course of the disease in clinical trials. One possible explanation is that drugs need to be administered earlier, before the onset of clinical symptoms. AD-related pathological processes that occur before clinical symptoms emerge define the preclinical phase of the disease. Neuroimaging biomarkers and genetics together present a powerful system for characterizing potential preclinical changes in the brain. The work presented in this volume is predicated on the need for a better understanding of genetic risk and neuroimaging biomarkers for AD in healthy adults. In Chapter 1, a thorough review of neuroimaging genetics in AD is presented. The studies described in Chapters 2 and 3 explore the relationship between functional connectivity and the apolioprotein E (APOE) risk allele, APOEε4. In the first study a pattern of context-dependent connectivity was uncovered that indicates APOEε4 carriers disengage key cortical regions from the hippocampus during a memory task. These findings support the growing consensus that functional connectivity changes may be among the earliest preclinical markers of AD-related changes in the brain. The second study utilized resting state fMRI scans from 570 healthy college-age adults. Young carriers of APOEε4 showed decreased connectivity between key regions involved in AD and increased segregation of task-positive and task-negative regions. This work is a crucial reminder that genetic risk for AD has important implications across the lifespan and that gene-biomarker associations must be tracked over time to identify changes that might be signs of imminent clinical decline. In Chapter 4, the focus expands to include additional genetic risk factors for AD beyond APOE. This study is the first to show that a genetic risk score for AD is significantly associated with hippocampal thinning over two years in a cohort of older, cognitively healthy adults. Finally, Chapter 5 is a call for the further development of polygenic approaches to studying neuroimaging markers of genetic risk for AD. Together, this volume represents steps toward understanding how genetic risk for AD and neuroimaging can be used to identify individuals at greatest risk for decline.