Cognitive Vulnerability to Stress in Individuals at Risk for Alzheimer's Disease

PROJECT SUMMARY/ABSTRACT In the wake of discouraging results from treatment trials in Alzheimer’s disease (AD), the need to identify novel approaches is urgent. There is emerging consensus that the lack of efficacy in AD clinical trials is attributable to disease heterogeneity. Accordingly, identifying predictors of specific AD endophenotypes that could become targets for intervention is of great interest. Among potential options, compelling evidence implicates the stress response as a promising candidate. Indeed, findings from numerous studies converge on the notion that individuals with a heightened sensitivity to stress are at greater risk of developing AD, suggesting that these individuals may represent a group who could be targeted in AD treatment trials. Translating these findings into clinical application has been hampered, however, by a lack of integration between studies that use rigorous experimental interrogation of the endocrine stress response and studies that include sophisticated characterization of patient samples. We aim to address this crucial gap. In this application, we propose to conduct a prospective study to examine the associations among the endocrine stress response, the negative cognitive effects of acute stress, and subsequent cognitive decline in 60 men and 60 women with mild cognitive impairment due to AD (MCI). For our basic study design, we will induce acute stress with the Trier Social Stress Test (TSST), and then measure the endocrine hormone and cognitive responses. The domains of memory and executive functioning will be the primary cognitive outcomes. Salivary samples collected at fixed intervals throughout the TSST will be used to measure stress hormone response; cortisol will be the primary hormone outcome. We will also examine the influence of the APOE gene and polygenic risk scores for AD and collect blood-based biomarkers associated with AD pathophysiology. Specific Aim #1: To determine the association between endocrine response to acute stress and memory and executive test performance following acute stress in individuals with MCI due to AD. Specific Aim #2: To examine the moderating effect of APOE genotype and polygenic risk score on the association between endocrine response to acute stress and cognitive test performance following acute stress in individuals with MCI due to AD. Specific Aim #3: To determine predictors of cognitive decline and neurodegeneration at 2-year follow-up. Secondary Aim: Conduct the analyses from Specific Aims 1-3 in men and women separately in order to identify sex-specific predictors of stress-induced cognitive impairment and cognitive decline and neurodegeneration after 2 years. Public health significance: Given the many recent failures of amyloid-lowering therapies in AD, it is important to identify new potential treatment mechanisms. The proposed study could lay the groundwork for future AD prevention trials targeting stress vulnerability and HPA-axis reactivity in at-risk individuals.