Investigating the impact of loneliness on brain aging and pre-symptomatic Alzheimer's disease progression

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Project Summary (Spreng/Bzdok, McGill University) Project Summary. Feelings of loneliness in later life are associated with poor health outcomes including loss of cognitive ability, greater dementia risk, and higher mortality rates. Yet surprisingly little is known about how loneliness impacts the brain in older adulthood. Feelings of loneliness may arise in response to brain changes, providing an early signal of insipient brain disease. Loneliness may also be an antecedent or accelerant, promoting the advance of neuropathological changes and increasing dementia risk. Previous work from MPIs Spreng and Bzdok has demonstrated that the default network, an assembly of regions closely overlapping the `social brain', is selectively vulnerable to both loneliness and Alzheimer's disease (AD). This suggests that loneliness and neuropathological changes may interact to shape the course of brain aging and progression to AD. However, the specific nature and direction of these interactions is poorly understood. The goal of the proposal is to investigate the relationship between loneliness and brain structure and function in typical aging and in individuals at risk for AD. There are two research aims. Studies in Aim 1 will examine associations between loneliness and normal brain aging in a large population data sample (UK Biobank). Anticipated outcomes include population-level normative trajectories of brain aging and estimates of `non-normative' change attributable to the experience of loneliness. Studies in Aim 2 will examine associations between loneliness and brain aging in pre-symptomatic AD in a local longitudinal cohort of older adults at elevated risk for AD. The anticipated outcome for this Aim is a better understanding of how longitudinal changes in loneliness interact with longitudinal changes in brain structure and function to influence pre-symptomatic AD progression. Studies in Aim 1 will use cross-sectional, population neuroscience methods (probabilistic hierarchical modeling) to derive normative trajectories of brain aging. These analyses will focus on the default network, drawing upon a high resolution cortical and subcortical parcellation scheme developed by MPI Bzdok. These normative trajectories will allow measurement of non- normative deviations attributable to the experience of loneliness in a population of older adults. Studies in Aim 2 will use longitudinal probabilistic hierarchical analyses to investigate interactions between loneliness and brain aging in the context of elevated AD risk. Participants will be from a local longitudinal cohort of older adults at elevated risk for AD. This work will leverage recent efforts by MPI Spreng, to collect cutting edge neuroimaging and behavioral data that will serve as a baseline for the next wave of data collection proposed here. This research will advance understanding of how loneliness interacts with brain structure and function in normal aging and pre-symptomatic AD. Loneliness is a tractable social condition, modifiable through individual or policy-level interventions. Greater understanding of the relationships between loneliness, brain aging, and disease may ultimately pave the way for better detection, monitoring, and interventions. !1