Imaging the change. Biological pathways for resilience and resistance to memory decline in older age.

Episodic memory declines with age and is the most prominent cognitive hallmark of dementia due to Alzheimer’s Disease, a major public health problem of high societal and economic burden. Yet, we do not all age equally. Some individuals exhibit substantial decline while others show memory preservation over time. These differences are determined by multiple, intersecting changes in the brain’s structure, function, and chemistry. Critically, understanding of the different pathways of brain aging is still insufficient due to the lack of large, longitudinal, multimodal datasets. Here, we aim to provide a comprehensive picture of the different routes leading to episodic memory preservation or decline in older age. To leverage our understanding of the conditions of memory function in aging, we will harmonize existing neuroimaging and cognitive data of ˜7000 participants followed over time with genetic and biomarker profiling and benefit from a recently developed analytic framework to model the different patterns of covariance of brain change. Using, polygenic scores and neurochemical biomarkers information we will inform on the biological mechanisms underlying the heterogeneity of the aging brain and delineate individual vulnerabilities to brain age and disease. Ultimately, we aim to provide a complete and interpretable account of brain aging by integrating genetic, molecular, and macrostructural hallmarks in a unitary framework. The project takes advantage of ongoing collaborations with the Lifebrain (Oslo-led) consortium and the Reserve&Resilience initiative, both focused on understanding the aging brain securing a unique pool of data and maximizing the quality, impact of the results, and public outreach. The outcome will be of substantial value for guiding preventive initiatives aiming to modify cognitive trajectories in older age.

Episodic memory declines with age and is the most prominent cognitive hallmark of dementia due to Alzheimer’s Disease. Yet, we do not all age equally. Some individuals exhibit substantial decline while others show preserved memory function over time. These differences are determined by multiple, intersecting changes of the brain’s structure, function, and chemistry. Critically, different patterns of brain change can equally lead to similar late-life memory function. Yet, knowledge of these brain aging pathways is still insufficient. In AgingBrainPaths, we will provide a comprehensive understanding of the different routes that lead to episodic memory preservation or decline in older age. Using 10 existing datasets, we will harmonize longitudinal MRI and cognitive data of ˜7000 unique participants followed over time with genetic and biomarker profiling. Using a new analytic framework, we will co-model changes in multiple aspects of the aging brain capturing changes in features of grey and white matter integrity, microstructural properties, and of the functional connectome. The findings will reveal the different patterns of brain aging and how they impact memory function in older age. Using pathway-specific polygenic scores, fluid biomarkers, and radiotracer data we will inform on the biological mechanisms underlying the specific patterns of the aging brain. Finally, we will group participants according to their specific brain aging profile and delineate individual vulnerabilities to age and disease. The project outcome will provide a comprehensive understanding of the mechanisms, influences, and etiology behind late-life memory decline including information on each individual’s pathways to brain aging. The outcome will be of substantial value for guiding preventive initiatives aiming to modify cognitive trajectories in older age and improve predictions on late-life performance based on subject-specific vulnerabilities.