Abstract Long-term survivors of childhood cancer may be at increased risk for accelerated aging and early-onset dementia, particularly survivors of Hodgkin lymphoma treated with thoracic radiation therapy. We have previously demonstrated that thoracic radiation in these survivors is associated with increased risk for cardiovascular and pulmonary disease, and recent findings suggest a four-fold increased risk for obstructive sleep apnea compared to community controls matched on age, sex and body mass index. In our sample we also see associations between these health conditions and with hippocampal-dependent memory impairment. In the elderly general population, this health-cognitive phenotype is at increased risk of dementia, however, our survivors demonstrate these risk factors in young to middle adulthood. Further, recent research from our team demonstrates shorter telomere length in Hodgkin lymphoma survivors and those treated with thoracic radiation compared to community controls, but also compared to survivors of brain tumors, leukemia and those treated with cranial irradiation. These findings suggest that survivors of Hodgkin lymphoma may be at increased risk for early-onset dementia, potentially due to accelerated brain aging resultant from radiation exposure during critical periods of pediatric development. Estimates of accelerated brain aging have been shown to predict dementia and mortality in the general population and thus, this metric may serve as a useful biomarker for early detection and intervention for dementia and/or Alzheimer's disease in cancer survivors. For this study, we propose to calculate brain age in a large sample of adult survivors of childhood Hodgkin lymphoma compared to community controls. Neurocognitive assessments related to dementia, brain imaging, metrics of frailty, co-occurring medical conditions, clinical factors, and biomarkers of aging have already been collected in 350 Hodgkin lymphoma survivors and 250 community controls matched for age, sex, and race. We propose to compare chronological age vs brain age discrepancies, identify demographic and clinical/treatment factors associated with accelerated brain age, and examine associations between accelerated brain age with neurocognitive impairment, chronic health conditions, frailty and sleep disturbances. We will also examine associations between brain age and molecular biomarkers (e.g., telomere length). This will be the first study to directly examine accelerated cognitive and brain aging in a cohort of adult survivors of childhood cancer. These survivors present with symptoms of memory impairment, consistent with dementia and/or Alzheimer's disease. The comprehensive longitudinal data available to us will inform dementia onset and progression, as we follow the survivors in our cohort for the remainder of their life's. Results of this study will have major implications for understanding the pathology of dementia and Alzheimer's disease, and will provide invaluable information concerning risk prediction and intervention development.

Relevance Statement This proposal will determine whether middle-aged adult survivors of childhood Hodgkin lymphoma demonstrate accelerated brain aging compared to matched community controls. Hodgkin lymphoma survivors have higher frequency of cardiopulmonary morbidity and sleep apnea, and demonstrate shorter telomeres compared to other cancer survivors. Such factors are associated with dementia in the general population, though present in lymphoma survivors at a much younger age.