Grant Number:	1R01CA279316-01A1 Interpret this number
Primary Investigator:	Warner, Erica
Organization:	Massachusetts General Hospital
Project Title:	Impact of Cancer on Cognitive Trajectories in Older Adults
Fiscal Year:	2024

PROJECT SUMMARY Cancer-related cognitive impairment (CRCI) represents an important clinical issue affecting up to 75% of people before, during, and after diagnosis and treatment. Understanding cognitive trajectories associated with cancer and cancer treatment is particularly important among older adults (age ≥ 65) who may be more susceptible to CRCI. However, older adults have been underrepresented and previous studies have been limited by a predominance of short-term follow-up, focus on breast cancer, and a lack of mechanistic investigation. The overall objective of this application is to determine risk, susceptibility, and biological mechanisms linking cancer, cancer treatment and cognitive functioning. We will leverage data from ASPREE (Aspirin in Reducing Events in the Elderly) and its observational follow-up study (ASPREE-XT). ASPREE was a trial of 19,114 individuals aged ≥70 years (≥ 65 for US minorities) enrolled in Australia (n=16,703) or the United States (n=2,411) in which participants were randomly allocated to daily low-dose (100 mg) aspirin or placebo. At enrollment, participants had no history of diagnosed dementia, cardiovascular disease, significant physical disability, or major cognitive impairment. Repeated measures of multiple domains of cognitive function were performed, including memory, executive function, and psychomotor speed, assessed at baseline and every 2 years (2010-2017), and then annually during follow-up (2018-2024). We will use a prospective longitudinal study design to examine the following specific aims: Aim 1. Determine the impact of cancer and cancer treatment on longitudinal trajectories of cognitive functioning. We will expand the cancer treatment data set to include treatment data for all cancer events through to 2024, and further investigate whether host factors such as age at diagnosis, assignment to aspirin or placebo, educational attainment, APOE risk genotype, dementia polygenic risk score, pre-diagnostic clonal hematopoiesis of indeterminant significance (CHIP), or biomarkers associated with Alzheimer’s Disease and related dementias (ADRD) neuropathology (Aβ, p-tau, NfL, and GFAP) impact risk. Aim 2. Determine the impact of cancer and cancer treatment on CHIP and ADRD biomarkers (Aβ, p-tau, NfL, and GFAP) and investigate potential mediating effects with respect to cognitive functioning. This study is significant because it addresses the high unmet need to elucidate the relationship between cancer and cancer treatment and cognitive functioning in older adults, to characterize pre-diagnostic factors that confer susceptibility, and identify mechanisms that underlie associations. In so doing, it enables early detection of high-risk individuals. It directly addresses the priorities outlined in NOT-CA-21-031. This study leverages a unique study population with longitudinal measures of cognitive function before and after cancer diagnosis, investigates cognitive trajectories, includes multiple cancer types, focuses on older adults, and advances mechanistic understanding of cancer- related cognitive impairment. The impact will be to help identify individuals at higher risk CRCI and the modifiable targets for intervention, ultimately improving quality of life and independent living.