Abstract Body: Introduction: The senescence-associated secretory phenotype (SASP) consists of paracrine signaling molecules with deleterious effects secreted by senescent cells. However, little human data exist linking circulating SASP proteins to cognitive decline.

Hypothesis: Plasma levels of SASP proteins will be associated with the development of mild cognitive impairment (MCI) or dementia and with subclinical neurodegenerative disease.

Methods: Among participants in the Atherosclerosis Risk in Communities (ARIC) cohort study 5^th visit (2011-2013), we measured 26 SASP plasma proteins using an aptamer-based platform (SomaScan). Participants underwent protocol cognitive evaluations at Visit 5, Visit 6 (2016-2017) and Visit 7 (2018-2019), and a subset underwent brain magnetic resonance imaging at Visit 5. Among MCI/dementia-free individuals at Visit 5, we assessed associations of SASP proteins with incident MCI or dementia at Visit 6 (median interval 4.9 years) or Visit 7 (median interval 6.6 years) using multivariable logistic regression. We further assessed the associations of cognitive decline-related SASP proteins with total brain volume, temporal lobe meta-ROI volume, and volume of white matter hyperintensities using multivariable linear regression. All models were adjusted for age, sex, race and visit center. Two-sample cis-Mendelian randomization (MR) was performed to evaluate potential causal effects of proteins on overall dementia and specific dementia etiologies.

Results: Among 2,024 participants included, mean age was 74±5 years, 59% were female, and 18% reported Black race. Between study Visit 5 and Visits 6 or 7, 639 (32%) participants developed MCI or dementia. Of the 26 SASP proteins, higher levels of 5 (GDF15, IGFBP7, CTSD, CST3 and HSPA8) were associated with higher risk of incident MCI or dementia (FDR-corrected p<0.05; Figure 1). Among these proteins, GFD15, CST3 and HSPA8 were associated with lower total brain volume and lower temporal lobe meta-ROI volume, and GDF 15, CST3, IGFBP7, and CTSD were associated with greater volume of white matter hyperintensities (Figure 2). Two-sample MR identified a potential causal effect of GDF15 on Alzheimer’s Disease (p<0.001).

Conclusions: Higher plasma levels of a subset of the SASP proteins are associated with higher risk of developing MCI or dementia, and with greater subclinical alterations on neuroimaging. These findings support the potential role of cellular senescence in cognitive impairment.