Circulating Inflammatory Proteins Associated with Dementia Risk in Older Adult Cancer Survivors in the Atherosclerosis Risk in Communities (ARIC) Study

Abstract

Background Inflammation is linked to cognitive impairment (CI) in cancer survivors. But its role in survivors who develop dementia is unclear. Methods We evaluated dementia risk per log2 increase in 580 inflammatory proteins in 391 dementia-free long-term (>5 yrs) older adult survivors of prostate, breast, colorectal, endometrial and bladder cancers in ARIC. Plasma inflammatory proteins were measured at visit 5 (2011–13) using SomaScan, an aptamer-based assay. Participants were followed through visit 6 (2016–17). We adjusted for age, sex, race, years since cancer diagnosis, ApoE4, renal function, anti-inflammatory drug use and cancer/CVD shared risk factors. We also investigated proteins associated with dementia in 196 prostate and 135 breast cancer survivors, accounting for multiple testing by Bonferroni correction and false discovery rate Q-values. Results Survivors were 20% Black, 54% male, mean age of 76yrs, median time since diagnosis of 12yrs. 67 dementia cases occurred in 1780 person-yrs. After FDR correction, 73 proteins were statistically significantly associated with dementia risk. TMEM87B, CD9, RAF1, IL21sR and FGF7 showed the strongest positive association, with HR:3.4–3.8 per Δlog2. LAIR1, IL36B, FGFR3, FLRT3 and LSAMP showed the strongest inverse association, HR:0.1–0.2. Only syntaxin12 (STX12) was significant after Bonferroni correction, HR:2.2. Associations of some inflammatory proteins with dementia were cancer site-specific. In breast cancer survivors, IL6, HMGA2, IFN-GR1, SAP, TNFRSF1a, TNFRSF14, and TNFAIP3, were associated with dementia. STX12 and RAF1 were significantly associated (q <0.05) with dementia in all, prostate, and breast cancer survivors. Conclusion Inflammatory proteins were associated with dementia in older adult cancer survivors, including STX12 (enriched in brain, linked to WNT signaling loss, exerts CNS effects) and RAF1 (regulates MAPK/ERK pathway, previously identified in dementia etiology). Inflammatory proteins previously associated with CI, including TNF proteins/receptors, were associated with dementia in breast cancer survivors. If confirmed, these proteins may warrant evaluation as potential biomarkers for dementia risk screening, and possibly preventive/therapeutic targets in cancer survivors. Funding: NHLBI, NCI, NPCR