Abstract 44: Plasma Sphingolipids in Relation to Cognitive Decline and Incident Dementia

Abstract

Introduction: Sphingolipids are fundamental components of brain structure and function. They are located in the myelin sheath insulating neuronal axons and in the cell membranes of neurons, astrocytes, and microglia involved in signal transduction. Although circulating sphingolipid profiles reflect clinical neurodegeneration, few prospective studies have investigated their utility as pre-clinical risk markers in community-based cohorts. For heart disease and diabetes, themselves risk factors for dementia, associations with sphingolipids differed across species and the length of the saturated fatty acid carried. Hypothesis: We hypothesized that plasma levels of sphingolipid species containing palmitic acid (16:0) would be positively associated with incident dementia risk and cognitive decline, while those with arachidic acid (20:0), behenic acid (22:0), and lignoceric acid (24:0) would be associated with lower risk. Methods: We measured 18 sphingolipid species in plasma samples from 4612 participants of the Cardiovascular Health Study (CHS) (mean age 76.2 years; 40% male; and 25% APOE ε4 allele carriers). Cognitive decline was assessed across 6 years using annual 100-point modified Mini-Mental State Examination (3MSE) and Digital Symbol Substitution Test (DSST) scores. A total of 3088 non-demented participants were enrolled in the CHS Cognition Study and followed with adjudication for dementia. To correct the analyses for multiple comparisons, we applied a false discovery rate (FDR) correction and used a significance threshold of 0.05. Results: Higher baseline levels of lactosylceramide-24:0 (LacCer-24) were associated with a faster 6-year cognitive decline (time x sphingolipid interaction p=0.04 for 3MSE and 0.03 for DSST). Conversely, higher baseline plasma levels of hexosylceramide -16:0 (HexCer-16) and sphingomyelin-22:0 (SM-22) were associated with slower cognitive decline measured with DSST (time x sphingolipid interaction p=0.02 for HexCer and p=0.05 for SM-22). During a median follow-up of 4.5 years, we identified 366 incident dementia cases. In proportional Cox regression analyses, higher plasma levels of ceramide-16:0 (Cer-16) were positively associated with incident dementia upon adjustment for demographics, lifestyle factors, medical history, C-reactive protein, and lipids [hazard ratio per SD: 1.18 (95% CI, 1.06; 1.31)]. Conclusions: In older adults without dementia, higher plasma levels of Cer-16, a species previously associated with cardiovascular disease and mortality, were associated with higher risk of clinical dementia as we hypothesized. LacCer-24 was associated with faster, and HexCer-16 and SM-22 with slower, cognitive decline, but these species were not statistically associated with dementia risk. These novel and inconsistent findings will need to be replicated in other longitudinal studies.