@article {6080, title = {Common FABP4 genetic variants and plasma levels of fatty acid binding protein 4 in older adults.}, journal = {Lipids}, volume = {48}, year = {2013}, month = {2013 Nov}, pages = {1169-75}, abstract = {

We examined common variants in the fatty acid binding protein 4 gene (FABP4) and plasma levels of FABP4 in adults aged 65 and older from the Cardiovascular Health Study. We genotyped rs16909187, rs1054135, rs16909192, rs10808846, rs7018409, rs2290201, and rs6992708 and measured circulating FABP4 levels among 3190 European Americans and 660 African Americans. Among European Americans, the minor alleles of six single nucleotide polymorphisms (SNP) were associated with lower FABP4 levels (all p~<=~0.01). Among African Americans, the SNP with the lowest minor allele frequency was associated with lower FABP4 levels (p~=~0.015). The C-A haplotype of rs16909192 and rs2290201 was associated with lower FABP4 levels in both European Americans (frequency~=~16~\%; p~=~0.001) and African Americans (frequency~=~8~\%; p~=~0.04). The haplotype combined a SNP in the first intron with one in the 3{\textquoteright}untranslated region. However, the alleles associated with lower FABP4 levels were associated with higher fasting glucose in meta-analyses from the MAGIC consortium. These results demonstrate associations of common SNP and haplotypes in the FABP4 gene with lower plasma FABP4 but higher fasting glucose levels.

}, keywords = {African Americans, Aged, Aged, 80 and over, Blood Glucose, Body Mass Index, Cohort Studies, European Continental Ancestry Group, Fatty Acid-Binding Proteins, Female, Gene Frequency, Genetic Association Studies, Haplotypes, Humans, Insulin, Linkage Disequilibrium, Male, Polymorphism, Single Nucleotide}, issn = {1558-9307}, doi = {10.1007/s11745-013-3838-7}, author = {Mukamal, Kenneth J and Wilk, Jemma B and Biggs, Mary L and Jensen, Majken K and Ix, Joachim H and Kizer, Jorge R and Tracy, Russell P and Zieman, Susan J and Mozaffarian, Dariush and Psaty, Bruce M and Siscovick, David S and Djouss{\'e}, Luc} } @article {9850, title = {Circulating Ketone Bodies, Pyruvate, and Citrate and Risk of Cognitive Decline, Structural Brain Abnormalities, and Dementia.}, journal = {Aging Dis}, year = {2024}, month = {2024 Nov 08}, abstract = {

The relationship between key energy metabolites and brain health is not well understood. We investigated the association between circulating ketone bodies, pyruvate, and citrate with cognitive decline, structural brain characteristics, and risk of dementia. We measured ketone bodies (acetoacetate, β-hydroxybutyrate, and acetone), pyruvate, and citrate species using NMR in plasma samples from 1,850 older adults in the Cardiovascular Health Study collected in 1989-90 or 1992-93. Cognitive decline was assessed using the modified Mini-Mental State Examination and the Digit Symbol Substitution Test. Dementia was adjudicated by a committee of experts through comprehensive evaluations including cognitive tests, medical records, and interviews with the next of kin. Dementia-related mortality was confirmed by a committee using death certificates and other clinical data from hospitalization. Multivariable linear mixed models were used to assess 9-year cognitive decline, while multivariable Cox regression models evaluated 6-year dementia incidence and 22-year dementia-related mortality. White matter lesions and ventricular size were measured using MRI in 1992-94 and were analyzed using multivariable linear regression models. Higher plasma levels of ketones, particularly β-hydroxybutyrate, were associated with faster cognitive decline (β, -0.10; 95\% CI, -0.15 to -0.05; P\&;lt.001) and dementia-related mortality (HR per SD, 1.29; 95\% CI, 1.07 to 1.56; P=0.023). Higher pyruvate concentrations were associated with slower cognitive decline, smaller ventricular size, lower dementia risk (HR per SD, 0.87; 95\% CI, 0.77 to 0.97; P=0.013; P=0.073), and lower dementia mortality. Higher citrate levels were associated with less cognitive decline and lower dementia risk. In adults aged 65 years and older, circulating ketone bodies are associated with faster cognitive decline and higher dementia mortality, while pyruvate and citrate are associated with lower dementia risk.

}, issn = {2152-5250}, doi = {10.14336/AD.2024.0754}, author = {Gutierrez-Tordera, Laia and Moseholm, Kristine F and Trius-Soler, Marta and Bull{\'o}, M{\`o}nica and Fitzpatrick, Annette and Connelly, Margery A and Lopez, Oscar L and Jensen, Majken K and Guasch-Ferr{\'e}, Marta and Mukamal, Kenneth J} } @article {9704, title = {Circulating sphingolipids and subclinical brain pathology: the cardiovascular health study.}, journal = {Front Neurol}, volume = {15}, year = {2024}, month = {2024}, pages = {1385623}, abstract = {

BACKGROUND: Sphingolipids are implicated in neurodegeneration and neuroinflammation. We assessed the potential role of circulating ceramides and sphingomyelins in subclinical brain pathology by investigating their association with brain magnetic resonance imaging (MRI) measures and circulating biomarkers of brain injury, neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) in the Cardiovascular Health Study (CHS), a large and intensively phenotyped cohort of older adults.

METHODS: Brain MRI was offered twice to CHS participants with a mean of 5 years between scans, and results were available from both time points in 2,116 participants (mean age 76 years; 40\% male; and 25\% ε4 allele carriers). We measured 8 ceramide and sphingomyelin species in plasma samples and examined the associations with several MRI, including worsening grades of white matter hyperintensities and ventricular size, number of brain infarcts, and measures of brain atrophy in a subset with quantitative measures. We also investigated the sphingolipid associations with serum NfL and GFAP.

RESULTS: In the fully adjusted model, higher plasma levels of ceramides and sphingomyelins with a long (16-carbon) saturated fatty acid were associated with higher blood levels of NfL [β = 0.05, false-discovery rate corrected () = 0.004 and β = 0.06, = < 0.001, respectively]. In contrast, sphingomyelins with very long (20- and 22-carbon) saturated fatty acids tended to have an inverse association with levels of circulating NfL. In secondary analyses, we found an interaction between ceramide d18:1/20:0 and sex ( for interaction = <0.001), such that ceramide d18:1/20:0 associated with higher odds for infarcts in women [OR = 1.26 (95\%CI: 1.07, 1.49), = 0.03]. We did not observe any associations with GFAP blood levels, white matter grade, ventricular grade, mean bilateral hippocampal volume, or total brain volume.

CONCLUSION: Overall, our comprehensive investigation supports the evidence that ceramides and sphingomyelins are associated with increased aging brain pathology and that the direction of association depends on the fatty acid attached to the sphingosine backbone.

}, issn = {1664-2295}, doi = {10.3389/fneur.2024.1385623}, author = {Moseholm, Kristine F and Horn, Jens W and Fitzpatrick, Annette L and Djouss{\'e}, Luc and Longstreth, W T and Lopez, Oscar L and Hoofnagle, Andrew N and Jensen, Majken K and Lemaitre, Rozenn N and Mukamal, Kenneth J} } @article {9743, title = {Circulating sphingolipids in relation to cognitive decline and incident dementia: The Cardiovascular Health Study.}, journal = {Alzheimers Dement (Amst)}, volume = {16}, year = {2024}, month = {2024 Jul-Sep}, pages = {e12623}, abstract = {

INTRODUCTION: Whether circulating levels of sphingolipids are prospectively associated with cognitive decline and dementia risk is uncertain.

METHODS: We measured 14 sphingolipid species in plasma samples from 4488 participants (mean age 76.2 years; 40\% male; and 25\% apolipoprotein E ( ε4 allele carriers). Cognitive decline was assessed annually across 6 years using modified Mini-Mental State Examination (3MSE) and Digital Symbol Substitution Test (DSST). Additionally, a subset of 3050 participants were followed for clinically adjudicated dementia.

RESULTS: Higher plasma levels of sphingomyelin-d18:1/16:0 (SM-16) were associated with a faster cognitive decline measured with 3MSE, in contrast, higher levels of sphingomyelin-d18:1/22:0 (SM-22) were associated with slower decline in cognition measured with DSST. In Cox regression, higher levels of SM-16 (hazard ration [HR]~=~1.24 [95\% confidence interval [CI]: 1.08-1.44]) and ceramide-d18:1/16:0 (Cer-16) (HR~=~1.26 [95\% CI: 1.10-1.45]) were associated with higher risk of incident dementia.

DISCUSSION: Several sphingolipid species appear to be involved in cognitive decline and dementia risk.

HIGHLIGHTS: Plasma levels of sphingolipids were associated with cognitive decline and dementia risk.Ceramides and sphingomyelins with palmitic acid were associated with faster annual cognitive decline and increased risk of dementia.The direction of association depended on the covalently bound saturated fatty acid chain length in analysis of cognitive decline.

}, issn = {2352-8729}, doi = {10.1002/dad2.12623}, author = {Moseholm, Kristine F and Cronj{\'e}, H{\'e}l{\'e}ne T and Koch, Manja and Fitzpatrick, Annette L and Lopez, Oscar L and Otto, Marcia C de Oliveira and Longstreth, W T and Hoofnagle, Andrew N and Mukamal, Kenneth J and Lemaitre, Rozenn N and Jensen, Majken K} } @article {9913, title = {Circulating non-esterified fatty acids, risk of dementia and cognitive decline: The cardiovascular health study and multi-ethnic study of atherosclerosis.}, journal = {Neurobiol Aging}, volume = {148}, year = {2025}, month = {2025 Apr}, pages = {71-79}, abstract = {

Circulating non-esterified fatty acids (NEFAs) have toxic effects on a variety of organs central to cardiometabolic disease and can cross the blood-brain barrier. Whether NEFAs associate with cognitive decline or dementia remains unknown. Circulating total NEFA levels were measured in 3242 participants without dementia among older adults of the Cardiovascular Health Study (CHS) and related to adjudicated dementia over 6 years (n = 456 cases) and annually assessed cognitive decline. For confirmation, we related circulating NEFAs to cognition assessed 10 years later among 4361 participants in the Multi-Ethnic Study of Atherosclerosis (MESA). In CHS participants, each SD higher NEFA levels were associated with a hazard ratio (HR) for all-cause dementia of 1.11 (95 \% CI: 1.01; 1.22). Baseline NEFA levels were also associated with more rapid decline in cognition over 6 years of follow-up. In MESA, circulating NEFA measurements were associated with lower cognitive scores measured 10 years later.{\textquoteright}

}, keywords = {Aged, Aged, 80 and over, Atherosclerosis, Cognition, Cognitive Dysfunction, Cohort Studies, Dementia, Fatty Acids, Nonesterified, Female, Follow-Up Studies, Humans, Male, Middle Aged, Risk, Risk Factors}, issn = {1558-1497}, doi = {10.1016/j.neurobiolaging.2025.01.009}, author = {Moseholm, Kristine F and Jensen, Majken K and B{\r u}zkov{\'a}, Petra and Aroner, Sarah A and Fitzpatrick, Annette L and Longstreth, W T and Lopez, Oscar and Siscovick, David S and Kizer, Jorge R and Ix, Joachim H and Hughes, Timothy M and Hayden, Kathleen M and Nomura, Sarah and Tsai, Michael Y and McClelland, Robyn and Djouss{\'e}, Luc and Mukamal, Kenneth J} }