TABLE 2.
Single‐metabolite associations with MCI or global cognitive decline in our analytic sample
| All participants | APOE Ɛ4 carriers | APOE Ɛ4 non‐carriers | |||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Metabolites | Super pathway | Effect | SE | Unadj‐P ‐value | FDR adj. P‐value | Effect | SE | Unadj P‐value | FDR adj. P‐value | Effect | SE | Unadj. P‐value | FDR adj. P‐value |
| Outcome: MCI | |||||||||||||
| MODEL 1 | |||||||||||||
| 3‐aminoisobutyrate | Nucleotide | –0.04 | 0.01 | 1.26E‐02 | 1.00E + 00 | –0.69 | 0.17 | 3.00E‐05 | 1.76E‐02 | –0.21 | 0.10 | 4.19E‐02 | 1.00E+00 |
| 1‐arachidonoyl‐GPE (20:4n6) | Lipid | 0.03 | 0.01 | 1.44E‐02 | 1.00E + 00 | –0.20 | 0.15 | 1.80E‐01 | 1.00E + 00 | 0.40 | 0.10 | 4.00E‐05 | 1.71E‐02 |
| Glycolithocholic acid 3‐sulfate | Lipid | 0.04 | 0.01 | 1.12E‐03 | 1.00E + 00 | –0.29 | 0.20 | 1.38E‐01 | 1.00E + 00 | 0.42 | 0.11 | 5.00E‐05 | 1.71E‐02 |
| 1‐palmitoyl‐2‐arachidonoyl‐gpe (16:0/20:4) | Lipid | 0.03 | 0.01 | 6.63E‐03 | 1.00E + 00 | –0.04 | 0.16 | 7.82E‐01 | 1.00E + 00 | 0.40 | 0.11 | 2.20E‐04 | 3.52E‐02 |
| Quinolinate | Cofactors and vitamins | –0.03 | 0.01 | 6.66E‐04 | 5.99E‐01 | –0.13 | 0.17 | 4.37E‐01 | 1.00E + 00 | –0.33 | 0.09 | 4.30E‐04 | 4.62E‐02 |
| 9,10‐DiHOME | Lipid | –0.04 | 0.01 | 4.16E‐04 | 3.74E‐01 | –0.13 | 0.20 | 5.23E‐01 | 1.00E + 00 | –0.38 | 0.11 | 5.10E‐04 | 4.66E‐02 |
| Glycodeoxycholatesulfate | Lipid | 0.04 | 0.01 | 8.64E‐04 | 7.77E‐01 | 0.02 | 0.20 | 9.23E‐01 | 1.00E + 00 | 0.34 | 0.09 | 1.70E‐04 | 3.52E‐02 |
| 2‐hydroxyoctanoate | Lipid | –0.04 | 0.01 | 2.06E‐04 | 1.86E‐01 | –0.08 | 0.14 | 5.64E‐01 | 1.00E + 00 | –0.36 | 0.10 | 3.10E‐04 | 3.93E‐02 |
| MODEL 2 | |||||||||||||
| 3‐aminoisobutyrate | Nucleotide | –0.04 | 0.02 | 1.93E‐02 | 1.00E + 00 | –0.66 | 0.14 | 1.90E‐01 | 8.50E‐04 | –0.17 | 0.11 | 1.11E‐01 | 1.00E + 00 |
| 3‐hydroxy‐3‐methylglutarate | Lipid | –0.02 | 0.01 | 9.42E‐02 | 1.00E + 00 | –0.68 | 0.16 | 1.00E‐05 | 4.27E‐03 | –0.06 | 0.11 | 6.16E‐01 | 1.00E + 00 |
| 1‐arachidonoyl‐GPE (20:4n6) | Lipid | 0.03 | 0.01 | 3.92E‐02 | 1.00E + 00 | –0.19 | 0.16 | 2.16E‐01 | 1.00E + 00 | 0.42 | 0.10 | 4.00E‐05 | 2.69E‐02 |
| Glycolithocholic acid 3‐sulfate | Lipid | 0.04 | 0.01 | 2.60E‐03 | 1.00E + 00 | –0.27 | 0.18 | 1.46E‐01 | 1.00E + 00 | 0.39 | 0.11 | 2.20E‐04 | 4.78E‐02 |
| 1‐palmitoleoyl‐GPC (16:1) | Lipid | 0.03 | 0.02 | 4.40E‐02 | 1.00E + 00 | –0.20 | 0.13 | 1.14E‐01 | 1.00E + 00 | 0.42 | 0.11 | 1.60E‐04 | 4.78E‐02 |
| MODEL 3 | |||||||||||||
| 3‐aminoisobutyrate | Nucleotide | –0.04 | 0.02 | 1.38E‐02 | 1.00E + 00 | –0.68 | 0.16 | 1.00E‐05 | 4.45E‐03 | –0.19 | 0.11 | 1.00E‐01 | 1.00E + 00 |
| 3‐hydroxy‐3‐methylglutarate | Lipid | –0.02 | 0.01 | 9.53E‐02 | 1.00E + 00 | –0.73 | 0.17 | 1.00E‐05 | 4.45E‐03 | –0.05 | 0.11 | 6.78E‐01 | 1.00E + 00 |
| Isocitrate | Energy | 0.01 | 0.01 | 5.44E‐01 | 1.00E + 00 | 0.57 | 0.16 | 2.60E‐04 | 3.38E‐02 | 0.04 | 0.12 | 7.49E‐01 | 1.00E + 00 |
| Sulfate | Xenobiotics | –0.01 | 0.01 | 4.19E‐01 | 1.00E + 00 | –0.52 | 0.14 | 1.70E‐04 | 2.72E‐02 | 0.08 | 0.12 | 4.82E‐01 | 1.00E + 00 |
| Tartarate | Xenobiotics | 0.01 | 0.01 | 7.72E‐01 | 1.00E + 00 | 0.52 | 0.14 | 1.70E‐04 | 2.72E‐02 | –0.14 | 0.10 | 1.64E‐01 | 1.00E + 00 |
| 1‐arachidonoyl‐GPE (20:4n6) | Lipid | 0.03 | 0.01 | 4.29E‐02 | 1.00E + 00 | –0.22 | 0.16 | 1.65E‐01 | 1.00E + 00 | 0.42 | 0.10 | 5.00E‐05 | 2.01E‐02 |
| Glycolithocholatesulfate | Lipid | 0.04 | 0.01 | 3.01E‐03 | 1.00E + 00 | –0.29 | 0.18 | 1.09E‐01 | 1.00E + 00 | 0.39 | 0.10 | 1.50E‐04 | 3.15E‐02 |
| 1‐palmitoleoyl‐GPC (16:1) | Lipid | 0.03 | 0.02 | 4.29E‐02 | 1.00E + 00 | –0.18 | 0.13 | 1.63E‐01 | 1.00E + 00 | 0.42 | 0.10 | 6.00E‐05 | 2.01E‐02 |
| Outcome: Global cognitive change | |||||||||||||
| MODEL 1 | |||||||||||||
| Kynurenine | Amino acid | 0.14 | 0.03 | 4.00E‐05 | 2.43E‐02 | 0.04 | 0.06 | 5.24E‐01 | 1.00E + 00 | 0.16 | 0.04 | 6.00E‐05 | 1.22E‐02 |
| 7‐Methylguanine | Nucleotide | 0.12 | 0.03 | 2.10E‐04 | 4.45E‐02 | 0.03 | 0.06 | 6.35E‐01 | 1.00E + 00 | 0.15 | 0.04 | 3.00E‐05 | 1.22E‐02 |
| Quinolinate | Cofactors and vitamins | 0.13 | 0.03 | 8.00E‐05 | 2.43E‐02 | 0.06 | 0.06 | 3.17E‐01 | 1.00E + 00 | 0.15 | 0.04 | 1.20E‐04 | 1.86E‐02 |
| Creatinine | Amino acid | 0.12 | 0.04 | 3.46E‐03 | 1.00E + 00 | 0.02 | 0.07 | 7.99E‐01 | 1.00E + 00 | 0.16 | 0.05 | 4.20E‐04 | 4.45E‐02 |
| Gamma‐glutamylleucine | Peptide | 0.11 | 0.03 | 6.60E‐04 | 5.93E‐01 | –0.02 | 0.07 | 7.51E‐01 | 1.00E + 00 | 0.16 | 0.04 | 4.00E‐05 | 1.22E‐02 |
| Gamma‐glutamylvaline | Peptide | 0.13 | 0.04 | 3.53E‐04 | 3.17E‐01 | 0.06 | 0.06 | 3.71E‐01 | 1.00E + 00 | 0.15 | 0.04 | 4.90E‐04 | 4.45E‐02 |
| N‐acetylcarnosine | Peptide | 0.16 | 0.05 | 4.95E‐04 | 4.45E‐01 | 0.09 | 0.08 | 2.60E‐01 | 1.00E + 00 | 0.19 | 0.05 | 2.90E‐04 | 3.68E‐02 |
| Thymol sulfate | Xenobiotics | 0.08 | 0.03 | 6.06E‐03 | 1.00E + 00 | –0.06 | 0.06 | 3.18E‐01 | 1.00E + 00 | 0.11 | 0.03 | 5.90E‐04 | 4.72E‐02 |
Abbreviation: APOE, apolipoprotein E; BMI, body mass index; eGFR, estimated glomerular filtration rate; FDR, false discovery rate; MCI, mild cognitive impairment; SE, standard error; T2D, type 2 diabetes.
Notes: The positive effect for MCI is risk increasing, and the positive effect for global cognitive change is risk decreasing.
MCI effect is log (odds ratio).
Model 1: Adjusted for sex, age, study center, self‐reported background, education, and duration in years between the visits.
Model 2: Model 1 with further adjustment for BMI, eGFR, T2D, and hypertension.
Model 3: Model 2 with further adjustment for APOE ɛ4 carriers, alcohol consumption, and smoking status.