Table 2.
1. FATTY ACIDS | |||||
---|---|---|---|---|---|
Reference | Sample | Participants* | Lipid Biomarkers |
Analytical
Technique |
Results |
Wang et al. [43] | Serum | Centre of Harbin Elderly Care Service, Heilongjiang (North of China), 58–92 yrs AD (n=46) HC (n=39) |
4 SFA (C14:0, C16:0, C18:0, C24:0), 3 MFA (C16:1n-7, C18:1n-9, C24:1n-9) and 8 PUFA (C18:2n-6, C18:3n-6, C18:3n-3, C20:2n-6, C20:4n-6, C20:5n-3, C22:5n-6, and C22:6n-3). | GC-MS | 2 SFA= C14:0 (p<0.001) + C16:0 (p<0.05) + 3 PUFA (C18:1 (p< 0.05) + C18:3p<0.05), +C22:6 (p<0.001)): ↓AD< HC. Total n-6 FFAs: ↓AD< HC (p < 0.05) |
Abdullah et al. [46] | Serum | Alzheimer’s Disease Anti-inflammatory Prevention Trial (ADAPT) MCI (n=15) AD (n=8) NCI (n=172) |
PL (AA, DHA) | HPLC-MS | AA, DHA, Aβ42/Aβ40 ratios and ApoE-ε4 genotype →AUC=0.910, whereas PL species alone →AUC=0.880 |
Lin et al. [50] | Serum | Volunteers from Taoyuan City, Taiwan 55-90 yrs. NCI (n=15) MCI (n=10) AD (n=15) |
40 ACs 15 SMs 40 GPs |
LC-MS/MS | ACs (C3 and C5): ↓AD<HC<↑MCI (p<0.05) ACs +PC (C38:2) + age→ discriminate NCI (AUC=0.77), AD (AUC=0.72), MCI (AUC=0.59) |
Olazaran et al. [44] | Plasma | 60-85 yrs From 6 Spanish university hospitals + 1 Spanish research institution HC (n=93), aMCI (n=58) AD (n=100) |
210 metabolites; ACs, NEFAs, LPC, LPE, LPI 256 metabolites; DAG, TG, SM, CER, CMH, PC, PE, and PI |
UPLC-MS | PI (40:6), PC (36:5), PC (37:6). PC (38:5), PC (38:6), PC (40:5) + PC (40:6): ↓AD+ ↓aMCI<<HC (p<0.05) Exceptions: PE (36:4), PE (38:5), PE (18:0/0:0) + PE (18:1/0:0): ↑aMCI+ ↑AD patients>HC (p<0.05) NEFAs (16:0, 18:1n-9, ω-3 FA (EPA, DPA, DHA)): ↓aMCI+↓ AD <HC (p<0.05) SM(39:1)+SM(41:1)+SM(42:1)+ CER(39:1)+CER(40:1)+ CER(41:1)+ CER(42:1)+ CER(43:1). +TGs: ↓↓aMCI+ ↓↓AD<<HC (p<0.05) |
Whiley et al. [47] | Plasma | AddNeuroMed cohort + King’s College London Dementia Case Register (UK). Age- and sex-matched Screen phase: AD (n=10), MCI (n=10), control (n=15) Validation phase:(1) AD (n=42), MCI (n=50), control (n=49) |
(1) PCs (2) ω-fatty acids (AA, DHA, EPA) (3) choline and phosphocholine, glycerophosphocholine |
Screen phase: LC-MS (1, 2), NMR Validation phase: LC-MS (1,2) |
Screen phase: 3 PCs (16:0/20:5 (p <0.001) + 16:0/22:6 (p <0.05) + 18:0/22:6 (p<0.005): ↓↓AD<↓MCI< HC. Validation phase: 3 PCs (16:0/20:5 (p <0.001) + 16:0/22:6 (p <0.05) + 18:0/22:6 (p<0.005): ↓AD< HC. EPA: HC<↑AD (p=0.023) |
Wang et al. [48] | Plasma | Department of Neurology, Rui Jin Hospital (Shanghai, China) AD (n= 57) aMCI (n=58) HC (n=57) |
6 metabolites (AA) 5 metabolites (AA, α-AAA, 2-aminoadipic acid) |
UPLC-QTOF-MS GC-TOF-MS |
14 FA: ↓AD<HC. 40 metabolites: aMCI ≠ HC. Panel 6 metabolites; ROC curves=1.00. Panel 5 metabolites; AUC = 0.998, 95% CI = (0.993,1.000) between aMCI and HC |
Xicota et al. [49] | Plasma | INSIGHT-preAD cohort Amyloid positive (n=47) Amyloid negative (n=47) |
3 MCFA; octanoic, undecanoic and hydroxyl-nonanoic acids | LC-MS | 3 MCFA: ↑amyloid positive group> amyloid negative group. And correlated over time in a subset of 22 subjects (p<0.05). |
Goozee et al. [45] | Blood: erythrocyte | McCusker Kerr Anglican Retirement Village Initiative in Ageing Health (KARVIAH) study cohort, 65–90 yrs High NAL(n=35) Low NAL (n=65) |
SFA (myristic acid, palmitic acid, stearic acid, arachidic acid, lignoceric acid), MUFAs, n-6 PUFA, n-3 PUFA | GC | SFA, MUFA. Not different n-6 PUFA+ AA: ↑high NAL >low NAL (p <0.05) DPA (C22:5n-3, p<0.05): high NAL<↑low NAL Positive trend= AA-NAL (β = 0.197, p = 0.050) and inverse trend= linoleic acid-NAL (β = −0.172, p = 0.088) |
2. GLYCEROLIPIDS AND GLYCEROPHOSPHOLIPIDS | |||||
Reference |
Sample
Type |
Participants* | Lipid Biomarkers |
Analytical
Technique |
Results |
Al-khateeb et al. [51] | Serum | Jordan University Hospital AD (mild-moderate) (n=41) HC (n=40) |
TG | Enzymatic colorimetric method | No difference in lipid profile |
Anand et al. [54] | Serum | Knight Alzheimer’s Disease Research Center (Knight ADRC) 1)MCI (n=10), mild AD (n=10), moderate AD (n= 9) HC (n=32) 2) MCI (n=9), mild AD (n=9), moderate AD(n=9) HC (n=30) |
87 lipids | ESI-TOF/MS | 35 markers (SMs, PCs, PEs, LPCs, DAGs, TGs...) can differentiate AD vs. HC (p<0.05), sensitivity=93%, specificity=80%. |
Varma et al. [56] | Serum | Alzheimer's Disease Neuroimaging Initiative (ADNI) database (prodromal AD); HC (n=216), MCI (n=366), AD (n=185) mean age = 75.19, %female = 42.63 Baltimore Longitudinal Study of Aging (BLSA) database (preclinical AD); Converters (n=92), Non-converters (n=115) mean age =78.68, %female = 42.63 |
26 metabolite panel (ACs, SMs, PCs) | FIA-MS/MS | BLSA database: ↑↑SM C16:0+ ↑↑SM C16:1+↑↑SM (OH) C14:1+ ↑↑SM C18:1→↑↑risk of AD. ↓/↑ PC (38:4), PC (C34:2) =↑ risk conversion to AD. ↑SLs =↑declines in cognition. ADNI database: ↓PC (C40:6) =AD-like pattern brain atrophy. ↑SM C18:1= ↑ risk AD among individuals MCI and HC. ↑PC (38:4) = ↑ risk of conversion to AD. |
Arnold et al. [59] | Serum | *ADNI cohort (n=1517) HC (n=362) MCI(n=490) AD (n=302) |
139 metabolites (PCs, SM..) | UPLC-MS/MS | 108 metabolites significantly gender associated. SMs+ PCs: ↑women >men ACs: ↑men>women (p<0.05). No differences by MCI/AD status. |
González-Domínguez et al. [61] | Serum | Over 65 yrs Neurologic Service of Hospital Juan Ramón Jiménez (Huelva, Spain) AD (n=19) HC (n=17) |
LPC, LPE, PC, PE | UPLC-ESI-QTOF-MS | LPC, LPE: ↓AD<HC (p<0.05). All PEs + total plasmalogens: ↓AD< HC (p<0.05) |
Proitsi et al. [38] | Plasma | Dementia Case Register at King’s College London + AddNeuroMed study ≥60 yrs AD (n=142) HC (n=135) |
2 PCs (40:4 y 36:3), 85 TG | UPLC-Q-ToF MS | 54 TG: ↓AD <HC (p<0.05) 2 PCs (40:4 y 36:3) ↑AD >HC (p<0.05) PC 36:3 is associated with faster ROD |
Olazaran et al. [44] | Plasma | 60-85 yrs From 6 Spanish university hospitals + 1 Spanish research institution HC (n=93), aMCI (n=58) AD (n=100) |
210 metabolites; ACs, NEFAs, LPC, LPE, LPI 256 metabolites; DAG, TG, SM, CER, CMH, PC, PE, and PI |
UPLC-MS | PI (40:6), PC (36:5), PC (37:6). PC (38:5), PC (38:6), PC (40:5) + PC (40:6):↓↓AD+ ↓↓aMCI<<HC (p<0.05) Exceptions: PE (36:4), PE (38:5), PE (18:0/0:0) + PE (18:1/0:0): ↑aMCI+ ↑AD patients>HC (p<0.05) NEFAs (16:0, 18:1n-9, ω-3 FA (EPA, DPA, DHA)): ↓aMCI+ ↓AD <HC (p<0.05) SM(39:1)+SM(41:1)+SM(42:1)+ CER(39:1)+CER(40:1)+ CER(41:1)+ CER(42:1)+ CER(43:1). +TGs: ↓↓aMCI+ ↓↓AD<<HC (p<0.05) |
Leeuw et al. [52] | Plasma | *Amsterdam Dementia Cohort AD (n=127) HC (n=121) |
26 metabolites (14 TG) | UPLC-MS/MS | 14 TG: ↓AD<HC, SM d18:1/20:1: ↑AD>HC (p<0.05) Combining 8,12-iPF-2a IV+ nitro-fatty acid NO2-aLA (C18:3) predictive AD vs. HC |
Kim et al. [53] | Plasma | Memory clinic of University-affiliated general hospital (Seoul, Korea) Female, 65-80 yrs NCI(n=13) MCI (n=23) AD (n=14) |
14 lipid classes (PE, PA, CER, PI, TG, DAG…) | UHPLC-ESI-MS/MS | TG 50:1, DG 18:1_18:1+ PE 36:2 MCI group + MMSE (→AUC =0.833, 0.847, and 0.917, respectively) |
Kim et al. [55] | Plasma | Dementia Case Register at King’s College London + AddNeuroMed study AD (n=205) Mean age= 77.35 Male/female= 81/123 NCI (n=207) Mean age= 74.88 Male/female= 77/130 |
CER, PCs | MS | CER 16:0 (p<0.01), CER 18:0 (p<0.01) + CER 24:1 (p<0.05) ↑AD>NCI CER 20:0, CER 22:0, CER 24:0= not different. PC36:5 +PC38:6: ↓AD<NCI (p<0.05). PC40:6 (n.s) PC36:5-+hippocampal volume positively associated (p<0.01) |
Costa et al. [57] | Plasma | Institute of Psychiatry, Faculty of Medicine, University of Sao Paulo, Brazil AD (n=34) Male/female=10/24 Mean age=75 yrs aMCI (n=20) Male/female=3/17 Mean age=73.9 yrs HC (n=25) Male/female=7/18 Mean age=74.4 yrs |
7 PCs, 1 LPC, 2 ACs | MS/MS | PC (C36:6), PC (C40:6), C16:1-OH: ↓MCI<HC (p<0.05) PC (C40:2): MCI<↑AD PC (C40:2), PC (C40:6): ↓MCI-AD<HC. (p≤0.05) |
Peña-Bautista et al. [60] | Plasma | *Neurology Unit of the Hospital La Fe, Valencia (Spain) 50-80 yrs Early AD (n=29) HC (n=29) |
GPs, LPC, CER, LPE, PC, cardiolipins | UPLC-Q-ToF MS | LPC (18:1) early AD> HC (p<0.05) |
Oberacher et al. [58] | Blood Lysate human platelets |
Hall/Tirol State Hospital, Austria. Training set (n=54): HC(n=18) MCI(n=15) AD(n=21) Validation set (n=26): HC(n=11), MCI(n=6), AD(n=9) Blinded follow up conversion study (9 months) (n=10) HC (n=3) AD(n=7) |
163 endogenous metabolites, including 40 ACs, hydroxyACs and dicarboxylACs and 15 SM and hydroxySMs, 77 PCs and 15 LPCs | FIA-MS/MS | Total PCs, LPCs+ SMs different between groups (p<0.05). Ratio of total PCs: LPCs = 2-fold ↑MCI >AD (p<0.001). SFA: MCI-AD ≠HC. (p<0.001) Training set + C4.5 decision tree algorithm→ accuracy 85.2%. Most discriminative variables→PC ae C32:2, PC ae C34:1, PC aa C36:5, lysoPC a C18:1, lysoPC a C16:0, (SM(OH) C14:1) Follow up study: PC ae C40:4→verify the clinical diagnosis (19/20 cases, cut-off of <0.30 μM) |
3. SPHINGOLIPIDS | |||||
Reference |
Sample
Type |
Participants | Lipid Biomarkers |
Analytical
Technique |
Results |
Mielke et al. [68] | Serum | Women’s Health and Aging Study (WHAS) II 70-79 yrs Females only Probable cognitive impairment (n=100) HC (n=123) |
SM, CER | ESI/MS/MS | ↑↑ total SMs+ CER 16:0, CER 18:0, CER 22:0, CER 24:1, CER 24:0, stearoyl + sulfatide significantly ↑↑increased risk of incident impairment on HVLT-delayed. No association with SMs/ CER-risk of TMT-B impairment. ↑↑SM/total cholesterol= triple risk of HVLT-delayed impairment (p=0.074). |
Olazaran et al. [44] | Plasma | 60-85 yrs From 6 Spanish university hospitals + 1 Spanish research institution HC (n=93), aMCI (n=58) AD (n=100) |
210 metabolites; ACs, NEFAs, LPC, LPE, LPI 256 metabolites; DAG, TG, SM, CER, CMH, PC, PE, and PI |
UPLC-MS | PI (40:6), PC (36:5), PC (37:6). PC (38:5), PC (38:6), PC (40:5) + PC (40:6):↓↓AD+ ↓↓aMCI<<HC (p<0.05) Exceptions: PE (36:4), PE (38:5), PE (18:0/0:0) + PE (18:1/0:0): ↑aMCI+ ↑AD patients>HC (p<0.05) NEFAs (16:0, 18:1n-9, ω-3 FA (EPA, DPA, DHA)): ↓aMCI+ ↓AD <HC (p<0.05) SM(39:1)+SM(41:1)+SM(42:1)+ CER(39:1)+CER(40:1)+ CER(41:1)+ CER(42:1)+ CER(43:1). +TGs: ↓↓aMCI+ ↓↓AD<<HC (p<0.05) |
Kim et al. [55] | Plasma | Dementia Case Register at King’s College London + AddNeuroMed study AD (n=205) Mean age= 77.35 Male/female= 81/123 NCI (n=207) Mean age= 74.88 Male/female= 77/130 |
CER, PCs | MS | CER 16:0 (p<0.01), CER 18:0 (p<0.01) + CER 24:1 (p<0.05) ↑AD>NCI CER 20:0, CER 22:0, CER 24:0=not different. PC36:5 +PC38:6: ↓AD<NCI (p<0.05). PC40:6 (n.s) PC36:5-+hippocampal volume positively associated (p<0.01) |
Mielke et al. [64] | Plasma | BLSA cohort Over 55 yrs NCI (n=992; 119/626 men developed AD; 73/366 women developed AD) |
CER, SMs | LC-ESI/MS/MS | Men: Most CER= ↑AD risk (→C16:0 (2-fold) +SMs: C18:0, C 18:1, C20:1 + C22:1(p≤0.001) Women: No associations CER-AD risk All SMs (exception C24:1) =↓ AD risk (p<0.001) |
Mielke et al. [65] | Plasma | Clinical Core of the Johns Hopkins Alzheimer's Disease Research Center Over 55 yrs HC (n=25) aMCI (n=17) Early probable AD (n=21) |
CER: C24:0, C24:1, C22:0, C16:0, C18:0, C20:0, C26:0, C26:1. | HPLC-ESI-MS/MS | CER: C22:0, C24:0+ C26:0: ↓MCI<HC+ ↑AD group. (p<0.05) CER: C16:0, C18:0+ C22:0: MCI < ↑AD (p<0.05) CER= C24:1, C26:1 (not different) |
Han et al. [67] | Plasma | Joseph and Kathleen Bryan Alzheimer’s Disease Research Center (Bryan ADRC) + Department of Psychiatry, (Duke University). AD (n=26) Mean age=77.2 % Male= 46 yrs NCI (n=26) Mean age=73 yrs % Male=42 |
9 lipid classes; 65 PC, 86 PE, 25 PI, 33 SM, 14 LPC, 29 CER, TG>500 | MDMS-SL | 8 SMs: ↓AD<NCI (p<0.05) 6 different levels SMs (p<0.1). 2 CER=N16:0+ N21:0 ↑AD>NCI (p<0.05) + 5 CER: ↑AD> NCI (p<0.1) |
Mielke et al. [69] | Plasma | Alzheimer’s Disease and Memory Disorders Center (ADMDC) at Baylor College of Medicine Probable AD (n=120) Mean age=71.8 yrs 60.8% female |
CER, DHCER, SM, DHSM | LC-ESI/MS/MS | ↓ DHCER + ↑ SM and ↑DHSM related to slower decline cognitive measures. DHSM/DHCER + SM/Ceramide ratios are strongly related to cognitive decline. TGs are not associated with progression. |
4. LIPID PEROXIDATION COMPOUNDS | |||||
Reference |
Sample
Type |
Participants | Lipid Biomarkers |
Analytical
Technique |
Results |
Padurariu et al. [26] | Serum | Psychiatry University Hospital, Iasi (Romania) HC (n=15) Females/males=7/8 Mean age=62.5 yrs MCI(n=15) Female/male= 5/10 Mean age: 63.2 yrs AD (n=15) Female/male=6/9 Mean age=65.8 yrs |
MDA | TBARS assay | MDA: ↑MCI + ↑AD >HC (p<0.0005) and between MCI and AD groups (p<0.0005). |
Ademowo et al.[27] | Serum | Carotenoid and AGE-Related Dementia Study (CARDS) at the Nutrition Research Centre Ireland (NCRI). AD mild-moderate (n=21) Mean age=79 yrs, %female=43 HC (n=16) Mean age=75 yrs 5female=50% |
oxPLs (POVPC + IsoP) | LC-MS ELISA |
POVC: 2-fold ↑AD>HC (p <0.05) IsoP not difference |
Peña-Bautista et al. [24] | Plasma | * Neurology Unit of the University and Polytechnic Hospital La Fe, Valencia (Spain) 50-80 yrs HC (n=26) MCI-AD(n=68) |
18 lipid peroxidation compounds; IsoPs, prostaglandins, NeuroPs, dihomo-IsoPs, dihomo-IsoFs | UPLC-MS/MS | 15(R)-15-F2t-IsoP+15-keto-15-E2t-IsoP+ 15-keto-15-F2t-IsoP+ 15-E2t-IsoP+ 4(RS)-F4t-NeuroP + ent-7(RS)-7-F2t-dihomo-IsoP:↑AD>HC (p<0.001) PGF2α+5-F2t-IsoP+ 7(RS)-ST-Δ8-11-dihomo-IsoF:↓MCI-AD<HC (p<0.001) |
Leeuw et al. [52] | Plasma | *Amsterdam Dementia Cohort AD (n=127) HC (n=121) |
26 metabolites (14 TG) | UPLC-MS/MS | 14 TG: ↓AD<HC, SM d18:1/20:1: ↑AD>HC (p<0.05) Combining 8,12-iPF-2a IV+ nitro-fatty acid NO2-aLA (C18:3) predictive AD vs. HC |
Peña-Bautista et al. [74] | Plasma | * Neurology Unit of the University and Polytechnic Hospital La Fe, Valencia (Spain) 50-80 yrs Early stages AD (n=80) HC (n=32) |
NeuroPs, IsoPs, neurofurans, isofurans, 17-epi-17-F2-dihomo-IsoP, PGF2α | UPLC-MS/MS | 8-iso-15(R)-PGF2α, 4(RS)-F4-NeuroP, neurofurans, IsoPs 17-epi-17-F2t-dihomo-IsoP=different levels between groups (p<0.05). PGF2α: HC>↓AD(p<0.05) Sensitivity=72.5%, specificity=100%. |
Yoshida et al. [75] | Plasma | Aoisoranosato Geriatric Health Services Facility + Arimakogen Hospital AD patients (n=39) Mean age= 76.2 yrs Male/females=15/24 VD (n=25) Mean age=80.4 yrs Male/female=8/17 HC (n=24) Mean age=68.4yrs Male/female=8/16 |
tHODE, t8-iso-PGF2α | HPLC-ESI-MS/MS | tHODE: ↑AD> HC. t8-iso-PGF2α: ↑AD > HC→ sensitivity 82%, specificity 71%. |
Peña-Bautista et al. [73] | Plasma Urine |
* Neurology Unit of the University and Polytechnic Hospital La Fe, Valencia (Spain) MCI-AD (n=70) Mean age=70 yrs % female=58.6 HC (n=26) Mean age=66 yrs % female=34.6 |
22 analytes of lipid peroxidation | UPLC-MS/MS | Plasma: 15(R)-15-F2t-IsoP+ 4(RS)-4-F4t-NeuroP+NeuroPs, IsoPs+ ent-7(RS)-7-F2t-dihomo IsoP +neurofurans +isofurans: ↑MCI-AD >HC as well as higher age +female proportion (p<0.05) ANN model→ sensitivity=88.2%, specificity=76.9%. Urine: 15(R)-15-F2t-IsoP+ 2,3-dinor-15-epi-15-F2t-IsoP+ 4(RS)-4-F4t-NeuroP+ ent-7(RS)-7-F2t-dihomo-IsoP+ 17-epi-17-F2t-dihomo-IsoP+ 10-epi-10-F4t-NeuroP+ 17-F2t-dihomo-IsoP+ neurofurans: ↑MCI-AD>HC as well as higher age+ female proportion(p<0.05). ANN model→sensitivity=80,9%, specificity=76.9%. |
Mufson et al. [71] | Plasma Urine |
Religious Orders Study NCI (n=134) Mean age= 79.6 yrs MCI (n=32) Mean age=83.5 yrs AD (n=14) Mean age= 86.3 yrs |
F2-IsoPs | GC/MS | Urine; F2-IsoPs: ↑men>women. Plasma + urine F2-IsoPs not correlated (p<0.0001) No differences among clinical groups. |
Sundelof et al. [72] | Urine | Uppsala Longitudinal Study of Adult Men (ULSAM) 70-77 yrs Males only n=679 (n=40 developed AD and n=86 developed all-cause dementia) |
F2-IsoPs (8-iso-PGF2α) | Radioinmuno-assay | F2-IsoPs are not associated with a higher incidence of AD or dementia. |
5. METABOLITES COMBINED PANEL | |||||
Reference |
Sample
Type |
Participants | Lipid Biomarkers |
Analytical
Technique |
Results |
Casanova et al. [76] | Serum | BLSA cohort: Converters AD (n=93) baseline age 77.9 yrs Non-converters AD (n=99) baseline age 76.6 yrs AGES-RS cohort: Converters (n=100) baseline age 78.18 yrs Non-converters (n=100) baseline age 78.23 yrs |
10 metabolite panel (by Mapstone) 187 targeted metabolites |
FIA-MS/MS | BLSA→10 metabolite panel: AUC=0.64, sensitivity/specificity=51.6%/65.7% converters vs. non-converters. AGES-RS→ 10 metabolite panel: AUC=0.394, sensitivity/specificity=47%/36% converters vs. non-converters. For symptoms onset; BLSA (AUC= 0.58, sensitivity/specificity= 53.8%/62.6%) AGES-RS (AUC=0.481, sensitivity/specificity=52%/48%) AD vs. non-converters. sensitivity/specificity=67.7%/66.7% |
Oresic et al. [77] | Serum | *PredictAD project, University of Kuopio HC (n=46) Baseline age=71 yrs Male/female= 21/25 MCI (n=143) Baseline age=71.5 yrs Male/female=47/96 AD (n=37) Baseline age=75 yrs Male/female=17/20 |
139 lipids in co-regulated clusters; PCs, LPCs, SMs… | UPLC-MS | Metabolic signature = 2 PC (18:0/18:2) from cluster 1 and PC (16:0/20:4) from cluster 5, lactic acid and ketovaline predicted AD→AUC=0.77 |
Toledo et al. [79] | Serum | *ADNI-1 cohort (n=702) HC (n=199) 75.3yrs, 49.7% male MCI (n=358) 75.1 yrs, 35.4% male AD (n=175) 75.6 yrs, 48.6% male ERF study (N = 905, CN) + Rotterdam Study (N = 2480, CN) Indiana Memory and Aging Study (IMAS)(n=34) CN (n=17) 68.4 yrs, 76.5% women MCI(n=10) 72.1 yrs, 60%women AD (n=7) 72.4 yrs, 71.4% women |
138 metabolites (PC, SM) | UPLC-MS/MS | 13 metabolites→ cognitive scores, CSF, and MRI measures (p<0.05). 6 metabolites-CSF Aβ1–42 positivity; PC (C36:2) + PC (C40) +, PC (C42:4) + PC (C44:4) + SM (OH)(C14:1)+ SM (C16:0), 4 associated with t-tau/Aβ1–42 ratio (C18+ PC (C36:2), SM (C16:0)+ SM (C20:2), 5 associated with ADAS-Cog13 scores (C14:1+ C16:1, SM C20:2 + α-aminoadipic acid [α-AAA], and valine), 6 associated with SPARE-AD scores (C12+ C16:1+ PC (C42:4)+PC (C44:4) + α-AAA,+ valine). |
Barupal et al. [33] | Serum | *ADNI database cohort (n=806) | 349 lipids (AC=9, FA=29, 8 CE, LPC=22, LPE=4, PC=53, PE=11, PI=11, CER=19, SM=34, DAG=13, TG=84…) |
LC-MS/MS | 168 lipids associated with at least 1 AD phenotype (p<0.05). 28 coregulated lipids sets (LM1 to LM28) established. Significant associations of ω-3+ ω-6 lipids with AD diagnosis + cognitive functions (p<0.05). PUFA +TG: ↓AD <HC (p<0.05) |
Mapstone et al. [7] | Plasma | Rochester/Orange County Aging Study(≥70yrs) (5 yrs follow-up) Discovery phase: aMCI/AD+ Converters (n=53) HC (n=53) Matched based on sex, age, and education level Blinded cross-validation: aMCI/AD+ HC (n=20) aMCI/AD (n=20) Converters (n=10) Discovery and validation groups did not differ on clinical measures (F(4,170) = 1.376, P = 0.244) or on any composite z-score (F(5,169) = 2.118, P = 0.066) |
Set 10 metabolites; PC diacyl (aa) C36:6, PC aa C38:0, PC aa C38:6, PC aa C40:1, PC aa C40:2, PC aa C40:6, PC acyl-alkyl (ae) C40:6, LPC a C18:2, ACs (C3, C16:1-OH) | SID-MRM-MS UPLC-ESI-QTOF-MS |
Discovery phase: Untargeted metabolomic analysis→PI ↓Converters<HC LASSO analysis→PC, AC ↓Converters < HC Targeted analysis→Set 10 metabolites in discovery phase + blinded cross-validation: ↓Converters+ ↓aMCI/AD < HC (→Accuracy=90%)(p<0.05) |
Fiandaca et al. [78] | Plasma | Rochester/Orange County Aging Study (≥70yrs) (5 yrs follow-up) matched for age, gender, and education and featured similar APOE allele status Discovery cohort. NCI (n=53), Phenoconverters (aMCI/AD) (n=18) 3/18 +ApoE ε4 alelle Internal Validation Cohort. NCI (n=20), Phenoconverters (aMCI/AD) (n=10) 2/10 +ApoE ε4 alelle |
24 Metabolites (13 PCs, 9 ACs…) | MRM-SID-MS | Discovery cohort: 174 metabolites significantly expressed differently (p<0.05) Panel 24/174 metabolites→ Discovery + internal validation cohort: 3/24 metabolites (ACs) ↑Phenoconverters > NCI (p<0.05) 21/24 metabolites ↓Phenoconverters < NCI (p<0.05) Panel 24 metabolites→AUC=1.00 (discovery group) and 0.995 (internal validation) |
*Studies with biologically defined cohorts (CSF biomarkers Aβ1-42, p-tau) to identify specifically AD groups.