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. 2022 Jun 29;20(8):1613–1631. doi: 10.2174/1570159X19666211102150955

Table 2.

AD studies evaluating lipid compounds and derivatives as early and minimally invasive samples.

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.