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Introduction: Altered lipid metabolism is implicated in Alzheimer's disease (AD), but the mechanisms remain obscure. Aging‐related declines in circulating plasmalogens containing omega‐3 fatty acids may increase AD risk by reducing plasmalogen availability. Methods: We measured four ethanolamine plasmalogens (PlsEtns) and four closely related phosphatidylethanolamines (PtdEtns) from the Alzheimer's Disease Neuroimaging Initiative (ADNI; n = 1547 serum) and University of Pennsylvania (UPenn; n = 112 plasma) cohorts, and derived indices reflecting PlsEtn and PtdEtn metabolism: PL‐PX (PlsEtns), PL/PE (PlsEtn/PtdEtn ratios), and PBV (plasmalogen biosynthesis value; a composite index). We tested associations with baseline diagnosis, cognition, and cerebrospinal fluid (CSF) AD biomarkers. Results: Results revealed statistically significant negative relationships in ADNI between AD versus CN with PL‐PX (P = 0.007) and PBV (P = 0.005), late mild cognitive impairment (LMCI) versus cognitively normal (CN) with PL‐PX (P = 2.89 × 10−5) and PBV (P = 1.99 × 10−4), and AD versus LMCI with PL/PE (P = 1.85 × 10−4). In the UPenn cohort, AD versus CN diagnosis associated negatively with PL/PE (P = 0.0191) and PBV (P = 0.0296). In ADNI, cognition was negatively associated with plasmalogen indices, including Alzheimer's Disease Assessment Scale 13‐item cognitive subscale (ADAS‐Cog13; PL‐PX: P = 3.24 × 10−6; PBV: P = 6.92 × 10−5) and Mini‐Mental State Examination (MMSE; PL‐PX: P = 1.28 × 10−9; PBV: P = 6.50 × 10−9). In the UPenn cohort, there was a trend toward a similar relationship of MMSE with PL/PE (P = 0.0949). In ADNI, CSF total‐tau was negatively associated with PL‐PX (P = 5.55 × 10−6) and PBV (P = 7.77 × 10−6). Additionally, CSF t‐tau/Aβ1‐42 ratio was negatively associated with these same indices (PL‐PX, P = 2.73 × 10−6; PBV, P = 4.39 × 10−6). In the UPenn cohort, PL/PE was negatively associated with CSF total‐tau (P = 0.031) and t‐tau/Aβ1‐42 (P = 0.021). CSF Aβ1‐42 was not significantly associated with any of these indices in either cohort. Discussion: These data extend previous studies by showing an association of decreased plasmalogen indices with AD, mild cognitive impairment (MCI), cognition, and CSF tau. Future studies are needed to better define mechanistic relationships, and to test the effects of interventions designed to replete serum plasmalogens. [ABSTRACT FROM AUTHOR]