CSF samples from cases with different degrees of memory dysfunction according to objective tests (AD or MCI) or subjective memory complaints (SCI) were analyzed by LC-MS/MS with regard to bioactive LMs, their fatty acid precursors, and intermediate derivatives. The resulting data were subject to statistical analysis in the entire cohort, i.e., including all cases, and in a sub-cohort, including cases from the AD, MCI, and SCI groups with similar age. The median detected level and interquartile range for each LM within the diagnostic groups are presented in Supplementary Tables 1 and 3.

Analysis of pro-resolving and pro-inflammatory LMs in CSF samples for all cases in the entire cohort showed that levels of the pro-resolving LMs RvD4 and NPD1 were lower in the AD (P < 0.00005 and P < 0.05, respectively) and MCI (P < 0.0005 and P < 0.05, respectively) group compared to the SCI group (Fig. 2), whereas levels of the pro-inflammatory LM LTB4 were higher in AD (P < 0.001) and MCI (P < 0.05) compared to SCI (Fig. 2). Analysis of the age-matched cohort showed the same results for RvD4, i.e., for AD (P < 0.005) and MCI (P < 0.005) compared to SCI (Fig. 3), whereas the differences between the diagnostic groups for NPD1 and LTB4 were not statistically significant. However, additional differences were found in the age-matched cohort, including a reduction in RvD1 in AD cases compared to SCI (P < 0.05; Fig. 3).

Pro-resolving LMs are reduced in CSF from MCI and AD patients, while pro-inflammatory LMs show a mixed pattern. Lipid mediators (LMs) were assessed in the cerebrospinal fluid (CSF) samples from patients with Alzheimer’s disease (AD) (n = 40), mild cognitive impairment (MCI) (n = 43), or subjective cognitive impairment (SCI) (n = 53), using liquid chromatography–tandem mass spectrometry (LC-MS/MS). The levels of resolvin (Rv) D4 (D4) and neuroprotectin D1 (NPD1) were reduced in CSF from AD and MCI compared to SCI, while the levels of the pro-inflammatory LM leukotriene B4 (LTB4) levels were higher in AD. The levels of maresin 1 (MaR1) and RvE4 were significantly lower in MCI patients compared to SCI. The levels of the intermediate precursor for RvD4, NPD1, and MaR1, 17-hydroxy docosahexaenoic acid (17-HDHA), were higher in AD than in MCI, and the levels of the intermediate precursor 15-hydroxyeicosatetraenoic acid (15-HETE) were lower in SCI compared to MCI and AD. The levels of prostaglandin (PG) D2 were lower in CSF from MCI patients compared with SCI, and the PGE2 levels were lower in AD and MCI patients compared to SCI. Comparisons between groups were performed by Kruskal–Wallis ANOVA with Dunn’s multiple comparisons post hoc test (*P < 0.05, **P < 0.005, ***P < 0.001, ****P < 0.0001)

Pro-resolving LMs are reduced in CSF from MCI and AD patients in an age-matched sub-cohort. Lipid mediators (LMs) were assessed in the cerebrospinal fluid (CSF) samples from patients with Alzheimer’s disease (AD) (n = 15), mild cognitive impairment (MCI) (n = 17), or subjective cognitive impairment (SCI) (n = 21), using liquid chromatography–tandem mass spectrometry (LC-MS/MS). The reduced levels of resolvin (Rv) D4 in AD and MCI compared to SCI are confirmed in this smaller age-matched sub-cohort. Also, the reduced levels of RvE4 and prostaglandin (PG) E2 in MCI compared to SCI are confirmed, whereas there is no difference between AD and SCI for PGE2 in the age-matched cohort. Similarly, the increased levels of the intermediate precursor 15-hydroxyeicosatetraenoic acid (15-HETE) in MCI compared to SCI are confirmed, but not the difference between AD and SCI. The other alterations seen in the total cohort do not reach statistical significance in the age-matched cohort, but two additional changes were observed, i.e., reduced levels of RvD1 in AD compared to SCI and of PGF2a in AD and MCI compared to SCI. Comparisons between groups were performed by Kruskal–Wallis ANOVA with Dunn’s multiple comparisons post hoc test (*P < 0.05, **P < 0.005)

Comparing the diagnostic groups within the male and female group separately showed that for RvD4, there was a significant difference between AD and SCI for both women and men, but the difference between MCI and SCI was seen only in women (Supplementary Fig. 2). In the case of LTB4, higher levels in AD than in SCI were seen in women, whereas the increase in MCI compared with SCI reached statistical significance only in men (Supplementary Fig. 2). The differences seen for NPD1 were small and not seen upon analyzing male and female groups separately. On the other hand, the levels of RvE1 were reduced in men with AD compared to SCI (Supplementary Fig. 2), but not in women or when analyzing both men and women together. Similarly, the levels of RvD3 were lower in MCI compared to SCI in women (Supplementary Fig. 2), but not in men or in both groups together.

The pro-resolving LMs MaR1 (P < 0.005; Fig. 2) and RvE4 (P < 0.005; Fig. 2) were lower in CSF samples from MCI patients compared to SCI cases in the entire cohort. In the age-matched cohort, there was no difference observed for MaR1, but the decrease in RvE4 in the MCI patients remained (P < 0.005; Fig. 3). The difference in MaR1 seems to be due mainly to a difference in men (Supplementary Fig. 2), whereas this difference was not seen for women. Interestingly, the levels of the pro-inflammatory LXA4 were lower in men with MCI than in SCI (Supplementary Fig. 2), a finding not seen when analyzing men and women together in the entire or the age-matched cohort.

The levels of PGD2 (P < 0.0005) and PGE2 (P < 0.0001) were lower in MCI patients compared to SCI in the entire cohort (Fig. 2), and these differences were seen both in women and in men (Supplementary Fig. 2). In addition, the PGE2 levels were lower in AD compared to SCI (P < 0.005; Fig. 2), a difference also seen in women (Supplementary Fig. 2). In the age-matched cohort, there was no difference between the diagnostic groups for PGD2, but in the case of PGE2, there were still reduced levels in MCI compared to SCI (P < 0.05), whereas the difference between AD and SCI were not seen in the age-matched cohort (Fig. 3). However, additional differences were found in the age-matched cohort for PGF2a showing lower levels in AD compared to SCI (P < 0.05; Fig. 3).

The levels of the intermediate LM precursor 17-HDHA were higher in AD than in MCI (P < 0.05), and levels of 15-HETE were higher in AD (P < 0.01) and MCI (P < 0.01) than in SCI within the entire cohort (Fig. 2). The difference between AD and SCI reached statistical significance in women (Supplementary Fig. 2). In the age-matched cohort, there was no difference between the diagnostic groups for 17-HDHA, but there was still an increase in MCI compared to SCI for 15-HETE (P < 0.05), whereas the difference between AD and SCI was not seen in the age-matched cohort (Fig. 3).

Regarding the n-3 and n-6 PUFA precursors, AA, EPA, or DHA, there were no significant differences between the three diagnostic groups, in either the entire cohort or in the age-matched cohort. An exception was in the case of DHA, where the levels in men were lower in AD compared to SCI (Supplementary Fig. 2).

Correlative relationships were investigated using the Spearman rank-order test. The complete results from the analysis of correlations, including all LMs and PUFAs, can be seen in Supplementary Tables 2 (entire cohort) and 4 (age-matched cohort).

Our analyses of correlations suggest that for several lipids, high levels are associated with less deterioration of cognition in AD cases as assessed by the MMSE test (Supplementary Tables 2a, 4a). Analysis of the entire cohort showed that the levels of RvD4 displayed the strongest positive correlation to MMSE score (r = 0.29, P < 0.001), and this correlation was confirmed in the age-matched cohort (r = 0.39, P < 0.005). Other lipids showing a positive correlation to MMSE when including all three diagnostic groups were DHA (r = 0.21), EPA (r = 0.18) and PGE2 (r = 0.18), and RvD1 (r = 0.17), all with a significance level of P < 0.05. Analysis of the age-matched cohort confirmed the correlation for DHA (r = 0.34, P < 0.05) but not for EPA. The correlations between MMSE and PGE2 and between MMSE and RvD1, respectively, were not seen in the age-matched cohort, but there was a positive correlation for PGF2a (r = 0.30, P < 0.05) and for RvE1 (r = 0.34, P < 0.05) in the latter cohort.

Separating the cases according to diagnosis provided stronger correlative relationships. In the group of AD cases within the entire cohort, the strongest correlations to MMSE were by DHA and 14-HDHA (r = 0.53, P < 0.0005 for both; Fig. 4), EPA (r = 0.51, P < 0.001; Fig. 4), AA (r = 0.42, P < 0.01; Fig. 4), and 20-HDHA (r = 0.33, P < 0.05). Among the cases diagnosed with MCI, only one negative correlation was found with MMSE, i.e., MaR1 (r = − 0.32, P < 0.05). Cases diagnosed with SCI showed positive correlations between MMSE and RvD4 (r = 0.42, P < 0.005; Fig. 4), RvD1 (r = 0.36, P < 0.01; Fig. 4), RvE4 (r = 0.34, P < 0.05), and LTB4 (r = 0.29, P < 0.05). In the group of AD cases within the age-matched cohort, there were positive correlations to MMSE scores for DHA (r = 0.76, P < 0.005), 14-HDHA (r = 0.77, P < 0.001), and AA (r = 0.62, P < 0.05), whereas the correlation to EPA did not reach statistical significance (Fig. 5). Among the cases diagnosed with MCI, there was one positive correlation with MMSE, i.e., for LTB4 (r = 0.52, P < 0.05; Fig. 5). Similar to the entire cohort, cases diagnosed with SCI in the age-matched cohort showed positive correlations between MMSE and RvD4 (r = 0.56, P < 0.01; Fig. 5) and RvE4 (r = 0.48, P < 0.05).

Low levels of bioactive LMs correlate with low test scores for cognitive function. The levels of lipid mediators (LMs) in cerebrospinal fluid (CSF) samples from the total cohort of patients with Alzheimer’s disease (AD) (n = 40), mild cognitive impairment (MCI) (n = 43), or subjective cognitive impairment (SCI) (n = 53) were correlated to the mini-mental state examination (MMSE) test scores and the r-value according to Spearman rank-order test is given together with the P-value. Resolvin (Rv) D1 and RvD4 show positive correlation to the MMSE scores in the SCI group and when analyzing all three diagnostic groups together (Supplementary Table 2a). The omega-3 fatty acids docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) and the intermediate precursor 14-hydroxy-docosahexaenoic acid (14-HDHA) are positively correlated to the MMSE scores in the AD group. Also, levels of the omega-6 fatty acid arachidonic acid (AA) are positively correlated to the MMSE scores in the AD group

Correlations of bioactive LMs with cognitive function in an age-matched sub-cohort. The levels of lipid mediators (LMs) in cerebrospinal fluid (CSF) samples from the age-matched cohort of patients with Alzheimer’s disease (AD) (n = 15), mild cognitive impairment (MCI) (n = 17), or subjective cognitive impairment (SCI) (n = 21) were correlated to the mini-mental state examination (MMSE) test scores and the r-value according to Spearman rank-order test is given together with the P-value. Resolvin (Rv) D4 shows positive correlation to the MMSE scores in the SCI group and when analyzing all three diagnostic groups together (Supplementary Table 4a). Unlike in the entire cohort, the levels of RvD1 did not correlate, but a positive correlation is observed in the MCI group between LTB4 and MMSE scores (r = 0.52, P < 0.05). The omega-3 fatty acid docosahexaenoic acid (DHA) and the intermediate precursor 14-hydroxy-docosahexaenoic acid (14-HDHA) are positively correlated to the MMSE scores in the AD group, whereas the eicosapentaenoic acid (EPA) is not. The levels of the omega-6 fatty acid arachidonic acid (AA) are also positively correlated to the MMSE scores in the AD group

Analysis of all diagnostic groups together in the entire cohort of cases showed that the CSF levels of Aβ42 were positively correlated to the levels of RvD4 (r = 0.29, P < 0.001), RvE1 (r = 0.23, P < 0.01), RvD1 (r = 0.18, P < 0.05), and NPD1 (r = 0.18, P < 0.05) (Supplementary Table 2b). Also, in the age-matched cohort, there were positive correlations between Aβ42 and RvD4 (r = 0.46, P < 0.001) and RvE1 (r = 0.42, P < 0.005) (Supplementary Table 4b).

The analysis of correlations according to diagnostic group within the entire cohort showed a positive correlation between Aβ42 and 12-HETE (r = 0.42, P < 0.01), LXA4 (r = 0.35, P < 0.05), LTB4 (r = 0.33, P < 0.05), and RvE4 (r = 0.32, P < 0.05) among the AD cases. In cases diagnosed with SCI, there was a positive correlation between Aβ42 and RvE1 (r = 0.27, P < 0.05). In the age-matched cohort, positive correlations were observed in the AD group between Aβ42 and 12-HETE (r = 0.58), LTB4 (r = 0.52), 14-HDHA (r = 0.54), 20-HDHA (r = 0.59), and AA (r = 0.53), all with a significance level of P < 0.05. In the MCI group, there was a negative correlation between Aβ42 and NPD1 (r = − 0.52, P < 0.05), and in the SCI group, a comparatively strong negative correlation between Aβ42 and MaR2 (r = − 0.68, P < 0.001).

The CSF levels of the tangle biomarkers t-tau and p-tau in the entire cohort showed weak correlative relationships to the lipids analyzed (Supplementary Table 2c, d). Analysis of the entire cohort showed a negative correlation between RvD4 and t-tau (r = − 0.17, P < 0.05), while there was no correlation to p-tau. Considerably more correlations were found to t-tau in the age-matched cohort (Supplementary Table 4c), i.e., negative correlations to EPA (r = − 0.40, P < 0.005), DHA (r = − 0.33, P < 0.05), RvD1 (r = − 0.33, P < 0.05), MaR1 (r = − 0.33, P < 0.05), RvE1 (r = − 0.27, P < 0.05), and 12-HETE (r = − 0.32, P < 0.05). Similarly, negative correlations were found to p-tau for EPA (r = − 0.38, P < 0.005), DHA (r = − 0.31, P < 0.05), RvD1 (r = − 0.32, P < 0.05), MaR1 (r = − 0.27, P < 0.05), and 12-HETE (r = − 0.32, P < 0.05) (Supplementary Table 4d). A positive correlation was found to LTB4 for both t-tau (r = 0.36, P < 0.01) and p-tau (r = 0.35, P < 0.05).

The analysis according to the diagnostic group within the entire cohort showed that for AD cases, MaR1 was negatively correlated to t-tau (r = − 0.35, P < 0.05), and PGD2 was positively correlated to p-tau (r = 0.32, P < 0.05) (Supplementary Table 2c, d). In cases diagnosed with MCI, there was a negative correlation between the levels t-tau and those of LXA4 and 12-HETE (r = − 0.33, P < 0.05 and r = − 0.32, P < 0.05, respectively) and between the levels t-tau and LXA4 (r = − 0.33, P < 0.05). There was no correlation to the CSF levels of t- or p-tau within the SCI group. In the age-matched cohort, negative correlations to t-tau were observed in the AD group for DHA (r = − 0.71, P < 0.005), EPA (r = − 0.81, P < 0.0005), 17-HDHA (r = − 0.56, P < 0.05), and 15-HETE (r = − 0.58, P < 0.05) (Supplementary Table 4c). Negative correlations were also found to p-tau for EPA (r = − 0.60, P < 0.05) and 15-HETE (r = − 0.55, P < 0.05) (Supplementary Table 4d). A positive correlation was found between PGD2 and t-tau (r = 0.61, P < 0.05) and p-tau (r = 0.83, P = 0.0001). In the SCI group there was a positive correlation between t-tau and RvE4 (r = 0.46, P = 0.05) and a negative correlation between p-tau and 12-HETE (r = − 0.47, P = 0.05).