## 3 Results
### Omega-3 Supplementation in AD
Adjusting for age, gender, and APOE genotype, no significant effects on neuropsychiatric symptoms were found, with the exception of the agitation domain. Indeed, a significant reduction in agitation scores was observed in patients carrying the APOE4 allele in the \(\omega\)-3 FA group compared to placebo (\(p=0.006\)). Non-APOE4 carriers in the \(\omega\)-3/\(\omega\)-3 group showed a decline in MADRS scores between 0 and 6 months (\(p\) = 0.005), compared to non-APOE4 carriers receiving the placebo [48]. In summary, while treatment with \(\omega\)-3 FA did not produce significant effects on neuropsychiatric symptoms or depression globally, there may be benefits in specific domains (such as hallucinations and agitation), with potential effects modulated by genetic profiles, particularly the APOE4 allele [48]. Moreover, [PERSON] et al. [46] studied the impact of a supplementation containing 430 mg of DHA and 150 mg of EPA for six months on IL-6, TNF-\(\alpha\), and soluble IL-1 receptor type II (sIL-1 RII) levels in plasma and CSF. A formulation containing 1 g of corn oil, including 0.6 g of linoleic acid, was used as a placebo. Both formulations contained 4 mg of vitamin E. No differences were found in IL-6 or sIL-1 RII levels in CSF, whereas TNF-\(\alpha\) significantly decreased in both groups (both \(p\) < 0.001). No statistically significant differences in the same markers were found in plasma [46]. Therefore, supplementation with \(\omega\)-3 FAs showed no effect on pro-inflammatory biomarkers in CSF or plasma [46]. [PERSON] et al. [47] measured levels of 8-iso-prostaglandin F2 \(\alpha\) (8-iso-PGF2\(\alpha\)) and 15-keto-dihydro- PGF2\(\alpha\), a biomarker relatable to oxidative stress and a biomarker of inflammatory response, respectively, in 37 patients who received 1.7 g of DHA and 0.6 g of EPA or placebo for 6 months [47]. No differences were observed in the urinary levels of 8-iso-PGF2\(\alpha\) and 15-keto-dihydro-PGF2\(\alpha\) between the supplemented group and the placebo group. At baseline, 15-keto-dihydro-PGF2\(\alpha\) levels showed negative correlations with \(\omega\)-3 FAs and a positive correlation with linoleic acid. These results suggest that \(\omega\)-3 FAs for 6 months in AD patients does not significantly affect free radical-induced F2-isoprostane formation or cyclooxygenase (COX)-mediated PGF2\(\alpha\) synthesis [47]. [PERSON] et al. [49] also reported that patients with mild-to-moderate AD administered with 2.3 g of \(\omega\)-3 FAs daily for six months showed significant increases in DHA, EPA, and total \(\omega\)-3 FA levels in CSF and plasma compared to placebo (\(p\) < 0.01) [49]. These results suggest that oral supplementation with \(\omega\)-3 FA may alter the endogenous \(\omega\)-3 FA profiles in CSF, indicating the potential transfer of these FAs across the blood-brain barrier in adults [49]. [PERSON] et al. [50] conducted a post hoc analysis involving 171 patients with AD. Of these, 88 patients received a daily dose of 1.7 g of DHA and 0.6 g of EPA for six months. The main goal of the analysis was to test whether the plasma levels of total Hcy affected the potential impact of \(\omega\)3 FAs on cognitive decline. In patients with total Hcy levels below 11.7 umol/L, \(\omega\)3 FA supplementation induced an improvement in cognitive performance, as assessed by the MMSE score (\(p\) = 0.033), and dementia, as measured by the \"Clinical Dementia Rating Scale Sum of Boxes\" (CDRsob, \(p\) = 0.009) compared to placebo [50]. [PERSON] et al. [51] performed an RCT to evaluate whether DHA may be useful in slowing cognitive decline. DHA supplementation did not affect the ADAS-cog score, which increased by 7.98 points in the DHA group (95% CI, 6.51-9.45) compared with 8.27 points in the placebo group (95% CI, 6.72-9.82, \(p\) = 0.41). Similarly, the CDRsob increased by 2.87 points in the DHA group (95% CI, 2.44-3.30) versus 2.93 points in the placebo group (95% CI, 2.44-3.42, \(p\) = 0.68). In 53 subjects administered with DHA and 49 with placebo, the rates of brain atrophy were similar.