## 4 Discussion  
The lack of therapies capable of managing the full spectrum of AD-related symptoms, only being able to slow down disease progression [82], underscores the need to explore other pharmacologically active compounds, such as NHPs, that could improve the quality of life and prognosis of AD patients. The RCTs reviewed here examined the potential of NHPs as complementary or alternative therapeutic options in AD. We analyzed 34 RCTs published in the last two decades that evaluated the effects that vitamins [26; 27; 28; 31; 32; 37; 38; 39], \(\omega\)-3 FAs [44; 45; 46; 47; 48; 49; 51; 52; 53; 54], micronutrients [61; 65; 66; 67; 68; 70; 71; 72], and other forms of NHP supplementation [74; 75; 76; 77; 78; 79; 80; 81] might have on the pathogenesis, progression, and treatment of AD symptoms. An improvement in disease management was reported in 50% of the studies [28; 31; 37; 38; 45; 53; 65; 66; 72; 73; 74; 75; 77; 78; 81]. Adverse reactions likely attributable to the used NHPs were found in 5.8% of the studies [26; 27]. Considering that AD is characterized by a persistent neuroinflammation caused by an increased release of inflammatory and oxidative markers (e.g., TNF-\(\alpha\), IL-6, F2-isoprostanes, and MDA), the effectiveness of NHPs, both as monotherapy and in combination with conventional therapies, in reducing the rate of these stressors has been investigated. Seven of the reviewed RCTs address this issue [28; 37; 46; 47; 74; 75; 77]. [PERSON] et al. and [PERSON] et al. reported a reduction in TNF-\(\alpha\) and IL-6 levels in patients treated with the probiotic \(L\). _mannosus_ or vitamin B12 (50 \(\upmu\)g) + folic acid (1.2 mg), respectively, compared to the control groups [28; 75]. [PERSON] et al. suggested that although a reduction in inflammation was observed after 6 months of treatment, longer follow-up studies are needed to assess the effect on cognitive performance [28]. In contrast, [PERSON] et al. investigated the use of \(\omega\)-3 FAs (DHA and EPA) in two consecutive studies and found no reduction in TNF-\(\alpha\) and IL-6, even when using increasing dosages in the second study compared to the first [46; 47]. These authors also found no reduction in F2-isoprostane levels [47], which, on the contrary, were reported to decrease by 19% by [PERSON] et al., studying the effect of an E/C/ALA regimen with CoQ [37]. Another marker of oxidative stress (MDA) was reported to decrease in the studies by [PERSON] et al. after a treatment with fenugreek seed and by [PERSON] et al. who investigated the effects of a mixture of five probiotic strains [74; 77]. According to a 2020 meta-analysis, probiotic supplementation decreased inflammation in patients with AD and mild cognitive impairment [83]. In contrast, the study by [PERSON] et al. [76] found that the co-supplementation of probiotics and selenium improves cognitive function but has no effect on the biomarkers of inflammation. Other studies also did not attribute a beneficial effect of probiotics on inflammation status [84]. The study by [PERSON] et al. [84] showed no changes in the levels of IL-6 and IL-10 in 48 AD patients taking probiotic supplementation. The different severity of the disease in the participants could explain the difference in studies. Indeed, as the severity of the disease increases, symptoms may become more difficult to improve. Consequently, as probiotics may be more effective in the early and less severe stage of the disease, the frequent lack of information on the stage of AD prevents a fair comparison between studies. With regard to \(\omega\)-3 FA supplementation, all RCTs found no benefit for the management of chronic inflammation, as well as the preservation of cognitive function and memory, and the counteraction of disability in AD patients. [PERSON] et al. found an increase in CSF \(\omega\)-3 levels after the administration of 2.3 g of \(\omega\)-3 FAs (high in DHA) [49], but neither [PERSON] et al. using 2 g of DHA [51] nor [PERSON] et al.