Neuropeptide Alterations in Alzheimer's Disease: A Meta‐Analysis of Cerebrospinal Fluid Concentrations

Abstract Background Neuropeptides are crucial proteins in the central nervous system, which significantly influence neurophysiological processes. This analysis explores cerebrospinal fluid alterations in Alzheimer's disease, offering insights to better understand the condition and explore novel diagnostic and therapeutic avenues. Method We systematically searched MEDLINE (PubMed), EMBASE, Cochrane, and Scopus using specific search strategies. Following PRISMA guidelines, our screening and extraction included studies that investigated neuropeptide concentrations in Alzheimer's patients' cerebrospinal fluid (CSF). Utilizing the 'meta' R package, particularly the 'metacont' tool, we analyzed mean concentration levels and standard differences via the random effects model. Data pooling utilized inverse variance weighting, with I² and tau² assessing heterogeneity. The restricted maximum−likelihood estimator and Q−profile informed tau² and its confidence interval. The primary outcome was the mean difference in CSF neuropeptide levels between Alzheimer's patients and controls, considering reported units separately. Result In our analysis of neuropeptides across diverse studies involving Alzheimer's Disease (AD) patients and controls, we observed distinct neurochemical alterations. Somatostatin showed a significant mean difference of ‐15.48 pg/mL (95% CI: ‐20.95 to ‐10.01, I² = 89%) in 9 studies (141 AD, 203 controls), and ‐8.05 pmol/L difference (95% CI: ‐13.35 to ‐2.76, I² = 0%) in 2 studies (44 AD, 57 controls). Neuropeptide Y (NPY) showed ‐8.83 pg/mL difference (95% CI: ‐19.81 to 2.16, I² = 65%) in 5 studies (76 AD, 95 controls), and ‐16.85 pmol/L difference (95% CI: ‐35.21 to 1.52, I² = 71%) in 3 studies (87 AD, 62 controls). Orexin exhibited a difference of 8.03 pg/mL (8 studies: 235 AD, 177 controls; ‐2.60; 18.67, I² = 27%, p‐value: 0.14). After excluding a study that significantly reduced heterogeneity, the adjusted result was 12.77 (95% CI: 1.16 ‐ 24.39, p‐value: 0.03). Substance P also showed a reduction in mean difference by ‐16.52 pg/mL (2 studies: 45 AD, 35 controls; ‐67.47; 34.42, I² = 87%) but was not statistically significant. Conclusion Somatostatin exhibited a consistent decrease in levels across studies, indicating potential relevance to AD pathophysiology. Additionally, orexin demonstrated a significant increase in levels in individuals diagnosed with Alzheimer's.