en Cellular and molecular Neuroscience Cellular and molecular Neuroscience Original Original <strong>Introduction</strong>: Klotho and dipeptidyl peptidase-4 (DPP4) are two proteins that modulate inflammatory pathways. We investigated the association between circulating klotho and DPP4 activity and their relationship with inflammatory cytokines, miR-29a, and miR-195 in Alzheimer disease (AD).<br> <strong>Methods</strong>: This study was conducted on 16 AD patients and 16 healthy age-matched controls. Plasma levels of tumor necrosis factor-alpha (TNF-&alpha;), interleukin-1 beta (IL-1&beta;, interleukin-6 (IL-6), klotho, and DPP4 were measured by enzyme-linked immunosorbent assay. Plasma expression of miR-29a and miR-195 were also measured and compared by a real-time polymerase chain reaction.<br> <strong>Results</strong>: There was a significant increase in TNF-&alpha; (p=0.006), IL-1&beta; (p=0.012), and IL-6 (p=0.012) levels in the AD subjects compared with controls. Also, we found a decrease in plasma levels of klotho and an increase in plasma levels of DPP4 in the AD group that was not significant compared with the controls. Lower expression of miR-29a (P=0.009) and higher expression of miR-195 (P=0.003) were observed in the AD group that was significant than controls. Further analysis showed a negative correlation between klotho and plasma levels of IL-6 (r=-0.58, p=0.01). Also, there was a positive correlation between plasma DPP4 activity and TNF-&alpha; levels (r=0.50, P=0.04) and IL-1&beta; (r=0.62, P=0.01). Likewise, plasma klotho concentration showed a negative correlation with the age of AD subjects (r=-0.56, P=0.02).<br> <strong>Conclusion</strong>: TNF-&alpha;, IL-1&beta;, and IL-6 are involved in AD pathophysiology, and dysregulation of DPP4 and klotho may be associated with the inflammatory response of AD. Down-regulation of miR-29a and up-regulation of miR‑195 indicated the role of miRNAs in the AD process. Alzheimer Disease (AD), Klotho, Dipeptidyl Peptidase-4, Inflammatory cytokines, MicroRNAs 349 358 http://bcn.iums.ac.ir/browse.php?a_code=A-10-1747-1&slc_lang=en&sid=1 Mohsen Sedighi sedighi.mo@tak.iums.ac.ir 13700319475328460027407 13700319475328460027407 No Cellular and Molecular Research Center, Iran University of Medical Sciences, Tehran, Iran. Tourandokht Baluchnejadmojarad tmojarad@yahoo.com 13700319475328460027408 13700319475328460027408 Yes Department of Neuroscience, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran. Soudabeh Fallah s.fallah@iums.ac.ir 13700319475328460027409 13700319475328460027409 No Department of Biochemistry, School of Medicine, Iran University of Medical Sciences, Tehran, Iran. Nariman Moradi nariman8463@yahoo.com 13700319475328460027410 13700319475328460027410 No Department of Clinical Biochemistry, Faculty of Medicine, Kurdistan University of Medical Sciences, Sanandaj, Iran. Siamak Afshin-Majd safshinmajd@yahoo.com 13700319475328460027411 13700319475328460027411 No Neurophysiology Research Center, Shahed University, Tehran, Iran. Mehrdad Roghani mehjour@yahoo.com 13700319475328460027412 13700319475328460027412 No Neurophysiology Research Center, Shahed University, Tehran, Iran.