ORIGINAL ARTICLE Decreased peripheral brain-derived neurotrophic factor levels in Alzheimer’s disease: a meta-analysis study (N = 7277) X-Y Qin 1,3 , C Cao 1,3 , NX Cawley 2 , T-T Liu 1 , J Yuan 1 , YP Loh 2 and Y Cheng 2 Studies suggest that dysfunction of brain-derived neurotrophic factor (BDNF) is a possible contributor to the pathology and symptoms of Alzheimer’s disease (AD). Several studies report reduced peripheral blood levels of BDNF in AD, but findings are inconsistent. This study sought to quantitatively summarize the clinical BDNF data in patients with AD and mild cognitive impairment (MCI, a prodromal stage of AD) with a meta-analytical technique. A systematic search of Pubmed, PsycINFO and the Cochrane Library identified 29 articles for inclusion in the meta-analysis. Random-effects meta-analysis showed that patients with AD had significantly decreased baseline peripheral blood levels of BDNF compared with healthy control (HC) subjects (24 studies, Hedges' g = - 0.339, 95% confidence interval (CI) = - 0.572 to - 0.106, P = 0.004). MCI subjects showed a trend for decreased BDNF levels compared with HC subjects (14 studies, Hedges' g = - 0.201, 95% CI = - 0.413 to 0.010, P = 0.062). No differences were found between AD and MCI subjects in BDNF levels (11 studies, Hedges' g = 0.058, 95% CI = - 0.120 to 0.236, P = 0.522). Interestingly, the effective sizes and statistical significance improved after excluding studies with reported medication in patients (between AD and HC: 18 studies, Hedges' g = - 0.492, P o0.001; between MCI and HC: 11 studies, Hedges' g = - 0.339, P = 0.003). These results strengthen the clinical evidence that AD or MCI is accompanied by reduced peripheral blood BDNF levels, supporting an association between the decreasing levels of BDNF and the progression of AD. Molecular Psychiatry advance online publication, 26 April 2016; doi:10.1038/mp.2016.62 INTRODUCTION Alzheimer’s disease (AD) is the most common neurodegenerative disease characterized by progressive loss of memory and impairment of cognitive ability. 1 It accounts for more than two-thirds of all cases of dementia. 2 The disease starts with mild symptoms and gradually becomes severe, and is one of the leading causes of mortality worldwide. 3 Before patients with AD exhibit typical clinical symptoms of dementia, they present with a stage known as mild cognitive impairment (MCI). 4 MCI is a condition in which an individual has mild but noticeable changes in thinking abilities, but do not significantly impact everyday activities of the individual. 5 Although research into AD has exploded over the last three decades, the etiology of AD is still poorly understood. However, two major hypotheses have been postulated. The amyloid beta hypothesis postulates that extracellular amyloid beta deposits, which initiate cell death in the central nervous system, are the fundamental cause of AD. 6–8 Another hypothesis is that hyperpho- sphorylated tau begins to form neurofibrillary tangles inside nerve cells, which initiate the cascade of the disease. 9,10 Unfortunately, intervention therapies targeted at amyloid beta and tau have been unsuccessful so far. Thus, investigation into alternative or additional hypotheses, on the etiology of AD and subsequent therapeutic intervention, are needed. Recently, accumulating evidence suggest that dysfunction of neurotrophins is involved in the cascade leading to AD. 11,12 Brain-derived neurotrophic factor (BDNF) is the most abundant and widely distributed neurotrophin in the central nervous system. 13 Thousands of publications have revealed biological functions of BDNF involved in cell differentiation, neuronal survival, synaptic plasticity, memory formation and cognitive functions. 14–16 Post-mortem studies have shown decreased levels and expression of BDNF in several brain regions of patients with AD, such as the hippocampus and the cortex. 17–22 However, other studies have presented conflicting results to these observations. 23,24 BDNF can cross the blood–brain barrier 25 and its levels in peripheral blood are highly associated with the BDNF levels in cerebrospinal fluid (r = 0.8), 25,26 although the concentration of BDNF in cerebrospinal fluid is much lower than in peripheral blood. 27 The 'peripheral as a window to the brain' hypothesis and easy access to the blood has driven a growing number of clinical studies measuring BDNF concentrations in peripheral blood over the last 10 years, in hope of better understanding of the etiology of AD and potentially use it as a biomarker in AD. Some studies found a decrease of circulating BDNF in AD or MCI subjects compared with healthy control (HC) subjects. 28–33 In contrast, other studies reported no significant difference or even increased BNDF levels in AD or MCI. 34–36 In light of the inconsistent findings, a meta-analysis of the subject was warranted. The present meta-analysis aims to test whether AD or MCI is accompanied by altered levels of BDNF in the blood. The meta- analytical techniques allow data from individual studies to be 1 Section on Translational Neuroscience, College of Life and Environmental Sciences, Minzu University of China, Beijing, China and 2 Section on Cellular Neurobiology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA. Correspondence: Dr Y Cheng, Section on Cellular Neurobiology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Building 49, Room 6C80, 49 Convent Drive, Bethesda, MD 20892, USA. E-mail: chengy4@mail.nih.gov 3 These authors contributed equally to this work. Received 24 November 2015; revised 10 February 2016; accepted 7 March 2016 Molecular Psychiatry (2016), 1 – 9 © 2016 Macmillan Publishers Limited All rights reserved 1359-4184/16 www.nature.com/mp