Commentary Efficacy of antibody-based therapies to treat Alzheimer's disease: Just a matter of timing? Jonathan Cedernaes⁎, Helgi B. Schiöth, Christian Benedict Department of Neuroscience, Uppsala University, Uppsala, Sweden abstract article info Article history: Received 28 April 2014 Received in revised form 4 May 2014 Accepted 5 May 2014 Available online 14 May 2014 Section Editor: Christian Humpel Keywords: Alzheimer's disease Antibody-based therapy Phase III clinical trials Lifestyle factors Cognitive decline A pharmaceutical intervention that has received great attention in recent years for treating Alzheimer's disease (AD) is the use of antibodies targeting amyloid beta (Aβ) in the brain, as the formation of Aβ plaques is consid- ered as being the driving force for the development and progression of AD. Recently, a Phase III trial in patients with mild-to-moderate AD has provided ambivalent evidence for the efficacy of this intervention. In this trial, the intravenous administration of bapineuzumab, a monoclonal antibody targeting Aβ in the brain, for 78 weeks led to a reduction of cerebrospinal fluid levels of phosphorylated tau and evidence for lower Aβ accu- mulation in the brain of AD patients who carried APOE ε4. However, this treatment did not improve clinical out- comes (e.g. the rate of cognitive decline) in these patients. Similar null results with respect to the rate of cognitive decline were found in a separate Phase III clinical trial after treatment with solanezumab. Based on these findings, one conclusion could be that antibodies targeting Aβ in the brain may unfold their highest efficacy when given before the development of clinical AD symptoms, i.e. during a period where neurodegeneration but not cognitive loss represents the major pathology. Another conclusion could be that antibody-based pharmaceutical interven- tions may fail to slow the progress of cognitive loss in patients who have AD because of their solely pharmaceu- tical therapeutic approach. Leisure activities that require patients' mental and physical abilities (e.g. exercise) are associated with a reduced risk of developing dementia. In the same manner, they may help to curb the progress of this devastating disease. Thus, combining the use of antibodies targeting Aβ with therapeutic strategies that re- quire patients' mental and physical abilities might help tackle the neurodegenerative dynamics and cognitive loss both in patients with AD, and its prodromal state, mild cognitive impairment. © 2014 Elsevier Inc. All rights reserved. Alzheimer's disease (AD), the most common form of dementia, was first described by the German psychiatrist and neuropathologist Alois Alzheimer in 1906. Albeit subject of intensive research spanning from preclinical experiments to large multicenter clinical trials (entering the key words Alzheimer's disease and Treatment at PubMed currently yields almost 35,000 hits (PubMed, 2014)), about 100 years later, clini- cians are a far way off from having a pharmaceutical therapy that effec- tively is able to curb both central nervous system neurodegeneration and cognitive loss in humans afflicted by this devastating disease. This is alarming for several reasons, not least as currently, an estimated 5 million people have AD in the United States, and yet this number is projected to more than triple by the year 2050 (World Health Organization and Alzheimer's Disease International, 2012). A promising pharmaceutical intervention that has received increasing attention to slow the progress of this devastating disease is the use of antibodies targeting amyloid beta (Aβ) in the brain, as the formation of Aβ plaques is considered as being the driving force for the development and pro- gression of AD (Hardy and Selkoe, 2002). For a list of previously pub- lished Phase II and Phase III clinical trials utilizing antibody-based strategies to curb the progress of AD, please see Table 1. Recently, two Phase III trials in patients with mild-to-moderate AD have provided encouraging evidence with respect to the efficacy of this intervention (Doody et al., 2014; Salloway et al., 2014a). For in- stance, in one of these key trials, the administration of bapineuzumab, a monoclonal antibody targeting Aβ in the brain, by intravenous infu- sion every 13 weeks for 78 weeks led to treatment differences in bio- markers (Salloway et al., 2014a). These differences were observed in the more AD-prone apolipoprotein (APOE) ε4 carriers, who exhibited a significant reduction of cerebrospinal fluid levels of phosphorylated tau and evidence for lower Aβ accumulation in the brain (Salloway et al., 2014a). In spite of the significant improvements regarding bio- markers in AD-prone subjects, the anti-amyloid immunotherapy with bapineuzumab did not improve clinical outcomes (e.g. the rate of cognitive decline) in either APOE ε4 carriers or non-carriers (Salloway et al., 2014a). Similar null results with respect to the rate Experimental Gerontology 57 (2014) 104–106 ⁎ Corresponding author at: Department of Neuroscience, Uppsala University, Box 593, SE-751 24 Uppsala, Sweden. E-mail addresses: jonathan.cedernaes@neuro.uu.se (J. Cedernaes), christian.benedict@neuro.uu.se (C. Benedict). Contents lists available at ScienceDirect Experimental Gerontology journal homepage: www.elsevier.com/locate/expgero http://dx.doi.org/10.1016/j.exger.2014.05.002 0531-5565/© 2014 Elsevier Inc. All rights reserved.