Beneficial effect of bilingualism on Alzheimer’s disease CSF biomarkers and cognition Ainara Estanga a , Mirian Ecay-Torres a , Almudena Ibañez a , Andrea Izagirre a , Jorge Villanua b, c , Maite Garcia-Sebastian b , M. Teresa Iglesias Gaspar d , Ane Otaegui-Arrazola a , Ane Iriondo a , Monserrat Clerigue a , Pablo Martinez-Lage a, * a Department of Neurology, CITA-Alzheimer Foundation, San Sebastian, Spain b Department of Neuroimaging, CITA-Alzheimer Foundation, San Sebastian, Spain c Donostia Unit, Osatek SA, Donostia University Hospital, San Sebastian, Spain d Clinical Epidemiology Unit, Donostia University Hospital, Biodonostia, CIBER-ESP, San Sebastian, Spain article info Article history: Received 29 July 2016 Received in revised form 6 October 2016 Accepted 9 October 2016 Keywords: Bilingualism Preclinical Alzheimer’s disease CSF biomarkers Cognitive performance Cognitive/brain reserve Cohort studies abstract Bilingualism as a component of cognitive reserve has been claimed to delay the onset of Alzheimer’s disease (AD). However, its effect on cerebrospinal fluid (CSF) AD-biomarkers has not been investigated. We assessed cognitive performance and CSF AD-biomarkers, and potential moderation effect of bilingualism on the association between age, CSF AD-biomarkers, and cognition. Cognitively healthy middle-aged participants classified as monolinguals (n ¼ 100, n CSF ¼ 59), early (n ¼ 81, n CSF ¼ 55) and late bilinguals (n ¼ 97, n CSF ¼ 52) were evaluated. Models adjusted for confounders showed that bi- linguals performed better than monolinguals on digits backwards (early-bilinguals p ¼ 0.003), Judgment of Line Orientation (JLO) (early-bilinguals p ¼ 0.018; late-bilinguals p ¼ 0.004), and Trail Making Test-B (late-bilinguals p ¼ 0.047). Early bilingualism was associated with lower CSF total-tau (p ¼ 0.019) and lower prevalence of preclinical AD (NIA-AA classification) (p ¼ 0.02). Bilingualism showed a moderation effect on the relationship between age and CSF AD-biomarkers and the relationship between age and executive function. We conclude that bilingualism contributes to cognitive reserve enhancing executive and visual-spatial functions. For the first time, this study reveals that early bilingualism is associated with more favorable CSF AD-biomarker profile. Ó 2016 Elsevier Inc. All rights reserved. 1. Introduction The role of bilingualism as a component of cognitive reserve and its effect in neurodegenerative diseases, particularly in Alzheimer’s disease (AD), is a matter of increasing interest (Guzman-Velez and Tranel, 2015). Reported evidence suggests that lifelong bilin- gualism may delay, by up to 5 years, the onset of symptoms of AD (Bialystok et al., 2007; Chertkow et al., 2010; Craik et al., 2010; Schweizer et al., 2012) and other type of dementia independently of gender, years of education, socioeconomic and immigration sta- tus (Alladi et al., 2013). Bilingualism may contribute to the strengthening of neural networks related to attention and executive function given the need to monitor and switch attention between two languages (Bialystok et al., 2012; Gold, 2015). However, po- tential effects on other cognitive functions have been less thoroughly studied (Bak et al., 2014a). According to the brain reserve hypothesis, life accomplishments could mould brain structure thanks to neural plasticity (Stern, 2013). Recent evidence has indi- cated that certain life habits attenuate age-related AD pathology (Almeida et al., 2015; Okonkwo et al., 2014). In this context, it is possible that bilingualism may play a role against AD. If this is so, underlying mechanisms might be related to either a contribution to cognitive reserve, defined as the ability to maintain cognitive function despite increasing age or underlying neural changes, on one hand, or a modulating effect on age-associated accumulation of AD pathology, but this has not been yet studied. At the same time, whether the age of acquisition of the second language is an important determinant remains largely unknown (Bak et al., 2014a). The Basque language (Euskera) is the only noneIndo-European language surviving in Western Europe with no close relation with other languages (Comrie et al., 2003). It is spoken in the Basque Country, an area spanning the western Pyrenees in northern Spain including Nafarroa and Euskadi (provinces of Gipuzkoa, Araba, and Bizkaia), and the French “Pyrenees Atlantiques” (Lapurdi, Nafarroa Beherea, and Zuberoa). Although decades ago Euskera was mostly * Corresponding author at: Fundación CITA-Alzhéimer Fundazioa, Parque Científico Tecnológico de Gipuzkoa, S.A. Mikeletegi 71, bajo 20009, San Sebastian, Gipuzkoa, Spain. Tel.: (0034) 943 021 792; fax: (0034) 943 004 637. E-mail address: pmlage@cita-alzheimer.org (P. Martinez-Lage). Contents lists available at ScienceDirect Neurobiology of Aging journal homepage: www.elsevier.com/locate/neuaging 0197-4580/$ e see front matter Ó 2016 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.neurobiolaging.2016.10.013 Neurobiology of Aging 50 (2017) 144e151