ORIGINAL RESEARCH Odor Identification Deficit as a Predictor of Five-Year Global Cognitive Change: Interactive Effects with Age and ApoE-e4 Jonas K. Olofsson Æ Michael Ro ¨nnlund Æ Steven Nordin Æ Lars Nyberg Æ Lars-Go ¨ran Nilsson Æ Maria Larsson Received: 9 March 2009 / Accepted: 8 July 2009 / Published online: 25 July 2009 Ó Springer Science+Business Media, LLC 2009 Abstract Olfactory impairments are present in common neurodegenerative disorders and predict conversion to dementia in non-demented individuals with cognitive impairment. In cognitively intact elderly, evidence is sparse regarding the role of olfactory deficits in predicting cognitive impairment. The present study investigated pre- dictors of 5-year prospective decline in the Mini-Mental State Examination (MMSE) in a large (n = 501), popula- tion-based sample of elderly (65–90 years) individuals. All participants were genotyped for the ApoE gene, assessed for health factors, and were non-demented at the baseline assessment. After partialling out the influences of demo- graphic and health-factors at baseline and dementia at follow-up, poor odor identification ability in combination with older age and the ApoE-e4 allele predicted larger prospective global cognitive decline. This effect could not be produced by a vocabulary test. In sum, the findings suggest that an olfactory deficit can dissociate between benign and malign global cognitive development in non- demented, very old e4-carriers, who are at high risk of developing dementia. Keywords ApoE Á Odor identification Á Olfaction Á Aging Á Dementia Introduction Aging is associated with a general decline in cognitive abilities (see e.g. Dixon et al. 2004). Cognitive impairment in the elderly may be a pre-clinical manifestation of neu- rodegenerative disease (Ba ¨ckman et al. 2002, 2005); identifying markers of cognitive decline is therefore important in order to detect such disease in pre-clinical stages. Neurodegenerative disease often entail olfactory dysfunction (Hawkes 2003; Mesholam et al. 1998). Persons in a pre-diagnostic phase of Alzheimer’s disease (AD) show olfactory impairments, suggesting that olfactory deficits might be caused by early-stage pathology (Bacon et al. 1998; Devanand et al. 2000). Olfactory impairments are present in first-degree relatives of individuals with AD (Handley et al. 2006; Serby et al. 1996) and in elderly persons with mild cognitive impairment (MCI) (Djordjevic et al. 2007; Murphy et al. 1998; Wang et al. 2002). Fur- thermore, poor olfactory performance predict later dementia conversion in MCI (Tabert et al. 2005). The apolipoprotein E (ApoE) gene is expressed in olfactory brain structures and is believed to play a role in neuronal regenerative processes as well as in the devel- opment of AD, the most common form of dementia Edited by Tatiana Foroud. J. K. Olofsson Á M. Ro ¨nnlund Á S. Nordin Department of Psychology, Umea ˚ University, Umea ˚, Sweden J. K. Olofsson (&) Á L.-G. Nilsson Á M. Larsson Department of Psychology, Stockholm University, 10691 Stockholm, Sweden e-mail: jonas.olofsson@psychology.su.se J. K. Olofsson Á L.-G. Nilsson Á M. Larsson Stockholm Brain Institute, Stockholm, Sweden M. Ro ¨nnlund Centre for Population Studies, Umea ˚ University, Umea ˚, Sweden S. Nordin Department of Psychology, San Diego State University, San Diego, CA, USA L. Nyberg Department of Radiation Sciences, Umea ˚ University, Umea ˚, Sweden 123 Behav Genet (2009) 39:496–503 DOI 10.1007/s10519-009-9289-5