Neurobiology of Aging 30 (2009) 1254–1264 APOE, ACT and CHRNA7 genes in the conversion from amnestic mild cognitive impairment to Alzheimer’s disease A. Barabash a , A. Marcos b , I. Anc´ın a , B. V´ azquez-Alvarez a , C. de Ugarte a , P. Gil c , C. Fern´ andez d , M. Encinas a , J.J. L ´ opez-Ibor e , J.A. Cabranes e,∗ a Laboratory of Psychoneuroendocrinology & Genetics, Hospital Cl´ınico San Carlos, 28040 Madrid, Spain b Department of Neurology, Hospital Cl´ınico San Carlos, 28040 Madrid, Spain c Department of Geriatric, Hospital Cl´ınico San Carlos, 28040 Madrid, Spain d Department of Epidemiology, Hospital Cl´ınico San Carlos, 28040 Madrid, Spain e Department of Psychiatry, Hospital Cl´ınico San Carlos, 28040 Madrid, Spain Received 7 May 2007; received in revised form 5 October 2007; accepted 4 November 2007 Available online 19 December 2007 Abstract We have investigated whether the −86 C/T promoter polymorphism in CHRNA7 gene, the signal peptide polymorphism of the 1- antichymotripsin (ACT) gene or the APOE genotype are associated with an increased risk of mild cognitive impairment (MCI) or affect the risk of evolution to Alzheimer’s disease (AD). We have followed up 89 patients with initial diagnoses of amnestic MCI for 49 months. Patients were separated into three groups: 27 subjects who remained with MCI, 40 that converted to AD before 20 months and 22 that converted to AD after. To assess the risk associated to each genotype a control group (n = 90) without cognitive impairment was included. APOE4 allele was associated with an increased risk of MCI (OR: 6.04, 95% CI: 2.76–3.23; p <0.001) but did not have an effect on the probability of evolving AD. ACT or CHRNA7 genotypes were not associated with MCI but both appear to modify the risk of progression to dementia in opposing manners: ACT polymorphism increasing the risk to evolve to AD before 20 months (HR = 2.03; 95% CI: 1–4.6; p = 0.06) and CHRNA7 polymorphism protecting from evolution to dementia. Cox regression model demonstrated that ACT genotype confers a higher risk of rapid evolution to dementia than age or years of schooling. We conclude that APOE is a risk gene for amnestic MCI and that ACT and CHRNA7 may act in these patients as modifier genes for the time of progression to AD. © 2007 Elsevier Inc. All rights reserved. Keywords: Mild cognitive impairment; Alzheimer’s disease; Genetics; APOE; CHRNA7; ACT; Prediction 1. Introduction Dementia is one of the most devastating diseases in devel- oped countries. The number of people suffering from this affliction will increase markedly during the next few decades and it is expected that within the next 50 years there will be approximately 16.2 million people affected by this disorder in the whole European region (Wancata et al., 2003). This may result in an enormous financial and emotional burden ∗ Corresponding author at: Instituto de Psiquiatr´ıa y Salud Mental, Hos- pital Cl´ınico San Carlos, C/Mart´ın Lagos s/n., 28040 Madrid, Spain. Tel.: +34 91 330 3808; fax: +34 91 330 3574. E-mail address: jcabranes.hcsc@salud.madrid.org (J.A. Cabranes). for society and particularly for caregivers. There are only palliative treatments available that can benefit some patients for a period of time when the disease is established (Evans et al., 2004). In contrast, we have evidence that pharmacologic intervention at an early stage may delay or prevent progres- sion to dementia (Birks, 2006). Thus, current research in this matter is focused in identifying this initial period of illness. Mild cognitive impairment (MCI) is a clinical diagnostic entity that may represent this early stage. It refers to individ- uals with cognitive deficits but who do not fulfil a diagnosis of dementia (Petersen et al., 2001). A considerable number of subjects with MCI develop dementia while a relative few do not; that has spurred major therapeutic interest in establish- ing preclinical prognostic markers for the progression from 0197-4580/$ – see front matter © 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.neurobiolaging.2007.11.003