Contents lists are available at the ScienceDirect Experimental Gerontology journal homepage: www.elsevier.com/locate/expgero. The ApoE gene is linked to Alzheimer's disease or cardiovascular disease, but its role in exceptional longevity (EL) is unclear. Our main objective was to determine if the ApoE gene is connected to EL using a case-control study. We compared the allele/genotype frequencies of ApoE among three cohorts: cases (centenarians, most with one or more major disease conditions; n = 163, 100-111 years) and healthy controls (n = 1039, 20-85 years) from Spain; disease-free cases (centenarians; n = 79, 100-104 years) and healthy controls (n = 597, age 27-81 years) from Italy; and cases (centenarians and semi-supercentenarians, most with one or more major disease conditions; n = 729, 100-116 years) and healthy controls (n = 498, 23-59 years) from Japan. Our main findings were twofold. First, the 4-allele was negatively associated with EL in the three cohorts with the following odds ratio (OR) values (adjusted by sex): 0.55 (95% confidence interval (CI): 0.33, 0.94), P = 0.030 (Spain); 0.41 (95%CI: 0.18, 0.99), P = 0.05 (Italy); and 0.35 (95%CI: 0.26, 0.57), P <0.001 (Japan). Second, though no association was found in the Spanish cohort (OR = 1.42 (95%CI: 0.89, 2.26), P = 0.145), the 2-allele was positively associated with EL in the Italian (OR = 2.14 (95%CI: 1.18, 3.45), P = 0.01) and Japanese subjects (OR = 1.81 (95%CI: 1.25, 2.63), P = 0.002). Despite the limitations of case-control designs, our data suggest that the ApoE gene might be a candidate to influence EL. The 4-allele appears to decrease the likelihood of reaching EL among individuals of different ethnic/geographic origins. An additional novel finding of our study was that the 2-allele might favor EL, at least in the Italian and Japanese cohorts. The ApoE is associated with having several age-related conditions such as cardiovascular disease (CVD, including coronary heart disease and cerebrovascular disease) (Kumar et al., 2012) and Alzheimer's disease (AD) (Liu et al., 2013), including late-onset AD (Sadigh-Eteghad et al., 2012), with the 4-allele being the unfavorable allele as it increases mortality risk (Christensen et al., 2006). Recent data also support an association of ApoE and mortality in long-lived individuals, with a genome-wide linkage analysis with nonagenarians identifying ApoE as a longevity gene (Beekman et al., 2013). This is in agreement with the results of a recent case-control genome-wide association study comparing long-lived individuals (mean age: 99.7 years) and younger controls from Germany (Nebel et al., 2011). However, whether ApoE influences exceptional longevity (EL), i.e., reaching 100+ years of age, is more controversial.

In the Spanish cohort, we conducted a longitudinal study of older subjects with no or mild cognitive impairment aimed at the early detection of AD. The history of past and current diseases was collected by personal interview with the participants. Exclusion criteria were having a stroke or traumatic brain injury with severe physical or cognitive impairment, clinically evident cancer, major psychiatric disorders, or severe systemic diseases (e.g., chronic renal or liver failure). None of the subjects had criteria of cognitive impairment after being submitted to an extensive neuropsychological battery that included: Mini-mental-State Examination (MMSE), Free and Cued Selective Reminding Test (FCSRT), Verbal Fluency Task (P, M & R), Rey-Osterrieth Complex Figure (ROCF), Drawing Clock Test, Global Deterioration Scale (GDS)-15 of Reisberg, and Global Clinical Dementia Rating (CDR). We excluded all subjects with CDR N 0 from the present study.