of a Genetic Variant at Alzheimer’s Disease Patients and

Irene Piaceria, Silvia Bagnolia, Ersilia Lucenteforteb, Michelangelo Mancusoc, Andrea Teddea, Gabriele Sicilianoc, Silvia Piacentinia, Laura Braccoa, Sandro Sorbia and Benedetta Nacmiasa,∗ aDepartment of Neurological and Psychiatric Sciences, University of Florence and Centro di Ricerca, Trasferimento e Alta Formazione DENOTHE, University of Florence, Viale Morgagni, Firenze, Italy bDepartment of Preclinical and Clinical Pharmacology, University of Florence, Florence, Italy cDepartment of Neuroscience, Neurological Clinic, University of Pisa, Pisa, Italy

Handling Associate Editor: Daniela Galimberti

13 December 2010

Abstract. A common polymorphism (rs3851179) in the PICALM (phosphatidylinositol-binding clathrin assembly protein) gene has been recently associated with reduced risk of developing late-onset Alzheimer’s disease (LOAD). We analyzed the genotype and allele distributions of the PICALM polymorphism in 813 Italian subjects, including LOAD patients and centenarians. The segregation of the PICALM rs3851179 showed no statistically significant difference between LOAD cases and controls. The implication of a genetic variant at PICALM is confirmed for the first time, in centenarians, thus suggesting a possible role in longevity.

Keywords: Alzheimer’s disease, apolipoprotein E, centenarian, genetic variation, PICALM

ease. It has become clear that the majority of common genetic variants contribute only slightly to an increased risk for the disease, but in combination they have an important impact on disease predisposition. Recently, three large Genome-wide association (GWA) studies, including more than 48,000 subjects, tested hundreds of single nucleotide polymorphisms (SNPs) and veri- fied strong evidence of five new susceptibility loci for AD, CLU (clusterin, chr 8), PICALM (phosphatidyli- nositol binding clathrin assembly protein, chr 11), CR1 (complement component [3b/4b] receptor 1, Chr 1), BIN1 (bridging integrator 1, chr 2) and EXOC3L2 (exocyst complex component 3-like 2, chr 19) [2–4]. Several large case control studies have recently con-

For almost twenty years, numerous molecular genetic studies in patients with the familial form of Alzheimer’s disease (FAD) have revealed more than 220 pathogenetic mutations in the three candidate \BP genes (A PP, PS1, PS2) contributing to the pathogene- sis of Alzheimer’s disease (AD) [1]. Despite numerous years of research, only one common genetic variant 4 (the 4 allele) in the gene encoding apolipoprotein E (APOE) has been considered a risk factor for the dis-

∗ Correspondence to: Benedetta Nacmias, Department of Neu- rological and Psychiatric Sciences, University of Florence, Viale Morgagni 85, 50134 Florence, Italy; Tel.: +39 055 4271379; Fax: +39 055 4271380; E-mail: nacmias@unifi.it.

ISSN 1387-2877/11/$27.50 © 2011 – IOS Press and the authors. All rights reserved

I. Piaceri et al. / Implication of a Genetic Variant at PICALM in Alzheimer’s Disease Patients and Centenarians

healthy individuals, as a control group, and 105 cente- narians (54.3% aged >100 years) (Table 1).

firmed the role of PICALM in more than 23,000 subjects [5–8].

All subjects were enrolled at the Neurology Unit of the Department of Neurological and Psychiatric Sci- ences of the University of Florence and Department of Neuroscience, Neurological Clinic, of the University of Pisa.

in PICALM rs3851179 with a reduced risk for Late Onset AD patients (LOAD) has been reported [2]. PICALM, located on 11q14.2, encodes the ubiqui- tously expressed 652 amino acid protein involved in clathrin-mediated endocytosis (CME) [9], which is an essential step in the intracellular trafficking of pro- teins, lipids, growth factors, and neurotransmitters. It is involved in endocytosis and in intracellular traf- ficking of VAMP2, a synaptic vesicle protein. The PICALM protein is indispensable for neurotransmitter release at the presynaptic membrane, which is impor- tant for memory formation and neuronal function [10].  Moreover, the protein may play a role in amyloid- clearance from the brain.

All cases (20% autopsy proven) were clinically eval- uated according to published guidelines and the AD diagnosis fulfilled the Diagnostic and Statistical Man-

Presence of a family history of dementia (at least two first-degree relatives in two generations) was consid- ered an exclusion criterion. All controls were carefully assessed using a rigorous clinical history evaluation and a general/neurological examination in order to exclude the presence of any neurological disorder. They were interviewed in order to exclude the presence of relatives with exceptional longevity (>100 years) in past generations.

The identification of protective variants against age-related illnesses, such as neurodegenerative disor- ders, may provide an important contribution to better understanding healthy aging. Many association stud- ies confirmed a key role of centenarian subjects in the identification of protective genetic profiles [11, 12]. In this regard, a recent study analyzed rs3850179 in the PICALM gene in the oldest old, finding a positive association between the A allele in subjects with better cognitive functioning [13].

Informed consent for genetic screening was obtai- ned from the study participants or, where appropri- ate, a relative or legal representative, and the study protocol was approved by the local ethics committee and conducted in accordance with the provisions of the Helsinki Declaration.

By using the demographic lists provided by the reg- istry offices, potentially eligible subjects with excep- tional longevity were identified and 60% agreed to participate. Centenarians were in good health, relative to their very advanced age, and did not present the more common age-related pathologies (e.g., severe cogni- tiveimpairment,severephysicalimpairment,clinically