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Apolipoprotein E Gene in Frontotemporal Dementia: an Association Study and Meta-Analysis

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Apolipoprotein E Gene in Frontotemporal Dementia: an Association Study and Meta-Analysis European Journal of Human Genetics (2002) 10, 399 – 405 ª 2002 Nature Publishing Group All rights reserved 1018 – 4813/02 $25.00 www.nature.com/ejhg ARTICLE Apolipoprotein E gene in frontotemporal dementia: an association study and meta-analysis Patrice Verpillat*,1,2, Agne`s Camuzat3, Didier Hannequin4,5, Catherine Thomas-Anterion6, Miche`le Puel7, Serge Belliard8, Bruno Dubois9, Mira Didic10,11, Lucette Lacomblez12,13, Olivier Moreaud14,Ve´ronique Golfier8, Dominique Campion4, Alexis Brice3,9,15 and Franc¸oise Clerget-Darpoux1 1INSERM U535, Le Kremlin Biceˆtre, France; 2De´partement d’Epide´miologie, de Biostatistique et de Recherche Clinique, Centre Hospitalier Universitaire Bichat-Claude Bernard, AP-HP/Universite´ Paris VII, Paris, France; 3INSERM U289, Centre Hospitalier Universitaire Pitie´-Salpeˆtrie`re, Paris, France; 4INSERM EPI 9906, Rouen, France; 5Service de Neurologie, Centre Hospitalier Universitaire, Rouen, France; 6Service de Neurologie, Centre Hospitalier Universitaire, Saint-Etienne, France; 7Service de Neurologie, Centre Hospitalier Universitaire Purpan, Toulouse, France; 8Service de Neurologie, Centre Hospitalier Universitaire Pontchaillou, Rennes, France; 9Fe´de´ration de Neurologie, Centre Hospitalier Universitaire Pitie´-Salpeˆtrie`re, Paris, France; 10Service de Neurologie et Neuropsychologie, Centre Hospitalier Universitaire de la Timone, Marseille, France; 11INSERM EMI U9926, Marseille, France; 12Fe´de´ration de Neurologie Mazarin, Centre Hospitalier Universitaire Pitie´-Salpeˆtrie`re, Paris, France; 13De´partement de Pharmacologie, Centre Hospitalier Universitaire Pitie´-Salpeˆtrie`re, Paris, France; 14Service de Neurologie, Centre Hospitalier Universitaire, Grenoble, France; 15De´partement de Ge´ne´tique, Cytoge´ne´tique et Embryologie, Centre Hospitalier Universitaire Pitie´-Salpeˆtrie`re, Paris, France No definite genetic risk factor of non-monogenic frontotemporal dementia (FTD) has yet been identified. Several groups have examined the potential association of FTD with the apolipoprotein E (APOE) gene, but the results are inconsistent. Our objective was to determine whether APOE is a risk factor of FTD, using the largest series of patients with FTD and controls analysed so far (94 unrelated patients and 392 age and sex-matched controls), and a meta-analysis. Homozygosity for the E2E2 genotype was significantly associated with FTD (odds ratio (OR)=11.3; P=0.033, exact test). After stratification on familial history (FH) for FTD, the OR for E2E2 was still found significant when analysing only patients with a positive FH (OR=23.8; P=0.019). The meta-analysis, using 10 case – control studies with available genotype or allele information, comprising a total of 364 FTD patients and 2671 controls, including the patients of the present study, did not reach statistical significance even if the E2E2 genotype was more frequent in patients than in controls (0.018 vs 0.006, respectively). Because of studies heterogeneity (Mantel-Haenszel statistics: P=0.004), we analysed on one hand the neuropathologically-confirmed studies, and on the other hand the clinical-based studies. In the neuropathologically-confirmed studies (Mantel – Haenszel statistics: P=ns), we found a significant increase of the E2 allele frequency in FTD patients (OR[E2 vs E3]=2.01; 95% CI=1.02 – 3.98; P=0.04). The same result was found in the clinical-based studies, but studies heterogeneity remained. No result was significant with the E4 allele. The E2 allele *Correspondence: Dr Patrice Verpillat; Hoˆpital Bichat, De´partement d’Epide´miologie, de Biostatistiques et de Recherche Clinique, 46 rue Henri Huchard, 75877 Paris cedex 18, France. Tel: +33 1 40 25 62 55; Fax: +33 1 40 25 67 73; E-mail: [email protected] Received 21 December 2001; revised 15 April 2002; accepted 18 April 2002 Apolipoprotein E gene in frontotemporal dementia P Verpillat et al 400 seems so to be a risk factor of FTD whereas this allele is associated with the lowest risk in Alzheimer’s disease. If this finding was confirmed, it could provide new insights into the mechanisms of differential risk related to APOE in neurodegenerative diseases. European Journal of Human Genetics (2002) 10, 399 – 405. doi:10.1038/sj.ejhg.5200820 Keywords: apolipoprotein E gene; frontotemporal dementia; genetic association; meta-analysis Introduction 88 FTD patients), we have re-examined the role of APOE Frontotemporal dementia (FTD) is one of the most in a larger case – control study of 94 FTD patients and common cause of neurodegenerative dementia after Alzhei- 392 controls. We performed also a meta-analysis using all mer’s disease (AD).1 Since the Lund and Manchester groups published findings of similar case – control studies consensus conference in April 1994,2 clinical and neuro- conducted until November 2001 to evaluate the effect of pathological criteria for FTD have been well established. APOE as a risk factor for FTD. This has lead to a better distinction of FTD from AD, which is the most frequent misdiagnosis of FTD.3,4 Recently, muta- Methods tions in the tau gene localised to 17q21 have been Subjects identified in several families with autosomal dominant All patients were ascertained over a 3-year period inheritance.5–8 To date, ten missense mutations, two dele- through consecutive admissions to 10 university hospitals tions, and three transition mutations not altering the in France. In this sample, we analysed the tau gene in encoded amino-acid sequence have been identified in probands with autosomal dominant inheritance by direct exons of the tau gene.9 In addition, six intronic mutations sequencing (exons 1 – 5, 7 and 9 – 14, and the corre- have also been found in the 5’ splice donor site of exon sponding flanking intronic sequences). The same 10.9,10 These mutations were detected in 25 to 40% of mutation, P301L, was found in six patients.8 After families with FTD that have autosomal dominant inheri- excluding these six patients with autosomal dominant tance.6,8,11 However, genetic heterogeneity has been inheritance and mutation of tau, our sample for the demonstrated, since another locus for FTD has been present study was thus composed of 94 unrelated mapped on chromosome 3 in a single large pedigree.12 patients with FTD (41.5% men). All patients with FTD The genetics of non-monogenic FTD has been less studied, underwent a thorough clinical examination, including although several groups have examined the potential asso- personal and familial medical history, neurological and ciation of FTD with the apolipoprotein E (APOE) gene, psychiatric investigations, psychometric testing (Mini- with inconsistent results.13 – 26 Mental State Examination35, Mattis Dementia Rating The E4 allele of the APOE gene is now undeniably the Scale36, Verbal Learning Test37 and Frontal Assessment most important risk factor in non-monogenic forms of Battery38), laboratory tests, computed tomography and AD. Although findings have not been as consistent as in magnetic resonance imaging, regional cerebral blood flow AD, an increase in the APOE E4 allele frequency has been measurement (single-photon emission computed tomogra- variably observed in other forms of dementia, including phy) and electroencephalography. The diagnosis of FTD diffuse Lewy body disease27 – 29 and vascular dementia.30,31 was established according to the Lund-Manchester clini- But it does not appear to be an important risk factor in cal consensus criteria for FTD.2 Age at onset was several other neurodegenerative processes, like progressive assessed by interviewing a next of kin and was defined supranuclear palsy32 and Parkinson’s disease.33,34 Some as the age at which relevant symptoms first appeared reports have suggested that APOE might also be a risk factor according to the family (mean+SD age at onset, in FTD. Initially, Gustafson et al13 reported a higher E4 60.6+8.5 years; range, 43 – 77 years). In our study, we allele and E4E4 genotype frequency in patients with FTD identified 31 patients with one or more first- or than in controls, and an even more significant increase of second-degree relatives with FTD (33%; 35.5% men; the E2 allele. Stevens et al14 have also found a significantly mean+SD age at onset, 60.2+7.9 years; range, 45 – 77 increased risk for the E4 allele and E4E4 genotype in FTD. years), but without clear autosomal dominant inheritance Subsequently, the results of a further study have suggested and without mutation in the tau gene. that the E2 allele, rather than the E4 allele, could be the Patients with FTD were compared with 392 age- and sex- risk factor for FTD.15 Finally, a recent study has shown a matched controls (44.9% men; mean+SD age at examina- significant increase of the E4 allele in an FTD population tion, 62.5+8.7 years; range, 38 – 77 years). Control compared to healthy controls.26 But ten other studies have subjects were the patients’ spouses or healthy blood donors not replicated this association.16 – 25 or individuals living in nursing homes. None of the Because all previous studies have been based on rela- controls showed cognitive deficits or behavioural distur- tively small samples (less than 35 except one study with bance. European Journal of Human Genetics Apolipoprotein E gene in frontotemporal dementia P Verpillat et al 401 All participants in this study were white and were living compare differences between mean age at onset and mean in France. Informed written consent was obtained for all age at examination in the two groups, and non parametric participants, either directly or from the legal tutor. Mann – Whitney test to compare differences between mean age at onset in the group with FTD according to APOE Meta-analysis genotypes. Mantel – Haenszel – Peto statistics was performed For the meta-analysis we searched through Medline for all to test for heterogeneity between studies selected for the studies performed for APOE in FTD until November 2001, meta-analysis and to compute weighted odds ratio.40,41 and reviewed the references in the retrieved articles.
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