Apolipoprotein E gene in frontotemporal dementia: an association study and meta-analysis

Abstract

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

The genetic epidemiology of neurodegenerative disease

“…In addition to linkage to chromosome 9q21 in a syndrome of FTD coupled with familial amyotrophic lateral sclerosis (ALS; see below), association has been observed between FTD and APOE, albeit with highly variable results. Interestingly, and similar to equivalent studies done in PD, a recent metaanalysis on all data published for APOE in FTD detected a significant risk effect associated with the ε2-allele but no significant results with ε4 (70). While this observation may be purely incidental, it is similar to findings on the H1-tau haplotype, which has also been associated in some FTD syndromes as well as PD.…”

APOE is a potential modifier gene in an autosomal dominant form of frontotemporal dementia (IBMPFD)

“…Analysis of a subset of studies using only neuropathologically confirmed cases showed a significant increase in APOE 2 allele frequency in FTD. 21,22 FTD is heterogeneous both clinically and pathologically. 23 An association between the fluent aphasic clinical form of FTD (but not other clinical FTD forms) and APOE 4 was found by Short et al 24 Recently, the APOE 4 allele has been found to be overrepresented in clinical FTD within a homogenous population in southern Italy, 14 and in neuropathologically-verified Pick's disease and dementia lacking distinctive histopathology (DLDH).…”

Revisão dos principais genes e proteínas associadas à demência frontotemporal tau-positiva

“…Os autores concluíram que o APOE alelo e2 pode ser fator de risco para a DFT, mas que os dados devem ser interpretados com cautela, devido à raridade do genótipo e2e2. 26 Muitos polimorfismos estão envolvidos diretamente com a neurotoxicidade, como por exemplo, mutações no gene da proteína precursora β-amiloide (APP), e/ou nos genes dapresenilina (PSEN1 e PSEN2). Mais de 28 mutações nesses genes já foram descritas como associadas à doença de Alzheimer, mas estes podem estar envolvidos no desenvolvimento de outras demências, exatamente pelo fato de alterações funcionais resultarem em toxicidade para o sistema nervoso.…”