APOE ε2/ε4 Genotype a Risk Factor for Primary Progressive Aphasia in Women

Frontotemporal dementia (FTD) is a clinically and pathologically heterogeneous entity characterized by focal degeneration of the cerebral cortex, which may present with behavioral and cognitive symptoms, especially linguistic deficits. Genetic factors might play an important role in FTD, which is a relatively common cause of early-onset dementia. We reported that the frequency of the ε2/ε4 genotype of the apolipoprotein E (APOE; GenBank AF286472) gene is significantly increased in primary progressive aphasia (PPA),¹ one of the syndromes associated with FTD. Primary progressive aphasia is characterized by progressive language impairment, while other cognitive functions remain relatively intact for at least the first 2 years of the course.²

We examined 125 patients with a clinical diagnosis of probable FTD,³ including a subgroup of 39 patients with PPA² and 343 age-matched controls (Table 1). Compared with controls, we observed a significant increase in ε2/ε4 genotype frequency in the overall FTD group and a highly significant increase in ε2/ε4 genotype frequency in the PPA subgroup. Compared with controls, a significant increase in ε4 allele frequency was detected in the FTD group, while a significant decrease in ε3 allele frequency was observed in the FTD group and the PPA subgroup. The APOE ε2/ε4 genotype was detected in 5 patients affected by PPA (4 women and 1 man) and in 1 woman affected by FTD not belonging to the PPA subgroup. Therefore, APOE genotype and allele frequencies were further analyzed according to sex (Table 2).

In men, a significant decrease in ε3/ε3 genotype and ε3 allele frequencies and a significant increase in ε3/ε4 genotype and ε4 allele frequencies were observed in the overall group with FTD and in the PPA subgroup. Moreover, the ε4/ε4 genotype was detected only in men with FTD, with a significant increase in frequency in men with FTD.

In women, we observed a significant increase in ε2/ε4 genotype frequency in the FTD group and a highly significant increase in ε2/ε4 genotype frequency in the PPA subgroup.

The results of the present study on a larger sample of patients with FTD and controls agree with our preliminary findings,¹ suggesting that the ε2/ε4 genotype might represent a genetic risk factor for PPA, while the ε3 allele might have protective effects for PPA and FTD. Moreover, the present results suggest that the ε2/ε4 genotype might represent a genetic risk factor, particularly for women with PPA. In men with FTD, by contrast, the ε3/ε3 genotype and ε3 allele might play a protective role, while ε3/ε4 genotypes and ε4 allele may increase the risk. Our findings only partially support a recent study that describes a significant increase in ε4 allele frequency and a trend toward a decrease in ε2 allele frequency in men with FTD.⁴

The ε2 allele might play a pathogenic role in other neurodegenerative conditions, as it might increase the risk of Parkinson disease. Patients with FTD carrying the ε4 allele show β-amyloid protein deposits more frequently than ε4 noncarriers, although β-amyloid deposition in FTD could be unrelated to primary pathological processes.⁵ Even if we cannot exclude the possibility that the association between ε2/ε4 genotype and PPA may be due to the insufficient size of our samples, such an association may be explained by molecular positive heterosis. When a certain chromosomal locus has 2 different alleles (for example, alleles A and B), heterozygosity occurs when a subject has both of the 2 alleles, A and B, and can be therefore defined as an AB heterozygote, while subjects having only the A or B allele can be defined as AA homozygotes and BB homozygotes, respectively. Usually, in a 2-allele polymorphism (where a single chromosomal locus has the 2 alleles, A and B), if the allele A is strongly associated with a certain phenotypic effect, subjects carrying the AA genotype (AA homozygotes) should show the greatest phenotypic effect, subjects carrying the BB genotype (BB homozygotes) should show the least phenotypic effect, and AB heterozygotes should show an intermediate phenotypic effect. Molecular positive heterosis is a counterintuitive phenomenon that occurs when subjects heterozygous for a specific genetic polymorphism (for example, AB heterozygotes) show a significantly greater phenotypic effect (positive heterosis) for a quantitative or dichotomous trait than homozygotes for either allele (AA homozygotes and BB homozygotes).⁶ Although the possible mechanisms involved in molecular positive heterosis are only partially known, this is a relatively common phenomenon that has been shown in several disorders and may be sex-specific, namely, it may be observed only in either men or women.⁶ Thus, in our series, women with the APOE ε2/ε4 genotype showed an increased risk for PPA compared with women with either ε2/ε2 or ε4/ε4 homozygosity. Further studies are needed to confirm the role of ε2/ε4 genotype as a risk factor in women with PPA and to clarify the possible pathogenic mechanisms related to APOE in this syndrome.

Correspondence: Dr Daniele, Institute of Neurology, Catholic University, Largo A. Gemelli, 8, Rome I-00168, Italy (adaniele@rm.unicatt.it).

Author Contributions: Drs Daniele and Seripa contributed equally to this study.

Financial Disclosure: None reported.

Funding/Support: This study was partially supported by grants No. AN/F9 and Istituti di Ricovero e Cura a Carattere Scientifico Research Program, Ricerca Corrente 2006-2008, Linea No. 2 “Malattie di rilevanza sociale” from the Italian Ministry of Health.