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Based on similarities in epidemiology and biochemistry, it has been suggested that cataract and Alzheimer’s disease (AD) share the same aetiological mechanisms. Comorbidity of cataract and AD in trisomy 21 (Down’s syndrome) is well known1,2 and both diseases are characterised by aggregated proteins exhibiting excessive glycation and racemisation of aspartyl residues.3 Several AD related proteins—amyloid precursor protein (APP), β amyloid (Aβ), and presenilin (PS)—are expressed in the lens4,5 and Aβ is accumulated in the cytosol of lens fibres in cataractous lenses of people with AD.6
Human apolipoprotein E (apoE) exists in three major isoforms encoded by distinct alleles (APOE ε2, ε3, and ε4). The different APOE alleles have been studied in relation to several human age related diseases: inheritance of the ε4 allele is a strong risk factor for AD and influences Aβ metabolism.7,8 The purpose of this study was to investigate the APOE ε2/ε3/ε4 polymorphism in patients with cataract.
After informed consent, patients with senile cataract and control individuals were recruited from two ophthalmic clinics in Tartu and the south Estonian area. The study was approved by the ethics committee at the University of Tartu, Estonia. Before surgery, the type of cataract was determined using biomicroscopy and ophthalmoscopy. Secondary cataracts were excluded. The case group included 502 patients; 77 with nuclear, 155 with cortical, 119 with posterior subcapsular, and 151 with mixed opacities. Mean age was 72.0 (SD 8.7) years (range 47–93 years) and 348 (69.3%) were women. The control group consisted of 187 individuals without cataract, uveitis, or glaucoma. Mean age was 65.8 (SD 6.9) years (range 43–90 years) and 136 (72.7%) were women. The power of the study was >99% as calculated according to Altman9 on the basis of APOE ε4 allele frequencies in a recent study on AD.10
The APOE alleles and genotypes were determined as previously described.11 The allele and genotype frequencies of cataract cases and controls were compared using a two tailed Fisher’s exact test, and odds ratios (ORs) and 95% confidence intervals (CIs) were calculated.9 All statistical analyses were performed using SYSTAT as software (SPSS Inc, Chicago, IL, USA). Statistical significance was defined as p<0.05.
APOE allele and genotype frequencies found in this study are well in accordance with those reported in other Northern European populations.12 No significant differences were seen between the control and cataract groups for any of the APOE alleles (table 1) or APOE genotypes (table 2). Neither were there any differences between the control group and the specific cataract subgroups. In order to prevent the data from being influenced by age differences between the groups studied, age matched control individuals were selected and compared with the cataract group and vice versa, without resulting in any significant changes in APOE allele or genotype frequencies.
Alzheimer’s disease and cataract both exhibit large aggregates of aberrant proteins, senile plaques composed of Aβ and neurofibrillary tangles containing the cytoskeletal protein tau in the former case, and light scattering high molecular weight aggregates of crystallins in the latter. Together with several other diseases characterised by protein aggregates, such as amyloidosis and prion diseases, the term “conformational disease” has been created, suggesting a common aetiology.3,13
The APOE ε4 allele is a strong risk factor for AD, and it is believed that in neuronal tissue, apoE is important for mobilisation and redistribution of lipids, and for maintenance and repair of neuronal cell membranes.14 However, in age related macular degeneration (AMD)—a condition characterised by accumulation of extracellular deposits termed drusen, containing among other things neutral lipids, cholesterol, and apoE—the ε4 allele appears to confer protection, whereas the ε2 allele is associated with a moderately increased risk of AMD.15,16 The APOE ε4 allele also seems to play a protective role during embryogenesis,17 suggesting different effects of the gene early and late in life.
To our knowledge, this is the first study to investigate the APOE polymorphism in cataract patients. No differences in the distribution of APOE alleles and genotypes could be seen between controls and cataract patients in spite of a large number of participants and a very high power. This indicates that if there is a common pathogenic mechanism for cataract and AD, it does not involve the APOE polymorphism. Of course the results need to be confirmed by other groups before the APOE polymorphism can be regarded as insignificant in cataractogenesis. Bearing in mind the similarities between cataract and AD is very important, however, as progress in aetiological research of one disease may contribute to elucidating the pathogenesis of the other.
This work was supported by grants from the Swedish Medical Research Council (projects #02226, #5932, and #12103), the Sahlgrenska University Hospital, the Göteborg Medical Society, Stiftelsen Kronprinsessan Margaretas Arbetsnämnd för Synskadade, De Blindas Vänner, Stiftelsen Hjalmar Svenssons forskningsfond, and Tore Nilsons Stiftelse för Medicinsk Forskning.