Although there have been reports addressing the relationship between depression, APOE genotype, and subjective memory impairment26,35
or APOE genotype and history of depression and diagnosis of AD dementia,36
or the frequency of the APOE-ε4 genotype in a cross-sectional comparison of subjects with depression and AD,20
this report is the first, to our knowledge, to evaluate the relationship between depressive symptoms, APOE status, and their interaction, and the rate of cognitive decline in a longitudinal follow-up study of middle-aged and older adults without dementia. Our results indicate that the APOE-ε4 allele, but not symptoms of depression or their interaction with APOE-status, is associated with a greater rate of decline in verbal memory. This is consistent with our previous report of group differences in the verbal memory measure when we performed a cross-sectional comparison of APOE-ε4 carriers and non-carriers.
In our group of subjects, both the APOE-ε4 carriers and non-carriers experienced some cognitive decline over the 2-year period. However, subjects experienced decline in different cognitive domains according to genetic risk, consistent with the literature identifying the APOE-ε4 allele as a modifying factor in cognitive decline.37–39
The presence of the APOE-ε4 allele was associated with a significantly greater rate of decline in verbal memory in middle-aged and elderly subjects without dementia. This finding is consistent with reports from other groups indicating that verbal memory and delayed recall are more impaired in the APOE-ε4 carriers.8,37,38
On the other hand, in the literature, the reported types of deficits associated with APOE are variable.40
Some report that APOE-ε4 is associated with decline in verbal (episodic) memory;41,42
others report an association between APOE and nonverbal memory43
or in domains that are not specifically affected in the “subclinical” or very early stages of dementia,40
and some report that APOE-ε4 carriers without dementia perform similarly to non-carriers on cognitive tests,44
despite group differences in cerebral metabolism. Consistent with the current findings, in a longitudinal study of cognitive decline in older community-dwelling adults, persons with the APOE-ε4 allele demonstrated decline in delayed verbal memory, compared with non–APOE-ε4 carriers, whereas immediate verbal memory, immediate spatial memory, vocabulary, attention, and information-processing speed were unrelated to APOE genotype.42
Methodological differences may explain the variability. O’Hara and colleagues42
suggested that the variability in the types of cognitive difficulties associated with APOE may be related to age of subjects, with older APOE-ε4 subjects demonstrating deficits in more cognitive domains than younger subjects. In some studies, only one or a limited number of domains were tested, and the pattern of impairment across cognitive domains cannot be determined. Also, homozygosity or heterozygosity in the APOE-ε4 carriers may be a factor, as Caselli et al.45
reported in a cross-sectional study, in which age-related verbal memory decline occurred earlier in APOE-ε4 homozygotes than in APOE-ε4 heterozygotes and non-carriers. A relatively small sample size may also be responsible for our finding of decline in only one cognitive domain.
The APOE-ε4 carriers presented with a greater number of depressive symptoms at baseline, as measured by the Ham-D. However, there was no difference in the severity of depressive symptoms between the groups at follow-up. These results may be related to the fact that the group of APOE-ε4 carriers had a greater proportion of people with a family history of AD than the non-carrier group (70% versus 55%), which, although not statistically significant, may have resulted in a greater awareness of memory impairment. This could also represent a greater vulnerability in the APOE-ε4 group for developing depressive symptoms, but would not explain the lack of difference in the severity of depressive symptoms between the groups at follow-up. Small and colleagues26
reported an association between depressive symptoms and memory complaints in non-APOE-ε4 carriers in a cross-sectional study. However, Mauricio et al.39
did not find an association between APOE-ε4 and change in depressive symptoms severity in a 5-year longitudinal study of community-dwelling elderly subjects, but they did not feel that this would compromise the specificity of APOE genotyping in AD diagnosis. In our sample of cognitively intact older adults with very mild depressive symptoms, neither the severity of depressive symptoms nor the interaction between depressive symptoms and APOE-ε4 status predicted cognitive decline.
Our findings support the role of APOE-ε4 in accelerating the rate of cognitive decline, especially in verbal memory. However, they do not support the role of depressive symptoms as risk factors for cognitive decline in these carefully selected individuals without major depressive disorder. Our results have limited generalizability because of the characteristics of our convenience sample and the small sample size. We excluded subjects with a more severe major depression, which has been identified as a risk factor for AD in other studies.16,17
None of our subjects met diagnostic criteria for syndromal depression. More than 50% of our sample had a family history of AD. We did not control for multiple comparisons. Additional studies including samples with the full range of depressive disorders are needed to clarify the role of the interaction between APOE-ε4 status and depressive symptoms in predicting cognitive decline.