Apolipoprotein ε4 Allele Status, Depressive Symptoms, and Cognitive Decline in Middle-Aged and Elderly Persons Without Dementia

Abstract

Objective

Because the apolipoprotein ε4 (APOE-ε4) allele or depressive symptoms may increase the risk for development of Alzheimer disease (AD), the authors assessed APOE-ε4 status, baseline level of depressive symptoms, and subsequent cognitive decline in middle-aged and older persons without dementia.

Methods

The 49 subjects (age range: 51–85 years) included 20 with and 29 without APOE-ε4. Baseline and follow-up neuropsychological assessments determined the degree of cognitive decline.

Results

Baseline mild depressive symptoms were greater in APOE-ε4 carriers than in non-carriers. The subject groups demonstrated significant cognitive decline at follow-up. APOE-ε4 carriers showed a significantly greater rate of verbal memory decline than non-carriers. Baseline depressive symptoms, however, did not predict future cognitive decline.

Conclusions

These results suggest that APOE-ε4 carriers may have a greater severity of depressive symptoms than non-carriers. The APOE-ε4 allele (but not baseline mild depressive symptoms) is associated with verbal memory decline in middle-aged and older persons. Because of the limited range of depression scores in our sample, these findings should be interpreted with caution and not be generalized to patients with syndromal depression.

Cognitive decline in middle-aged and older adults can represent either normal change associated with aging or early signs of dementia. Alzheimer disease (AD) is the most frequent cause of dementia, accounting for two-thirds of dementia cases.¹ Identifying predictors of decline in individuals without dementia may aid in the early diagnosis and treatment of AD.

Genetic studies have identified the apolipoprotein ε-4 (APOE-ε4) allele as a major risk factor for sporadic and familial late-onset AD and early-onset AD.^2–5 The presence of the APOE-ε4 allele is associated with the increased risk for AD and earlier age at onset in late-onset AD cases.^3–6

APOE genotyping has been used in studies of milder forms of age-related cognitive loss. Several groups have shown that having the APOE-ε4 allele predicts future cognitive decline in older persons with mild cognitive impairment.^7–10 Some investigators have reported that persons with APOE-ε4 perform more poorly than persons without APOE-ε4 on cognitive tests of episodic (e.g., verbal and visual memory) and semantic (e.g., verbal fluency and confrontation naming) memory.^11,12 However, some do not find this relationship in community-dwelling elderly persons.¹³ Small and colleagues¹⁴ reported previously an association between the APOE-ε4 carrier status and lowered inferior-parietal, lateral-temporal, and posterior-cingulate metabolism in 20 subjects without dementia in a 2-year follow up. In these subjects, the APOE-ε4 carriers demonstrated decline in metabolic rate on PET but not in memory scores after 2 years. Although the APOE-ε4 allele may modestly affect the ability to predict cognitive decline in older persons, using the APOE genotype alone is not considered a useful predictor in persons without dementia.¹⁵

The relationship between depression and cognitive impairment in late life has been reported in a number of studies.^16–18 Depression in late life is a risk factor for developing AD in community-dwelling elderly persons.¹⁶ Clinically, AD may manifest with an episode of major depression (MDD) or depressive symptoms. Also, late-onset MDD with onset after age 60 is known to be associated with cognitive impairment, commonly identified as “pseudodementia,” which frequently leads to the later development of AD.^17,18

The identification of the ε-4 isoform of apolipoprotein E (APOE) as a risk factor for AD has intensified the search for genetic risk factors that are predisposing for other late-onset neuropsychiatric disorders.^4,19 There have been conflicting reports about the role of APOE status in depression.^20–23 Zubenko et al.²⁴ reported an association between APOE-ε4 and late-onset depression with psychotic features. On the other hand, a recent report did not find any relationships between APOE-ε4 and depression in late life.²² We found an association of the APOE-ε4 status with earlier age at depression onset, along with a greater number of depressive episodes, chronic course of depression, and increase in white-matter hyperintensities (WMH) size on MRI in a longitudinal follow up study of elderly patients with major depression.²⁵

Small and colleagues²⁶ reported an association between depressive symptoms and memory self-appraisal in APOE-ε4 non-carriers in a cross-sectional study. In this report, we examined the relationship between depressive symptoms, the APOE-ε4 allele, and cognitive decline on objective neuropsychological tests in middle-aged and older persons without dementia in a 2-year follow up. We hypothesized that both depression and the APOE-ε4 carrier status would be associated with a greater rate of decline.

METHODS

The methods have been described previously.^14,27 In brief, the 49 subjects (32 women, 17 men; 46 Caucasian; mean age, 66.5 years [standard deviation {SD}: 9.4]; age range: 51–85 years; education: 15.3 years [SD: 2.5]) included 20 with APOE-ε4 and 29 without APOE-ε4. All subjects were reassessed approximately 2 years later (mean: 26.2 months). Because our previous work has focused on early detection strategies in AD, and because the odds of AD are increased among APOE-ε4 carriers as early as the fifth decade of life, we included adults as young as 55 years of age.^14,26–28 Recruitment through advertisements and physician referral emphasized middle-aged and older people with memory complaints and family histories of dementia. Any subjects with a neurological, medical, or psychiatric condition that could affect memory or other cognitive processing were excluded. Subjects with major depression at baseline were excluded. The study participants had only mild depressive symptoms identified by the Hamilton Rating Scale for Depression (Ham-D;²⁹ the mean Ham-D score was 4.5 [SD = 4.3]). The neuropsychological assessment at baseline and follow-up at 26.2 (SD: 4.4) months determined the pattern of cognitive decline.

We report on a convenience sample, based on the availability of the follow-up neuropsychological data, which was drawn from a larger longitudinal study of mild age-related memory loss designed to determine neuropsychological, neuroimaging, and genetic predictors of subsequent cognitive decline.^14,28 As reported previously,^27,28 standardized laboratory screening tests for a dementia evaluation and magnetic resonance imaging (MRI) scans were performed to uncover potentially treatable causes of mental impairment.¹ In order to eliminate people with conditions that could reduce memory performance, those with neurological and medical disorders or major depressive disorder were excluded from participation. A family history of subjects’ relatives was obtained and corroborated by medical records. A positive family history was defined as one or more first-degree relatives (parent, sibling) with documented AD. Volunteers with ambiguous family histories were excluded. A negative family history was defined as no first- or second-degree relative with a history of dementia. Of the 306 volunteers, 267 were excluded because of illnesses or medications that could influence memory (N = 141), age younger than 50 years (N = 75), unclear or ambiguous family history (N = 26), or other reasons (N = 15). An attrition analysis was conducted to determine whether the 49 subjects who completed the follow-up study differed from those who did not complete the study on demographic variables or the cognitive battery. The results of the attrition analysis indicated that study completers and dropouts did not significantly differ in age, education, APOE genotype ratio, gender ratio, depression severity, or on the cognitive test battery.

A neuropsychological test battery was administered to quantify cognitive performance. For the present study, we selected neuropsychological tests that are widely used in research on normal aging and that also have demonstrated sensitivity to the types of cognitive changes associated with early AD. Tests included measures of verbal memory (Buschke-Fuld Selective Reminding, Total Score [BFR]),³⁰ nonverbal memory (Rey-Osterrieth Complex Figure, Delayed Recall [Rey delayed]),³¹ visuospatial functioning (Rey-Osterrieth Complex Figure, Copy [Rey copy]),³¹ verbal fluency (C.F.L. test),³² and naming (Boston Naming Test [BNT]).³³

DNA was obtained from blood samples, and APOE genotypes were determined with the use of standard techniques, as previously described.² Investigators blind to the genetic findings performed all of the clinical procedures. Written informed consent was obtained in accordance with the procedures set by the UCLA Institutional Review Board.

We compared the demographic and clinical characteristics of the two genetic groups, APOE-ε4 carriers and non–APOE-ε4 carriers, at baseline and follow-up, using t-tests. Data regarding rates of previous history of depression, family history of dementia, and gender were compared with the use of chi-square tests. Analysis of covariance was used to examine the association of cognitive decline with the APOE-ε4 genetic factor and the baseline Ham-D scores. We also controlled for age, sex, and education. The significance level was set at p <0.05.

Because our patients had only mild depressive symptoms, and those with major depression were excluded, we also explored the correlation between the Ham-D and the Geriatric Depression Rating Scale (GDS),³⁴ a self-administered test, available for 30 subjects, in order to confirm the consistency of the Ham-D-detected depressive symptoms.

RESULTS

Only one subject met the criteria for dementia at follow-up. However, the results of our analyses did not change after we re-analyzed the data without this subject. The groups did not differ on demographic variables (Table 1), or the time to follow-up (t_[47] = −0.2; p=0.8). The APOE-ε4 carriers were more depressed at baseline than the non-carriers (Table 2). Only 10 subjects in our sample had Ham-D scores of 7 or greater (six APOE-ε4 carriers and four non-carriers). None of the subjects met criteria for any depressive disorders at the time of their assessment. Only eight subjects (three APOE-ε4 carriers and five non-carriers) had previous history of depression, and controlling for this did not change our results. The groups did not differ in cognitive performance at baseline, with the exception of the Boston Naming Test, on which the APOE-ε4 carriers had lower scores than the non-carriers (Table 2). Both groups demonstrated some cognitive decline over time, but the rate of decline in various cognitive domains was somewhat different (Table 3). The APOE-ε4 carriers had a statistically significant decline on the tests of verbal memory (BFR) and visuospatial skills (Rey copy), whereas the non-APOE-ε4 group showed a decline on the tests of visuospatial skills and visual memory (Rey copy and Rey delayed), as well as naming (BNT; Table 3). The rate of cognitive decline was greater in the APOE-ε4 carriers only on the test of verbal memory (Buschke-Fuld mean change scores of 14.4 versus 4.2; t_[47] = 2.3; p<0.05).

TABLE 1.

Demographic characteristics at baseline

	APOE ε4 Carriers (N=20)	Non-APOE ε4 Carriers (N=29)	t [df]	p (t)
Age, years	66.2 (9.9)	66.8 (9.2)	0.2[47]	0.8
Education, years	15.2 (2.5)	15.3 (2.5)	0.2[47]	0.8
			χ2	p (χ2)
Female gender, N (%)	15 (75%)	17 (58.6%)	1.4	0.2
Family history, N (%)	14 (70%)	16 (55.2%)	1.1	0.8
HRT status (N=22), N (%)	5 (41.7%)	6 (60%)	0.7	0.4

Note: Values are mean (standard deviation), unless otherwise indicated.

HRT: Hormone-replacement (estrogen) status.

TABLE 2.

Clinical characteristics at baseline

	APOE ε4 Carriers (N=20)	Non-APOE ε4 Carriers (N=29)	t[df]	p
Ham-D	6.3 (5.5)	3.3 (2.7)	−2.2[25.2]	0.04*
BFR	97.9 (18.7)	103.9 (18.3)	1.1[47]	0.27
Rey copy	34.7 (2.1)	34.4 (2.1)	−0.5[47]	0.6
Rey delayed recall	18.9 (6.9)	19.8 (7.3)	0.4[47]	0.7
CFL	46.3 (13.9)	46.2 (11.8)	−0.002[47]	0.9
Boston Naming Test	55 (4.7)	57.6 (2.2)	2.4[25.2]	0.03*

Note: Values are mean (standard deviation), unless otherwise indicated.

Ham-D: Hamilton Rating Scale for Depression;²⁹ BFR: Buschke-Fuld Selective Reminding, Total Score, a measure of verbal memory;³⁰ Rey copy: Rey-Osterrieth Complex Figure, Copy, a measure of visuospatial functioning;³¹ Rey delayed: Rey-Osterrieth Complex Figure, Delayed Recall,³¹ a measure of nonverbal memory; CFL: test of verbal fluency;³² BNT: Boston Naming Test, a measure of naming.³³

^*p<0.05.

TABLE 3.

Cognitive decline (change scores) within and between the two groups

	APOE ε4 Carriers (N=20)	APOE ε4 Within-Group (t[df]; p)	Non-APOE ε4 Carriers (N=29)	Non-APOE ε4 Within-Group (t[df]; p)	Between-Group (t[df]; p)
BFR	−14.4 (18.9)**	−3.4[19]; 0.003	−4.2 (12.5)	−1.8[28]; 0.08	2.1[47]; 0.03*
Rey copy	−1.9 (4.9)**	−3.3[19]; 0.004	−2.9 (5.1)**	−3.6[28]; 0.001	−0.7[47]; 0.5
Rey delayed recall	−2.2 (3.1)	−1.7[19]; 0.1	−2.4 (3.6)**	−3.1[28]; 0.005	−0.16[47]; 0.9
CFL	1.3 (9.4)	0.6[19]; 0.5	2.0 (8.1)	1.3[28]; 0.18	0.29[47]; 0.8
BNT	−2.2 (8.3)	−1.2[19]; 0.2	−0.7 (1.5)*	−2.3[28]; 0.03	0.8[19.9]; 0.4

Note: Values are mean (standard deviation), unless otherwise indicated.

BFR: Buschke-Fuld Selective Reminding, Total Score, a measure of verbal memory;³⁰ Rey copy: Rey-Osterrieth Complex Figure, Copy, a measure of visuospatial functioning;³¹ Rey delayed: Rey-Osterrieth Complex Figure, Delayed Recall,³¹ a measure of nonverbal memory; CFL: test of verbal fluency;³² BNT: Boston Naming Test, a measure of naming.³³

^*p<0.05 within-or between-group comparisons in the test change scores;

^**p<0.01 within-or between-group comparisons in the test change scores.

The APOE-ε4 carriers reported more depressive symptoms at baseline than the non-carriers (mean Ham-D score of 6.3 [SD = 5.5] versus 3.3 [SD = 2.7]; t_[47] = −2.5; p<0.02). Only 30 subjects responded to the GDS. The APOE-ε4 carriers reported more depressive symptoms at baseline than the non-carriers, although the difference was not statistically significant (mean GDS score of 6.8 [SD: 7.7] in carriers versus 4.2 [SD = 3.7] in non-carriers; t_[28] = −1.1; p = 0.3). The correlation coefficient between Ham-D and GDS was moderately high, 0.63 (p = 0.0002), which suggests that both instruments measured the severity of depressive symptoms in a similar fashion. The severity of depressive symptoms lessened at follow-up in the absence of specific treatment and was not different between the groups. In the analysis of covariance, after controlling for age and education, APOE-ε4 status was a significant predictor of decline in verbal memory (F_[1,43] = 3.7; p = 0.05). The severity of baseline depressive symptoms, however, was not predictive of future cognitive decline (F_[1,43] = 0.19; p = 0.66), and neither was the interaction between depressive symptoms and the APOE-ε4 status (F_[1,43] = 0.53; p = 0.47).

DISCUSSION

Although there have been reports addressing the relationship between depression, APOE genotype, and subjective memory impairment^26,35 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.