Association Between Elevated Depressive Symptoms and Cognitive Function Moderated by APOE4 Status: Framingham Offspring Study

Abstract

Background:

Depression and Apolipoprotein E4 (APOE4) are associated with decreased cognitive function and differences in brain structure.

Objective:

This study investigated whether APOE4 status moderates the association between elevated depressive symptoms, cognitive function, and brain structure.

Methods:

Stroke- and dementia-free participants (n = 1,968) underwent neuropsychological evaluation, brain MRI, and depression screening. Linear and logistic regression was used to examine all associations. Secondary analyses were performed using interaction terms to assess effect modification by APOE4 status.

Results:

Elevated depressive symptoms were associated with lower cognitive performance in several domains. In stratified analyses, elevated depressive symptoms were associated with poorer visual short- and long-term memory performance for APOE4 + participants. Elevated depressive symptoms were not associated with any brain structure in this study sample.

Conclusion:

Elevated depressive symptoms impact cognitive function in non-demented individuals. Having the APOE4 allele may exacerbate the deleterious effects of elevated depressive symptoms on visual memory performance. Screening for elevated depressive symptoms in both research studies and clinical practice may be warranted to avoid false positive identification of neurodegeneration, particularly among those who are APOE4 +.

INTRODUCTION

Community-based cohort studies have reported that depressed participants have more than a 50% increased risk of developing dementia [1]. Furthermore, they have indicated that earlier-life depression is associated with a twofold increase in dementia risk [1], and late-life depression increases risk for Alzheimer’s disease (AD) and vascular dementia [2]. Depression has been similarly related to cognition [3-12] and in nondemented depressed individuals, dysfunction in domains of processing speed [3], attention [4, 9-11], executive function [7, 8, 10, 12], verbal fluency [11], working memory [5, 11], and verbal and non-verbal short-term and long-term memory [6, 10-12] have been observed.

Depression is also associated with differences in brain structure, including reduced whole brain volume [13, 14], reduced frontal lobe volume [13, 15-17], and reduced temporal lobe volume [13]; however, several studies have found no association between depression and these brain regions [15, 17-20]. One meta-analysis found that hippocampal volume is reduced in patients with depression [21]. Furthermore, elderly depressed patients were found to have significantly smaller right hippocampal volume compared to controls [22]. However, a separate study found no differences between depressed and non-depressed participants in terms of hippocampal volume [6]. Late-life-onset major depression has also been associated with increased severity of periventricular hyperintensities and deep white-matter hyperintensities compared to age-matched participants with early-life-onset major depression [12]. Depressive symptoms have also been found to be associated with large cortical white-matter lesions and severe subcortical white-matter grade [23]. In a longitudinal, population-based cohort study, baseline white matter hyperintensities were positively associated with change in depression scores [24]. Furthermore, those with extensive white matter hyperintensities at baseline were shown to have high risk of developing severe depressive symptoms. While these findings suggest an association between depression and the development of white-matter hyperintensities (which have been linked to cognitive impairment and dementia [25]), a separate community-based population study found that white matter severity was not associated with depressive symptoms [26].

Apolipoprotein E4 (APOE4) is a well-documented genetic factor that increases risk for AD and accelerated cognitive decline [27] and is associated with lower cognitive function [28] and smaller brain volumes [29-34] in healthy individuals. The mixed findings of depression related to brain structure, along with the more consistent findings related to cognition and relationship of APOE4 to both brain aging indices raises the question of whether APOE4 status may moderate the association between elevated depressive symptoms, cognitive function, and brain structure in a non-demented community-based sample. While several studies have investigated depressive symptoms, APOE4 status, and cognition [35-37], no study to date has stratified analyses relating elevated depressive symptoms to specific domains of cognitive performance by APOE4 status.

MATERIALS AND METHODS

Study sample

The Framingham Heart Study (FHS) is a community-based study that began with prospective examination of the original cohort, recruited initially in 1948. The offspring cohort was recruited in 1971 and comprises people who had at least one parent who was a member of the original Framingham Study cohort and a subset of the offspring spouses [38].

The present study includes participants from the offspring cohort, which underwent periodic physical and medical examinations on average every 4 years. The initial offspring cohort consisted of 5,124 men and women; 88% of survivors (3,539/4,031) participated in examination 7 in 1998–2001. During examination 7, participants were screened for depressive symptoms using the Center for Epidemiologic Studies Depression Scale (CES-D) [39]. As part of a large ancillary study, offspring participants were invited to undergo neuropsychological (NP) assessment and volumetric brain magnetic resonance imaging (MRI) between 1999–2005. To be considered for the current study, participants had to be dementia- and stroke- free at the time of CES-D and NP/MRI assessment, and NP/MRI had to occur within 1 year before and 4 years after the CES-D. The dementia and stroke diagnostic procedures have been previously described [40].

The Boston University Institutional Review Board approved the study protocol, and all participants provided written informed consent.

Depressive symptoms assessment

Depressive symptoms were evaluated using the CES-D, a 20-item scale consisting of 4 factors: depressive affect, somatic complaints, positive affect, and interpersonal relations. Scores on the CES-D range from 0 to 60, with higher scores reflecting greater depressive symptoms. Based on the CES-D guidelines, a score of ≥ 16 was used to indicate elevated depressive symptoms [39]. Antidepressant medication use was self-reported at examination 7 as well. For the analyses of the current study, ‘elevated depressive symptoms’ was used as a dichotomous variable (yes, no). ‘Elevated depressive symptoms’ was defined as a score of ≥ 16 on CES-D, and/or current antidepressant use, including selective serotonin reuptake inhibitors, tricyclic antidepressants, trazodone, venlafaxine, bupropion, and mitazapine.

Neuropsychological assessment

Neuropsychological tests were administered using standardized testing protocols, details of which have been described previously [41]. The battery was composed of tests measuring performance across major cognitive domains. The tests included the original Wechsler Memory Scale Logical Memory Immediate and Delayed Recall (Story A only) [42], which tests verbal short-term and long-term memory, respectively; the original Wechsler Memory Scale Visual Reproduction Immediate and Delayed Recall [42], which tests visual short-term and long-term memory, respectively; Hooper Visual Organization Test, which tests visuospatial function; Trail Making Test A and B which test attention and executive function, respectively; and the original Wechsler Adult Intelligence Scale Similarities [43], which tests abstract reasoning ability. Raw values for the cognitive measures were used in the analyses. The Hooper Visual Organization Test, Trail Making Test A and B, and Similarities were natural log transformed to normalize their skewed distributions. For consistency in interpreting direction of results, Trail Making Test A and B values were resigned such that higher scores reflect better performance.

MRI acquisition parameters

The MRI scans were done within 6 months of the cognitive testing with 1,917 (97.41%) occurring on the same day. The imaging parameters, measurement protocols, and reproducibility of these measures have been described previously [44]. All analyses were performed using QUANTA 6.2, a custom-designed image analysis package, operating on an Ultra 5 workstation (Sun Microsystems, Santa Clara, CA). MRI volumetric measures included total cerebral brain volume, frontal lobe volume, temporal lobe volume, hippocampal volume, left hippocampal brain volume, right hippocampal brain volume, and white matter hyperintensity volume (WMHV). All brain volumes except WMHV were expressed as a percentage of total cerebrum cranial volume to correct for differences in head size. WMHV was also examined as a dichotomous variable (extensive versus no). For segmentation of WMHV from other brain tissues, the first and second echo images from T2 sequences were summed and a log-normal distribution was fitted to the summed data. A segmentation threshold for WMHV was determined as one SDs in pixel intensity greater than the mean of the fitted distribution of brain parenchyma. Extensive WMHV was defined as one SD above age-group means.

Ascertainment of APOE status

The presence of particular alleles of APOE genotype was determined by means of isoelectric focusing of the plasma and confirmed by DNA genotyping [45, 46]. Participants were grouped by APOE4 status: positive (3/4 or 4/4 genotype) or negative (2/2, 2/3, or 3/3 genotype). Participants with 2/4 genotype were excluded (N = 45) as APOE2 is a potential protective AD genetic factor [47].

Covariates

Covariates were collected at the time of the seventh examination and included age, sex, diabetes mellitus (non-fasting blood glucose ≥ 200 mg/dL or fasting blood glucose ≥ 126 mg/dL or use of oral hypoglycemic or insulin), current cigarette smoking status, alcohol use (self-report yes/no), history of cardiovascular disease (coronary heart disease, angina, coronary insufficiency, myocardial infarction, heart failure, and intermittent claudication) and Stage I hypertension (systolic blood pressure ≥ 140 mmHg or diastolic blood pressure ≥ 90 mmHg or on anti-hypertensive treatment). Inclusion of cardiovascular risk factors as covariates is warranted given research evidence of their association with cognitive decline [48-58] and brain volume [50,52,59, 60]. Education was collected at the time of the cognitive testing and divided into three level categories: high school degree or less, some college, and college degree or greater.

Statistical analysis

Linear and logistic regression was used to examine the association between elevated depressive symptoms, cognitive function, and brain structure. Model 1 analyses were adjusted for age, sex, education, and time between CES-D and NP/MRI evaluation. Model 2 analyses were additionally adjusted for cardiovascular risk factors (hypertension, history of diabetes, current smoking, any alcohol use, and history of cardiovascular disease) and APOE4 status. Logistic regression was used for the categorical outcome of extensive WMHV.

Secondary analyses were performed using interaction terms to assess effect modification by APOE4 status. Two-sided significance was set at p < 0.10 for analyses assessing effect modification (to enhance sensitivity), and at p < 0.01 for all other analyses (to counteract the problem of multiple comparisons). Prior FHS research has used p < 0.10 for analyses assessing effect modification [51]. All data were analyzed using SAS version 9.4 (SAS Institute Inc., Cary, NC).

RESULTS

Table 1 lists the characteristics of participants in the study sample (N= 1,962; mean age = 60.98 ± 9.35; age range = 34–88; 53.82% female; 40.01% college graduate) by depressive symptom status. At the time of CES-D, 292 participants (14.88%) had elevated depressive symptoms. Compared with those without elevated depressive symptoms, participants with elevated depressive symptoms were younger, more likely to be women, more likely to smoke cigarettes, and less likely to use alcohol. Participants with elevated depressive symptoms did not have significantly different APOE4 genotypes compared to participants without elevated depressive symptoms.

Table 1.

Study sample characteristics for Framingham Heart Study Offspring Cohort participants at Exam 7 (N = 1,962)

	Elevated Depressive Symptoms (CES-D≥ 16, or antidepressant use)
	No (N = 1,670)	Yes (N = 292)	p
Continuous characteristics [mean (SD)]
Age (y)	61.22 (9.32)	59.55 (9.34)	0.005
Range	36–86	34–88
Years between Exam 7 and NP/MRI	0.72 (0.66)	0.71 (0.65)	0.850
Range	0–4	0–3.6
Categorical characteristics [n (%)]
Women	849 (50.84)	207 (70.89)	<0.001
Education level
High school graduate or less	563 (33.71)	108 (36.99)	0.249
Some college	426 (25.51)	80 (27.40)
College graduate	681 (40.78)	104 (35.62)
History of diabetes	163 (9.89)	27 (9.64)	0.897
Current smoker	188 (11.26)	57 (19.52)	< 0.001
Alcohol use	1084 (64.91)	159 (54.45)	< 0.001
History of cardiovascular disease	163 (9.76)	30 (10.27)	0.785
Hypertension	686 (41.10)	129 (44.18)	0.325
APOE4+	345 (20.66)	61 (20.89)	0.928
CES-D	3.53 (3.60)	14.85 (10.47)	< 0.001
Range	0–15	0–52
Logical Memory Immediate Recall	11.52 (3.27)	11.52 (3.74)	0.980
Range	1–22	1–21
Logical Memory Delayed Recall	10.50 (3.50)	10.75 (3.97)	0.328
Range	0–22	0–21
Visual Reproduction Immediate Recall	9.23 (3.13)	8.60 (3.27)	0.002
Range	0–14	1–14
Visual Reproduction Delayed Recall	8.33 (3.32)	7.80 (3.51)	0.016
Range	0–14	0–14
Hooper Visual Organization Test	25.22 (2.94)	24.76 (3.34)	0.030
Range	3–30	13.50–30
Trail Making Test A (s)	32.00 (12.47)	33.97 (16.81)	0.057
Range	12–137	14–213
Trail Making Test B (s)	81.92 (55.35)	92.01 (75.36)	0.030
Range	24–600	28–600
Similarities	16.85 (3.52)	16.58 (3.58)	0.236
Range	3–25	3–24
Total cerebral brain volume (cm3)	1240.19 (123.28)	1216.96 (120.18)	0.002
Range	884.82–1708.87	943.87–1563.46
Frontal lobe brain volume (cm3)	345.46 (38.99)	340.89 (37.76)	0.060
Range	243.70-473.25	248.03–451.86
Temporal lobe brain volume (cm3)	199.45 (22.21)	195.24 (21.87)	0.002
Range	139.13–282.37	146.13–250.59
Hippocampal brain volume (cm3)	6.68 (0.72)	6.55 (0.72)	0.008
Range	3.63–9.20	4.70–8.52
White matter hyperintensity volume (cm3)	1.24 (2.79)	1.10 (1.92)	0.297
Range	0.01–43.99	0.04–17.60

Table 2 summarizes the linear regression results for the association between elevated depressive symptoms and cognitive performance. After adjustment for cardiovascular risk factors and APOE4 status (Model 2), elevated depressive symptoms remained associated with poorer performance on Visual Reproduction Immediate Recall (R² = 0.199), Visual Reproduction Delayed Recall (R² = 0.203), Hooper Visual Organization Test (R² = 0.157), Trail Making Test A (R² = 0.182), and Trail Making Test B (R² = 0.237).

Table 2.

Association between elevated depressive symptoms and cognitive performance

Cognitive measure	Model 1*			Model 2**			p for interaction term between APOE4 status and elevated depressive symptoms
	B	SE	p	B	SE	p
Logical MemoryImmediate Recall	0.189	0.202	0.350	0.208	0.207	0.314	0.876
Logical MemoryDelayed Recall	−0.016	0.214	0.937	−0.012	0.220	0.954	0.950
Visual Reproduction Immediate Recall	−0.064	0.017	< 0.001	−0.062	0.017	< 0.001	0.048
Visual Reproduction Delayed Recall	−0.049	0.016	0.002	−0.045	0.016	0.007	0.068
Hooper Visual Organization Test‡	−0.101	0.030	< 0.001	−0.098	0.031	0.001	0.453
Trail Making Test A‡	−0.033	0.008	< 0.001	−0.030	0.008	< 0.001	0.134
Trail Making Test B‡	−0.046	0.010	< 0.001	−0.038	0.011	< 0.001	0.227
Similarities‡	−0.037	0.024	0.127	−0.029	0.025	0.237	0.382

^*Adjusted for age, sex, education, and time between CES-D and NP evaluation.

^**Additional adjustments for hypertension, history of diabetes, current smoking, any alcohol use, history of cardiovascular disease, and APOE4 status.

^‡Measure natural log transformed. Two-sided significance set at p < 0.10 for analyses assessing effect modification, and at p < 0.01 for all other analyses.

Visual Reproduction Immediate Recall and Visual Reproduction Delayed Recall demonstrated a significant interaction term between APOE4 status and elevated depressive symptoms (p = 0.048 and 0.068, respectively). Table 3 summarizes the association between elevated depressive symptoms and cognitive performance stratified by APOE4 status. After adjustment for covariates, elevated depressive symptoms were associated with poorer Visual Reproduction Immediate Recall (R² = 0.214) and Visual Reproduction Delayed Recall (R² = 0.237) for APOE4 + participants (see Fig. 1 for graphical representation of Table 3 findings).

Table 3.

Association between elevated depressive symptoms and cognitive performance by APOE4 status

	APOE4+*			APOE4−*
Cognitive measure	B	SE	p	B	SE	p
Visual Reproduction Immediate Recall	−0.11	0.03	< 0.01	−0.04	0.01	0.02
Visual Reproduction Delayed Recall	−0.09	0.03	0.01	−0.03	0.01	0.10

^*Adjusted for age, sex, education, time between CES-D and NP evaluation, hypertension, history of diabetes, current smoking, any alcohol use, and history of cardiovascular disease. Two-sided significance set at p <0.01.

Fig. 1.

Graphical representation of Table 3 findings. Forest plot of the association between elevated depressive symptoms and cognitive performance stratified by APOE4 status, adjusted for age, sex, education, time between CES-D and NP evaluation, hypertension, history of diabetes, current smoking, any alcohol use, and history of cardiovascular disease. Two-sided significance set at p < 0.01.

Table 4 summarizes the linear regression results for the association between elevated depressive symptoms and brain volume. In Model 1 and 2, elevated depressive symptoms were not associated with any brain structure. Elevated depressive symptoms were also not associated with extensive WMHV. Furthermore, no significant APOE4 interaction was observed.

Table 4.

Association between elevated depressive symptoms and brain volume

MRI outcome measure	Model 1*			Model 2**			p for interaction term between APOE4 status and elevated depressive symptoms
	B	SE	p	B	SE	p
Total cerebral brain volume	−5.836	6.194	0.346	−5.050	6.315	0.424	0.322
Frontal lobe brain volumea	< 0.001	< 0.001	0.818	< 0.001	< 0.001	0.852	0.472
Temporal lobe brain volumea	0.001	< 0.001	0.027	< 0.001	< 0.001	0.112	0.827
Hippocampal brain volumea	< 0.001	< 0.001	0.142	< 0.001	< 0.001	0.249	0.509
Left hippocampal brain volumea	< 0.001	< 0.001	0.092	< 0.001	< 0.001	0.161	0.237
Right hippocampal brain volumea	< 0.001	< 0.001	0.279	< 0.001	< 0.001	0.445	0.944
White matter hyperintensity volume	0.004	0.166	0.978	0.086	0.168	0.605	0.805
	Model 1*			Model 2**
	C-statistic	OR (95% CI)	p	C-statistic	OR (95% CI)	p
Extensive white matter hyperintensity volume (yes versus no)	0.593	1.310 (0.823–2.083)	0.254	0.635	1.137 (0.700–1.846)	0.603

^aExpressed as a percentage of total cerebrum cranial volume.

^*Adjusted for age, sex, education, and time between CES-D and MRI.

^**Additional adjustments for hypertension, history of diabetes, current smoking, any alcohol use, history of cardiovascular disease, and APOE4 status. Two-sided significance set at p < 0.01.

Of note, analyses were rerun excluding participants who endorsed current antidepressant use and this did not change the findings.

DISCUSSION

Consistent with previous research [4, 7-12], elevated depressive symptoms were associated with poorer performance on visual short- and long-term memory, attention, aspects of executive function, and visuospatial ability. Although we found elevated depressive symptoms to be associated with lower scores on tests of visual short- and long-term memory, we did not find a significant association between elevated depressive symptoms and verbal short- and long-term memory. Taken together, our results suggest that elevated depressive symptoms may affect frontal, temporal, and parietal mediated tasks.

Several studies have demonstrated a relationship between depression and verbal memory performance [10, 12], but in our study we did not find such an association. One possible explanation for our results might be our use of a story recall measure (Logical Memory) to assess verbal memory as opposed to list learning (California Verbal Learning Test, Rey Auditory Verbal Learning Test, Paired-Associates Learning) measures used in other studies [10, 12]. Because stimuli with emotional content may be easier to recall than stimuli without emotional content [61], it is possible that individuals with elevated depressive symptoms may be able to attend to stimuli with emotional content (Logical Memory) better than that with no emotional content (California Verbal Learning Test, Rey Auditory Verbal Learning Test, Paired-Associates Learning), leading to no observed difference in verbal memory performance. Moreover, there is evidence that list learning and visual memory tasks may be inherently more difficult than story memory tasks due to executive function demands [62, 63]. Our finding of an association between elevated depressive symptoms and poorer performance on aspects of executive function may explain why we observed an association between elevated depressive symptoms and visual memory performance (Visual Reproductions), but not verbal memory performance (Logical Memory).

Stratified analyses indicated this relationship was specific to poorer visual short- and long-term memory performance for APOE4 + participants. To our knowledge, our study is the first to stratify analyses relating elevated depressive symptoms to specific domains of cognitive performance by APOE4 status. Prior research has investigated depressive symptoms, APOE4 status, and cognition; however, these studies either did not conduct a moderation analysis [35] or used a measure of global cognitive functioning to assess cognition [36, 37]. Our results suggest that having the APOE4 allele may exacerbate the deleterious effects of elevated depressive symptoms on visual memory performance. These results suggest that research studies and clinicians may need to screen for elevated depressive symptoms in order to minimize potential misclassification of cognitive impairment, especially among those who are APOE4 +. Indeed, individuals meeting criteria for mild cognitive impairment perform worse on visual working memory and episodic memory tests compared to verbal working memory and episodic memory tests [64, 65].

Given that APOE4 is a well-documented genetic risk factor for AD [27], and early AD is associated with deficits in delayed recall and learning ability [66], it is possible that nondemented, stroke-free participants with APOE4 may experience subtle cognitive deficits in delayed recall and learning ability and that these deficits are magnified if the individual has elevated depressive symptoms, particularly in the domain of visual short- and long-term memory. This may explain why other cognitive domains that were associated with elevated depressive symptoms (i.e., attention, aspects of executive function, visuospatial ability) did not demonstrate a significant interaction term between APOE4 status and elevated depressive symptoms.

We did not find any association between elevated depressive symptoms and various brain regions. While a couple studies linked depression to differences in hippocampal volume [21, 22], another found no differences [6] (similar to our results) and a meta-analysis concluded this association as inconsistent [21]. Similarly, the literature relating depression to whole brain volume [13, 14], frontal lobe volume [13, 15-17], and temporal lobe volume [13] has produced heterogeneous and often conflicting results. WMHV, however, was associated with depression in other studies [12, 23, 24]. There are several possible explanations for our null results. Many studies that found a significant association between depression and brain structure/WMHV used age-matched healthy control study designs [13-16, 21, 22], as opposed to a healthy community-based sample. The use of control subjects in research introduces varying magnitudes of bias [67]. Further, many studies, including our own, used a cross-sectional design [13-16, 21-23]. Future research should investigate the association between elevated depressive symptoms and brain structure longitudinally, and whether APOE4 status moderates this association. Longitudinal examination would also allow for assessment of elevated depressive symptoms at varying time-points. There is evidence that lifetime depression is associated with structural brain volume changes [68]. Future research should also consider other clinical factors that have been associated with structural brain volume changes, including depressive symptom severity [69], illness duration [70], age of onset of depression [71], and number of episodes of depression [70, 71].

The strengths of our study are its community-based design and use of volumetric MRI measures. We were also able to adjust for several cardiovascular risk factors, which have been associated with risk of developing AD [72, 73], cognitive decline [48-58], as well as differences in brain volume [50, 52, 59, 60]. In our non-stratified analyses, we also adjusted for APOE4 status, which has been linked to sporadic late-onset AD [74], cognitive decline [75], as well as smaller brain volumes, greater brain atrophy, and increased white matter hyperintensities [76]. Taken together, our study was able to consider confounding factors that could not be accounted for comprehensively in other community-based and clinical studies.

There are, however, several limitations. The study participants were predominantly of European ancestry and most had at least some college education. Hence, these results cannot be generalized for a population with different demographics. Also, it is possible that our use of a non-clinical sample with a wide age range resulted in significant findings being washed out, as a recent meta-analysis found a stronger relationship between depression and executive dysfunction in those with clinical (as opposed to subclinical) depression and in samples with an older mean age [77]. Depressive symptoms were assessed via the CES-D, a self-report measure, and not through formal psychiatric assessment and documentation by a mental health professional. Furthermore, since we examined depressive symptom status at one time point, we were unable to account for the duration of elevated depressive symptoms and did not have information regarding adherence of antidepressant medication. We cannot exclude misclassification of depressive symptom status, as symptoms of depression are commonly underreported [78]. Moreover, because of our inclusion window (NP/MRI had to occur within 1 year before and 4 years after CES-D), we cannot rule out the inclusion of individuals who had elevated depressive symptoms at time of CES-D but not at time of NP/MRI. While we were able to control for a number of potentially confounding factors, we were not able to control for sleep patterns and physical activity, both of which have been linked to depression [79,80] and cognitive function [81,82]. We were also unable to consider performance validity/effort [83] and anxiety [84], two factors which could have influenced our findings. Furthermore, it is possible that in our elevated depressive symptoms sample we included individuals with insomnia and anxiety, as antidepressant medication is commonly prescribed to treat these conditions [85, 86]. Lastly, with an observational cohort-based study design, we cannot exclude residual confounding and we cannot infer causality from our results.

In summary, our study suggests that having elevated depressive symptoms may impact cognitive function in non-demented individuals and having the APOE4 allele may exacerbate the deleterious effects of elevated depressive symptoms on visual memory performance. Screening for elevated depressive symptoms in both research studies and clinical practice may be warranted to avoid false positive evidence of cognitive impairment, particularly among those who are APOE4 +.