Age exacerbates the negative effect of depression on executive functioning in racial and ethnic minorities

Age and depression may interact to produce a “double jeopardy” for cognitive impairment, and executive functioning, in cognitively unimpaired aging. Few studies have considered middle age or the ethnoracial diversity of subjects, despite evidence of more severe cognitive outcomes in historically minoritized people. In this pilot study, we investigated the impact of age on depression-related cognitive impairment and the underlying brain volumes in middle-aged non-Hispanic White adults (116), and Hispanic and Black adults (60), with a total number of 176 adults. The result shows a significant interaction between age and depression for executive functioning, specifically for middle-aged Hispanic and Black adults, but not non-Hispanic White adults. Prefrontal cortex volumes, which were reduced in the Black and Hispanic compared to the non-Hispanic White adults, partially mediated the relationship between depression level and executive functioning, across age and ethnoracial group. Collectively, these results suggest that the negative impact of depression on executive functioning and Prefrontal cortex volumes integrity may be exacerbated by age and that historically minoritized people may be particularly sensitive to this double jeopardy.


Introduction
Major depressive disorder (MDD) is highly prevalent across an adult's lifetime with a risk rate of 15-18% (Malhi & Mann, 2018).Evidence shows a increase rate of MDD from adolescence with relative stability through middle age (Goodwin et al., 2022).Adults over the age of 55 are less likely to experience MDD than younger individuals but are more likely to experience sub-threshold depressive symptoms (Biella et al., 2019).Both MDD and sub-threshold depressive symptoms not only negatively impact quality of life, but also may contribute to impairments in cognitive functioning, perhaps most notably in executive functioning (Lam et al., 2014;Rock et al., 2014;Rutherford et al., 2023;Wu et al., 2019).Importantly, greater levels of depressive symptomology in older adults are associated with an increased risk of developing dementia (Morimoto et al., 2014).Thus, it is important to identify the mechanisms of depressionassociated cognitive impairment earlier in the adult lifespan for the future development of interventions that can delay or prevent cognitive decline.Neuroimaging studies are particularly important for elucidating neurobiological mechanisms that contribute to both mood and cognitive dysfunction that may serve as targets for future pharmacological and non-pharmacological interventions.
There are several reasons why age may exacerbate depression-related impairments in executive functioning.Both aging(e.g., Campbell et Zhang et al., 2018).Even sub-threshold depressive symptoms in middleaged and older adults are associated with smaller OFC and ACC volumes (Dotson et al., 2009a).Given the importance of these regions in executive functioning as shown in numerous fMRI and patient studies (Pizzagalli & Roberts, 2022), such reductions could contribute to the cognitive de cits observed in both depression and aging.Finally, as shown in a recent meta-analysis, depression-related executive dysfunction in both MDD and subthreshold depression is magni ed by age (Dotson et al., 2020).Collectively, these results suggest that higher levels of depression may move forward the point at which cognitive impairments characteristic of aging appear.
Few studies have assessed depression-related executive dysfunction in historically minoritized people despite evidence of racial and ethnic differences in depressive symptom prevalence.Black and Hispanic adults have a lower lifetime prevalence of diagnosed MDD but higher prevalence of sub-threshold depressive symptoms than Non-Hispanic Whites adults(Abrams & Mehta, 2019; Barnes & Bates, 2017).In both Hispanic and Black adults, symptoms may increase and be more severe in the mid-to-older adult age range when compared to non-Hispanic White adults in the same age range (Abrams & Mehta, 2019;Vyas et al., 2020), and episodes of depression tend to be more severe, persistent, and disabling (e.g., Breslau et al., 2006;Williams et al., 2007).Furthermore, depressive symptoms tend to be prolonged and associated with with more severe consequences in Black adults like higher levels of distress and higher rates of treatment drop-out (Bailey et al., 2019;Barnes & Bates, 2017).Few studies have examined depression-related cognitive impairments in these racially/ethnically minoritized groups but recent evidence shows that older (> 65) Hispanic adults with depression are more susceptible to cognitive impairment than older non-Hispanic White adults (Babulal et al., 2022).Given prior evidence that age may exacerbate depressionrelated cognitive impairments in samples consisting largely non-Hispanic White adults (Dotson et al., 2009a;James & Duarte, 2023), it is critical to understand whether such "double jeopardy" effects are also observed in historically racially/ethnically minoritized adults and the underlying neural mechanisms of these impairments.This pilot study aims to examine 1) the potential mediating role of PFC volumes in the relationship between depressive symptoms and executive functioning and; 2) the moderating in uence of age on these associations in historically minoritized, speci cally Black and Hispanic adults, and non-Hispanic White middle-aged adults.We predicted that individuals with greater levels of depressive symptoms would show lower executive functioning and smaller laterial, orbital, and/or ACC frontal volumes, with PFC volumes mediating associations between depression and executive functioning.Finally, we explored the possibility that depression-cognition associations differ between ethnoracial minorities and non-Hispanic White adults, with potentially stronger associations in racial/ethnic minority groups given some recent evidence (Babulal et al., 2022;Hokett et al., 2022).We tested the possibility that age would exacerbate these associations more for these historically minoritized groups than non-Hispanic White adults (i.e., "double jeopardy").

Participants
We enrolled 257 individuals between the ages of 40-61.This sample includes some of the adults whose data were published in a prior study (Foret et al., 2021).All participants self-reported that they were uent English speakers, with normal or corrected to normal vision, and right-handed.None of the participants reported a history of neurological disease or disorders, major psychiatric illness (i.e., Schizophrenia, bipolar disorder, MDD), history of substance abuse, or MRI contraindications.Of the 257 participants enrolled, we excluded 47 with missing MRI data, and 34 with missing education or incomplete cognitive and BDI scores.Of the remaining 176 participants, participants are self-identi ed as Non-Hispanic White adults (116), Hispanic or Black American adults(60).We collapsed across Hispanic and Black participants for the subsequent analyses to increase power.Demographic characteristics of each group are shown in Table 1.

Hierarchal regression analysis
Hierarchal regression analyses were performed using R studio.For all regression models, in step 1, we included sex, years of education, chronological age, and race as predictors (adding intracranial volume for models with brain volume outcomes).We added depression level, measured with the BDI, as a predictor in step 2. The interaction between age and BDI was added in step 3. Executive functioning scores, and each of the ROI volumes served as the outcome variables in separate models.

Mediation analysis
In order to explore potential mediators of the relationship between depression and cognitive abilities and/or brain volumes, we included bilateral PFC brain volumes for each ROI as a mediator of relationships, should they be observed, in RStudio (Fig. 2).We tested the total, direct and indirect in uence of PFC volumes.We used bootstrapping with 1000 simulations to generate a sampling distribution and test the statistical signi cance of the effects.

Results
Correlations between the study variables are shown in Table 2.As can be seen in the table, across subjects, depression severity scores were negatively correlated with LPFC and ACC volumes and executive functioning scores were positively correlated with LPFC, ACC, and OFC volumes.Note that a larger executive functioning score indicates slower reaction times and worse executive functioning.

Depression and executive functioning
The results of the hierarchical regression model with executive functioning score as the outcome are shown in Table 3.As can be seen in the table, higher depression scores, minoritized racial and ethnic status, and fewer years of education were signi cantly related to lower executive functional ability (larger RT) across groups.The 3-way interaction between depression, race and age was signi cant.To explore the source of the interactions including Race, we conducted regression analyses separately for non-Hispanic White and Black & Hispanic American groups.We found that higher depression scores were signi cantly associated with lower executive functioning (higher RT) in both groups (Non-Hispanic White: B = 0.027, F = 3.949, R 2 = 0.034, p = 0.049; Black & Hispanic: B = 0.062, F = 6.263,R 2 = 0.097, p = 0.015).The interaction between Depression and Age was signi cant in the Black and Hispanic American group (B = 0.016, F = 19.616,R 2 = 0.226, p < 0.001) but not the Non-Hispanic White group (B = 0.001, F = 0.306, R 2 = 0.0023, p = 0.581).As can be seen in Fig. 3

Mediation analysis
To explore the underlying mechanisms of the relationship between depression and executive functioning, we conducted mediation analyses to examine whether PFC brain volumes mediate this relationship, across race and age, in order to increase statistical power.As can be seen in Fig. 4, there were signi cant indirect effect between depression and executive functioning through each of the PFC volumes.Direct effects for each model remained signi cant, suggesting that PFC volumes were partial mediators of the relationship between depression and executive functioning.Indirect effects in the same mediations strati ed by racial group were not signi cant.

Discussion
Executive dysfunction is one of the primary cognitive impairments in MDD and depressive symptoms, even in the absence of diagnosed ).These and other psychosocial and health factors may directly or indirectly negatively impact cognition and neural integrity.It is possible, for example, that these or other factors contributed to the the smaller PFC volumes in the ethnoracial minority group compared to the non-Hispanic White adults in this study, which in turn contributed to depression-related executive dysfunction.It will be important to explore the extent to which these and other factors, especially modi able ones, explain racial and ethnic group differences in depression-related impairments.

Conclusion
This pilot study aims to examine the potential moderating in uence of age and mediating in uence of PFC volume on relationships between depressive symptoms and executive functioning in historically minoritized, namely Black and Hispanic adults, and non-Hispanic white middle-aged adults.We predicted that individuals with greater levels of depressive symptoms would show lower executive function scores and smaller PFC brain volumes and tested the novel hypotheses that age would exacerbate these associations particularly in the minoritized group.Our results were largely consistent with these predictions.We found that depression predicted worse executive functioning across groups, with age exacerbating this relationship exclusively in the Black and Hispanic adults group.PFC volumes, which were

Table 1
(Ashburner, 2010)994)2)tics of subjects.Group differences were evaluated with twosample t-tests.All subjects provided written informed consent approved by the U.T Austin Institutional Review Board.Subjects provided a self-reported medical history, the Beck Depression Index II (BDI-II)(Beck et al., 1996), and were given a battery of neuropsychological tests to assess executive functioning and other cognitive domains: Trail Making Test(Reitan & Reitan, 1992), California Verbal Learning Test II (CVLT-II)(Delis et al., 2000), Digit span, vocab and matrix subtests of the Wechsler Adult Intelligence Scale, 3rd edition (WAIS-III)(Wechsler, 1997), controlled oral word association test (COWAT) total score from multilingual aphasia examination (MAE)(Benton et al., 1994).The BDI-II has been validated for assessing depressive symptoms in the general population across the adult lifespan.Scores range from 0-63 with the following cutoffs: minimal depression 0-13, mild depression 14-19, moderate depression 20-28, severe depression > 29.BDI-II scores in the sample ranged from 0-39.Only 11 of the enrolled participants had scores in the moderate or severe range supporting a range of depression levels and subthreshold depression levels for the bulk of the sample.These neuropsychological assessments and structural imaging (see below) were completed in separate visits within a 1-month period.Our cognitive domain of interest in this study was executive functioning.However, only 158 subjects were also administered the other test of executive functioning, the Color-Word Stroop.Consequently, we focused on the Trail Making Test as our measure of executive functioning.Speci cally, as has been used in prior studies (Bickford et al., segmented into gray matter, white matter and cerebral spinal uid components.We used the Diffeomorphic Anatomic Registration Through Exponentiated Lie algebra algorithm (DARTEL) toolbox in order to generate a study-speci c template for the segmented 3D data.Segmented, modulated, grey matter images were normalized into standard Montreal Neurological Institute (MNI) space and smoothed with an 8-mm fullwidth-half-maximum (FWHM) Gaussian smoothing kernel.Intracranial volume (ICV) was calculated with the SPM12 automated Module Tissue Volumes(Ashburner, 2010).)lateralprefrontal cortex (LPFC) including middle and inferior frontal gyri; 3) and the anterior cingulate cortex (ACC) as shown below in Fig.1.Volumes of these ROIs were extracted using get_total.mRidgway,2007and imported into Rstudio for further analyses.
Note.Means shown with standard deviation, *inducates p < 0.05 Neuropsychological assessments , 2018; Dulas & Duarte, 2016; Enright et al., 2015), we subtracted transformed Trails A reaction time from transformed Trails B reaction time, z-scored the difference scores and used them as dependent variables in regression analyses described below.Structural MRI acquisition and analysis Scanning was performed on a 3Т Siemens Skyra scanner at the UT Austin Brain Imaging Center.A highresolution T1-weighted magnetization prepared rapid gradient echo (MPRAGE) image was collected (TR = 2530 ms, TE = 30 ms, 256 × 256 matrix, 42 axial slices, 1 mm slice thickness, no gap).Preprocessing and statistical analyses of structural imaging data were performed using Statistical Parametric Mapping software for Matlab (SPM 12, Wellcome Department of Cognitive Neurology, London, UK).For voxel-based morphometry (VBM) analyses, the T1-weighted MRI scans were bias-correctedRegion of Interest (ROI) de nition Four bilateral regions of interest (ROIs) were generated from the Anatomical Automatic Labeling (AAL) system (Tzourio-Mazoyer et al., 2002) implemented in the WFU Pick Atlas software toolbox (Maldjian et al., 2003): orbitofrontal cortex, consisting of superior orbital frontal, inferior orbital frontal, and medial orbital frontal gyri; 2

Table 2
Descriptive statistics and correlation coe cient of study variables (N = 176).

Table 3
Hierarchical regression with age, race, and depression predicting executive functioning , the Johnson-Neyman signi cance region for depression score as a predictor of executive function was beyond age 46.75 within the observed data age interval of 40 to 60.In other words, for Black & Hispanic American group only, a higher depression score was signi cantly predictive of lower executive functioning as age increased.
(Zahodne et al., 2014)21)et al., 2017)ance on numerous tests of executive functioning (i.e., Trails, Stroop, and Flanker) in adults across the lifespan(Dotson et al., 2020).Numerous studies have shown under-recruitment of lateral PFC regions during the performance of executive functioning tasks in MDD compared to non-depressed adults as well as depression-related volume reductions in lateral and orbitofrontal (e.g.,Hurley & Tizabi, 2013; Pizzagalli & Roberts, 2022).Our results showing depression-associated executive functioning impairments, which were partially mediated by reduced lateral, orbitofrontal, and ACC volumes are consistent with this literature.Our results add to a growing literature showing that even minimal depressive symptoms, in the absence of MDD, may predict executive dysfunction and extend these ndings to middle-aged adults(Dotson et al., 2009b;Li et al., 2017).Importantly, our results extend this prior work showing ethnoracial moderations of these relationships.Speci cally, greater depressive symptom severity was associated with worse executive functioning in Black and Hispanic adults, particularly with increasing age (i.e., > 46 years).The same age moderation was not observed in non-Hispanic White adults.Emerging work has shown that depression-related cognitive impairments may be magni ed in older age.For example, recent meta-analyses, including from our group, have shown that depression-related impairments in tests of episodic memory(James etal., 2021) and executive functioning (Dotson et al., 2020) are magni ed in older age, particularly in later decades.Given that PFC volume reductions are well-established in both cognitively unimpaired aging (Raz, 2000; Raz & Rodrigue, 2006) and depression (e.g., Hurley and Tizabi, 2013; Pizzagalli and Roberts, 2022), it follows that age may magnify depression-related executive dysfunction.Prior studies are limited, however, in a relative lack of middle-aged adults with most studies focusing on young or older subjects, and a lack of racial and ethnic diversity of research subjects.Our results ll in this gap by showing that executive dysfunction is subject to synergistic effects of depressive symptom severity and age even within middle age.Importantly, this synergistic effect was only signi cant in the ethnoracial minority group.Although few studies that have assessed depression-related cognitive impairment in Blacks and Hispanics, emerging research has shown that depressive symptoms may have greater consequences for these individuals than for non-Hispanic White adult.For example, moderate executive functioning impairments have been observed for a number of executive functioning tasks in these minority groups compared to non-Hispanic White adultADULTSs across the adult lifespan, with little difference between Blacks and Hispanics adults(Rea-Sandin et al., 2021).Some evidence suggests that depressive symptoms are more strongly related to executive dysfunction in Black compared to non-Hispanic White older adults(Zahodne et al., 2014).Here, we show that even in middle-age, mild depressive symptoms may have more severe consequences in ethnoracial minorities, effectively moving forward the point at which age-related executive functioning impairments appear.As depression has been associated with a greater risk of cognitive decline in Black and Hispanic individuals than age-matched, older, non-Hispanic White adults(Abrams & Mehta, 2019; Babulal et al., 2022; Barnes & Bates, 2017; Vyas et al., 2020), these results suggest that depressive symptoms in middle age may be an early indicator of subsequent cognitive decline speci cally in Black and Hispanic individuals.This study has a few limitations.The sample is relatively small, expecially the historically minoritized sample, although this did not preclude our ability to detect signi cant associations between our factors of interest.Nonetheless, it will be important for future studies to replicate these effects in larger samples and to separate the minoritized group.We did not observe any associations between depression symptom severity and episodic memory performance or between depression and hippocampal volumes (data not shown), in contrast to prior evidence(James et al., 2021).The most likely explanation for these null effects is the restricted range of performance on the episodic memory measure, where participants, across groups, (González & Tarraf, 2013;Joynt et al., 2003;Kim & Cho, 2020;Zuelsdorff et al., 2020reatest evidence of age-related volume loss in later decades(Salami et al., 2012), were insensitive either age or depression level in the middle-aged sample in this study.Given that this study used an archival dataset, our ability to explore other potential mediating factors was limited.For example, some evidence shows that life stress and cardiovascular disease are related to depression, and ethnoracial minorities are more likely to experience these conditions than non-Hispanic White adults(González & Tarraf, 2013;Joynt et al., 2003;Kim & Cho, 2020;Zuelsdorff et al., 2020