Perceived Stress is Associated with Alzheimer’s Disease Cerebrospinal Fluid Biomarkers in African Americans with Mild Cognitive Impairment

Abstract

Background:

African Americans (AA) have a higher Alzheimer’s disease (AD) prevalence and report more perceived stress than White Americans. The biological basis of the stress-AD link is unclear. This study investigates the connection between stress and AD biomarkers in a biracial cohort.

Objective:

Establish biomarker evidence for the observed association between stress and AD, especially in AA.

Methods:

A cross-sectional study (n = 364, 41.8% AA) administering cognitive tests and the perceived stress scale (PSS) questionnaire. A subset (n = 309) provided cerebrospinal fluid for measurement of Aβ₄₂, Tau, Ptau, Tau/Aβ₄₂ (TAR), and Ptau/Aβ₄₂ (PTAR). Multivariate linear regression, including factors that confound racial differences in AD, was performed.

Results:

Higher PSS scores were associated with higher Ptau (β= 0.43, p = 0.01) and PTAR (β= 0.005, p = 0.03) in AA with impaired cognition (mild cognitive impairment).

Conclusion:

Higher PSS scores were associated with Tau-related AD biomarker indices in AA/MCI, suggesting a potential biological connection for stress with AD and its racial disparity.

Keywords

African Americans Alzheimer’s disease tauopathy amyloid-β peptides cognitive function mild cognitive impairment neurocognitive tests psychological stress

INTRODUCTION

Older African American (AA) adults have a higher prevalence of Alzheimer’s disease (AD) as compared to similarly aged non-Hispanic White adults, according to some reports [1, 2]. There is also evidence that ethnic differences in the incidence and prevalence of AD may be less than expected [3 –5]. Results from a meta-analysis exploring racial disparities in the incidence and prevalence of AD suggests an increased risk for incident and prevalent AD among AA as compared to Whites, which may indicate differences in biological, social, and socioeconomic factors [6]. Stress may be a factor as well. Reports of racial disparities in health indicate that across age and socioeconomic status AA in general experience higher perceived stress as compared to Whites [7, 8]. The experience of higher stress may contribute to health disparities, including the higher AD prevalence noted by some studies [9, 10]. Although stressors are recognized risk factors that impact health across multiple domains [8], the concept of stress itself is complicated and has numerous definitions.

In contrast to objective measures of stressors, perceived stress appraises the interplay between people and their environments and their evaluation of challenges and available resources for coping [11]. The Perceived Stress Scale (PSS) is a global measure of perceived stress with sensitivity to chronic stressors and can study stress and health outcomes [12]. Perceived stress is associated with adverse health effects such as hypertension [13, 14] and age-related cognitive decline [9, 10]. Brain tau pathology per studies in animals and a European population is linked to chronic stress, and indicates a link between stress and AD biomarkers [15, 16]. However, evidence of this link in an AA population, who report higher levels of stress, remains undetermined. This study aims to establish biomarker evidence for the observed association between stress and AD, especially in AA, as it may offer insight into the complex pathway from perceived stress to AD. Prior investigations of stress and AD lacked biomarker evidence. These studies may not provide confidence in the association between stress and AD due to increasing non-AD related cognitive decline [10, 16]. However, recent advances have enhanced the ability to identify neurodegenerative diseases using biomarkers, including those in cerebrospinal fluid (CSF) [17]. Although studies have increasingly incorporated CSF biomarkers, the number of investigations evaluating biomarkers that include AA are scarce [18 –20]. Using baseline data collected by the Brain Stress Hypertension and Aging Research Program (B-SHARP) team at Emory University in Atlanta, GA, we explored relationships between perceived stress and CSF AD biomarkers (Aβ_1–42 [Aβ₄₂], total-Tau [Tau], phosphorylated-Tau181p [Ptau], total-Tau/Aβ_1–42 ratio [TAR]), and phosphorylated-Tau181p/Aβ_1–42 ratio [PTAR]) along with cognitive performance in a biracial sample (White versus AA) of persons with normal cognition (NC) and amnestic mild cognitive impairment (MCI).

METHODS

Participants

The study sample included community-dwelling adults 50 years or older with NC or MCI that completed a baseline assessment for B-SHARP. Potential participants were identified either through a referral from the Emory Alzheimer’s Disease Research Center or through strategic community partnerships with grassroots health education organizations, health fairs, advertisements, and mail-out announcements. Study informants were identified with the ability and willingness to provide information about their respective participants and maintain regular contact with them at least once per week (in person or via telephone). Each potential participant attended a screening visit where they underwent cognitive testing. A study physician also performed a clinical evaluation. Subsequently, the physicians and the neuropsychologist evaluated the participant’s cognitive assessment to determine their study group assignment (NC versus MCI). The Emory University Institutional Review Board approved this study, and each participant provided written informed consent.

Exclusion criteria included a history of stroke in the past three years, not having a study informant, age under 50 years, clinical diagnosis of dementia of any type, or abnormal thyroid-stimulating hormone (>10 mU/L) [21] or vitamin B12 (<250 pg/mL) [22]. Factors that impact stress and cognition, including a history of severe head injury, alcohol abuse disorder, and severe or prolonged psychiatric illness were exclusion criteria as well.

Cognitive assessment

MCI categorization was based on the modified Peterson criteria, which uses the Montreal Cognitive Assessment (MoCA) [23] instead of the Mini-Mental State Exam (MMSE). The MoCA has a higher sensitivity to detect MCI compared to the MMSE [23, 24] and is a valid screen for MCI in AA [25, 26]. The MoCA also contains executive functioning items such as Trails B and the Clock that is useful given the high prevalence of executive dysfunction in AA [27]. The criteria for inclusion in the MCI group was based on MoCA score <26, Clinical Dementia Rating (CDR) global score = 0.5 [28], Functional Activities Questionnaire (FAQ) <7 [29], abnormal delayed memory function per education-adjusted cutoff scores on the Logical Memory subscale from the Weschler Memory Scale-Revised (score <11 for 16 or more years of education, score <9 for 8 to 15 years of education, and score <6 for 7 or fewer years of education) [30], and subjective memory complaints. Each participant’s cognitive performance underwent a reviewed by the study physician (IH, AT) and neuropsychologist (FG). In instances where the participant’s assessment did not reveal a clear cognitive category (e.g., one test did not fit the other cutoffs for a group classification or a conflicting informant versus participant report), a consensus diagnosis was sought (IH and FG) [31]. The evaluators did not achieve consensus in only 6 of 364 cases (1.64%), for which a third independent cognitive neurologist was consulted as a tiebreaker.

Stress measure

The 10-item Perceived Stress Scale (PSS) questionnaire was administered to study participants. The PSS measures the degree of stress that results from multiple influences such as the stressor itself, coping resources, and individual factors such as personality [11]. It requires recall of the frequency (never, almost never, sometimes, fairly often, and very often) in the month preceding administration wherein the respondent experienced the emotions indicated by questions. Sample questions include, “In the last month, how often have you felt nervous and “stressed”?’ and “In the last month, how often have you felt that things were going your way?” The PSS has been validated for use with older adults, including populations with MCI, to investigate the impact of perceived stress on health outcomes [32].

Lumbar puncture

All participants were asked to undergo a lumbar puncture (LP) during the baseline assessment to obtain CSF for AD biomarker analysis. The procedure occurred after a fast of no fewer than six hours. It was performed per the Alzheimer’s Disease Neuroimaging Initiative (ADNI) procedure manual at the L3-4 or L4-5 interspace with a 24-gauge Sprotte atraumatic spinal needle to decrease the post-LP headache risk [33].

CSF biomarkers

The CSF AD biomarkers Aβ₄₂ and Tau were used in this study cohort based on the amyloid- β deposition, pathological tau, and neurodegeneration (ATN) classification system in the National Institute on Aging-Alzheimer’s Association research framework [34]. A multisite, clinical investigation with the ADNI cohort show that Aβ₄₂ and Tau as CSF biomarker signatures of AD can detect mild AD and predict the conversion of MCI to AD [35]. The LP procedure was performed to obtain CSF for the measurement of Aβ₄₂, Tau, and Ptau using the multiplex xMAP Luminex platform (Luminex Corp, Austin, TX) with Innogenetics immunoassay kit–based reagents (INNO-BIA AlzBio3, Ghent, Belgium, for research use–only reagents). TAR and PTAR were calculated from measured Tau, Ptau, and Aβ₄₂. The CSF samples were collected in sterile polypropylene tubes, separated into 0.5 cc aliquots, and stored at –80°C. Following collection, the CSF samples were shipped to the Biomarker Research Laboratory at the University of Pennsylvania for analyses (LS). The CSF biomarkers, Aβ₄₂, and Tau, are stable over repeated testing (coefficients of variation of <10%) [35]. The test-retest values for Tau, Aβ₄₂, and pTau are 0.98, 0.90, and 0.85, respectively.

Statistical analyses

The characteristics of the study participants were compared by four groups based on self-reported race (AA versus White), and cognitive classification (NC versus MCI) using analysis of variance (ANOVA) or chi-square (χ²) statistics and presented as means with standard deviations and counts with percentages, respectively. The distributions of CSF AD biomarkers and PSS scores did not deviate from normality. Multivariate linear regression evaluated the associations between PSS and cognitive function and CSF AD biomarkers. We first conducted the analyses in the full sample and then, in the two race groups and finally in the race/cognitive groups. Covariate adjustments were made for factors that potentially confound racial differences in AD risk, including age, sex, educational attainment, body mass index (BMI, calculated from weight [kilograms] divided by height [meters] squared) [36], family history of dementia including AD, and comorbid conditions of diabetes [37] and history of depression [38, 39].

Regression models also included blood pressure, arterial stiffness, and resting heart rate because they are associated with racial differences in cognitive decline [40 –42] and an increased prevalence of vascular diseases in AA with MCI [43 –45]. We calculated parameter estimates with 95% confidence intervals for the full sample, two race groups, and the four race/cognitive groups. The CSF AD biomarkers were the dependent variables and the PSS scores were the independent variable for the analyses. All statistical analyses were performed using SAS version 9.4 (SAS Institute, Cary, NC). A two-sided p-value <0.05 was used to determine significance for all tests.

RESULTS

Sample

Data from 364 participants recruited between March 1, 2016, and January 31, 2019 (309 underwent LP for CSF analyses) for B-SHARP were available for review (152 AA [41.8%]; 231 female [63.4%] and 133 male [36.5%]; 187 MCI [51.9%]; mean age 65.8 years, and average educational attainment of 15.8 years). The key characteristics of the study sample by race and the cognitive groups, including demographics, medical history, PSS scores, cognitive test scores, and CSF AD biomarker concentrations, are presented in Table 1. White and AA participants in the MCI group were older, had fewer years of education, higher PSS scores, and lower cognitive test scores as compared to the NC group. The concentrations of CSF AD biomarkers for White and AA participants in the MCI group were higher than the NC group except for Aβ₄₂, which had a lower level in the MCI group. These results are in Table 1. The CSF AD biomarker concentrations in the White/MCI group showed significantly higher concentrations of Tau and Ptau, lower Aβ₄₂, and higher TAR and PTAR than in the AA/MCI group. Demographic comparisons showed that the AA/MCI group was significantly younger and had less education than the White/MCI group. The comparison of the physical examination showed that the AA/MCI group had significantly higher BMI and diastolic blood pressure (DBP) than the White/MCI group and significantly higher systolic blood pressure (SBP) than the White/NC group. The White/MCI group had a significantly lower heart rate than the AA/NC group.

Table 1

Key Demographic, Clinical, Cognitive, and CSF Characteristics by Race and Cognitive Groups

	White/NC	AA/NC	White/MCI	AA/MCI	p
	(n = 106)	(n = 67)	(n = 103)	(n = 84)
Demographics
Age (y), mean (SD)	64.7 (7.51)	62.8 (6.15)	70.1 (8.11)*	63.6 (7.33)*	<0.0001
Male, No. (%)	36 (27.3)	20(15.2)	43 (32.3)	33 (25)	0.38
Education (y), mean (SD)	16.6 (2.56)	15.6 (2.36)	16.1 (3.06)*	14.5 (2.63)*	<0.0001
Examination
BMI, mean (SD)	26.9 (5.45)	30.7 (6.64)	26.4 (5.46)*	30.2 (.656)*	<0.0001
SBP (mmHg), mean (SD)	122.8 (17.7)*	131.7 (19.2)	128.4 (15.4)	132 (21.6)*	0.004
DBP (mmHg), mean (SD)	73.3 (12.1)	79.4 (14.5)	70 (11.6)*	77.4 (12.1)*	<0.0001
Heart rate, mean (SD)	70.2 (11.5)	74.2 (12.7)*	67.8 (12.7)*	72.4 (11.6)	0.008
Pulse wave velocity	8.08 (2.31)	8.42 (2.32)	8.52 (2.49)	8.30 (2.56)	0.63
Lumbar puncture (n = 309), No. (%)	102 (33)	50 (16.2)	92 (30)	65 (21)	<0.0001
Medical History^†
Hypertension, No. (%)	51 (28.8)	48 (27.1)	25 (14.1)	53 (30)	<0.0001
Heart failure, No. (%)	1 (10)	2 (20)	1 (10)	6 (60)	0.03
Depression, No. (%)	26 (26.3)	14 (14.1)	32 (32.3)	27 (27.3)	0.30
Diabetes, No. (%)	8 (16.3)	16 (32.7)	7 (14.3)	18 (36.7)	0.0003
High cholesterol, No. (%)	51 (32.1)	31 (19.5)	38 (23.9)	39 (24.5)	0.43
Renal disease, No. (%)	4 (33.3)	3 (25)	1 (8.33)	4 (33.3)	0.44
Hepatic disease, No. (%)	5 (50)	2 (20)	2 (20)	1 (10)	0.49
Myocardial infarction, No. (%)	6 (20.7)	5 (17.2)	11 (37.9)	7 (24.1)	0.58
Family history of AD, No. (%)	46 (35.7)	21 (16.3)	38 (29.5)	24 (18.6)	0.16
Stress and Cognitive Tests
PSS Score, mean (SD)	19.8 (6.98)*	21.6 (7.24)	21.6 (6.99)	22.8 (6.62)*	0.03
MoCA Score, mean (SD)	27.1 (1.88)*	25.3 (2.75)	25.3 (3.42)	21.1 (3.25)*	<0.0001
Composite Executive Function Score, mean (SD)	0.73 (0.57)*	0.52 (0.49)	0.15 (0.70)	0.07 (0.57)*	<0.0001
HVLT-R (Delayed Recall # Words), mean (SD)	10.1 (1.76)*	8.65 (2.11)	5.76 (3.99)	7.01 (2.92)*	<0.0001
Boston Naming (Total Correct), mean (SD)	14.5 (0.76)*	13.9 (1.38)	13.9 (1.54)	13 (1.72)*	<0.0001
Digit Span Backward (Total Points), mean (SD)	7.09 (2.51)*	6.38 (2.50)	5.93 (2.58)	5.35 (2.21)*	<0.0001
Trails B - A, mean (SD)	45.6 (35.9)*	69.7(55.3)	88.8 (77.3)	106.3 (72.6)*	<0.0001
CSF Biomarkers
Tau (pg/dL), mean (SD)	54.7 (24.7)	44.6 (29.8)	86.6 (56.4)*	51 (29.3)*	<0.0001
Ptau (pg/dL), mean (SD)	15.2 (8.17)	12.5 (5.86)	25.9 (18.2)*	13.6 (6.77)*	<0.0001
Aβ₄₂ (pg/dL), mean (SD)	261.4 (65.5)	249.2 (73.4)	206.4 (73.5)*	248 (81.4)*	<0.0001
Tau/Aβ₄₂, mean (SD)	0.23 (0.16)	0.19 (0.11)	0.51 (0.48)*	0.26 (0.34)*	<0.0001
Ptau/Aβ₄₂, mean (SD)	0.06 (0.04)	0.05 (0.03)	0.15 (0.13)*	0.07 (0.08)*	<0.0001

AA, African Americans; BMI, body mass index; SBP, systolic blood pressure; DBP, diastolic blood pressure; PSS, Perceived Stress Scale; MoCA, Montreal Cognitive Assessment; HVLT-R, Hopkins Verbal Learning Test-Revised; CSF, cerebrospinal fluid. *Groups with significant differences. ^†Percentages may differ based on number missing.

Race/cognitive group comparisons

The linear regression results for CSF AD biomarkers in the full sample and race groups (White and AA) are presented in Table 2. In the full sample, higher PSS scores were associated with higher Tau, higher Ptau, and higher Tau/Aβ₄₂ and Ptau/Aβ₄₂ ratios (Fig. 1). A trend for lower Aβ₄₂ with higher PSS scores was present in the full sample as well. There were no significant relationships between PSS scores and CSF AD biomarkers among White participants. In the AA group, higher PSS scores were associated with higher Ptau and PTAR and a trend between higher PSS scores and higher Tau and TAR (Table 2). The race/cognitive subgroup analyses are presented in Table 3. In the AA with MCI group, higher PSS scores were associated with higher Ptau and higher PTAR (Fig. 2). Although not statistically significant, the trend of lower Aβ42 with higher PSS scores was present in the AA/MCI group and to lesser extent in the White/MCI group. The distribution of the PSS scores for the race/cognitive groups are presented in Supplementary Figure 1.

Table 2

Association of CSF Biomarkers in pg/dL with Perceived Stress Scale Scores in the Full Sample and the two Race Groups

	Parameter estimate	p	95% Confidence limits
Full sample			Lower	Upper
Tau	0.76	0.06	–0.02	1.54
Ptau	0.21	0.05	0.0005	0.41
Aβ₄₂	–1.36	0.07	–2.85	0.13
Tau/Aβ₄₂	0.009	0.01	0.002	0.02
Ptau/Aβ₄₂	0.003	0.01	0.0004	0.004
White
Tau	1.12	0.06	–0.04	2.29
Ptau	0.24	0.14	–0.07	0.55
Aβ₄₂	–1.20	0.23	–3.16	0.75
Tau/Aβ₄₂	0.01	0.05	0.0002	0.02
Ptau/Aβ₄₂	0.002	0.08	–0.0003	0.004
AA
Tau	0.81	0.08	–0.11	1.73
Ptau	0.33	0.004	0.11	0.55
Aβ₄₂	–1.04	0.46	–3.87	1.78
Tau/Aβ₄₂	0.009	0.07	–0.0008	0.012
Ptau/Aβ₄₂	0.003	0.02	0.0005	0.005

Parameter estimates with 95% CI are from linear regression models that includes age, sex, education level, body mass index, blood pressure, history of diabetes, and family history of dementia.

Table 3

Association of CSF Biomarkers in pg/dL with Perceived Stress Scores in the four Race/Cognitive Groups

	Parameter estimate	p	95% Confidence limits
Normal Cognitive Group
White			Lower	Upper
Tau	0.08	0.86	–0.89	1.05
Ptau	–0.01	0.95	–0.37	0.35
Aβ₄₂	0.80	0.53	–1.76	3.37
Tau/Aβ₄₂	–0.002	0.57	–0.008	0.004
Ptau/Aβ₄₂	–0.0006	0.55	–0.002	0.001
AA
Tau	0.44	0.55	–1.04	1.92
Ptau	0.25	0.16	–0.11	0.60
Aβ₄₂	1.81	0.51	–3.75	7.37
Tau/Aβ₄₂	–0.0003	0.94	–0.009	0.009
Ptau/Aβ₄₂	0.0007	0.39	–0.0009	0.002
MCI Group
White
Tau	1.71	0.14	–0.55	3.96
Ptau	0.42	0.15	–0.15	0.99
Aβ₄₂	–1.50	0.29	–4.31	1.31
Tau/Aβ₄₂	0.02	0.05	–0.00009	0.04
Ptau/Aβ₄₂	0.004	0.10	–0.0007	0.008
AA
Tau	0.99	0.10	–0.21	2.19
Ptau	0.43	0.01	0.10	0.75
Aβ₄₂	–2.68	0.21	–6.94	1.57
Tau/Aβ₄₂	0.02	0.07	–0.001	0.03
Ptau/Aβ₄₂	0.005	0.03	0.0004	0.009

Parameter estimates with 95% CI are from linear regression models that includes age, sex, education level, body mass index, blood pressure, history of diabetes, and family history of dementia.

Fig. 1

CSF Biomarkers by PSS for Full Sample.

Fig. 2

CSF Biomarkers by PSS for AA with MCI.

DISCUSSION

This investigation builds on previous evidence of a relationship between perceived stress and cognitive performance in AA with MCI [10, 16]. The results of this study show an association between perceived stress and CSF AD biomarkers. In the full sample, higher PSS scores are associated with CSF AD biomarkers; however, subgroup analyses by race and cognitive status show that the association is present in persons with MCI, in particular the AA participants. This report, to our knowledge, is the first study using a biracial sample that demonstrates a link between perceived stress and CSF AD biomarkers in persons with MCI. The association between higher PSS scores and CSF AD biomarkers in the AA/MCI group is not necessarily race-specific as there is a trending relationship between PSS scores and CSF AD biomarkers in the White/MCI group. Since the association between PSS scores and CSF AD biomarkers is present in persons with MCI, it may be possible that a higher PSS score can indicate persons at increased risk for developing AD. Potential explanations for the association between perceived stress and CSF AD biomarkers include differences in inflammatory pathways and psychiatric pathology [46, 47]. Further, the association between PSS scores and CSF AD biomarkers is only significant in persons with MCI. Thus, the method of stress assessment, such as asking questions about stressors during clinical encounters or administering a stress scale, could be a factor in the finding as well [48].

The results of this study also show that the AA participants in the cohort are younger than the White participants including in the MCI group. Interestingly, the AA/MCI group has lower levels of Tau and Ptau than the White/MCI group. Despite this evidence of a lesser degree of neuropathology, the association between PSS scores and CSF AD biomarkers is significant in the AA/MCI group. One potential explanation is the higher burden of cardiovascular disease among AA in the United States [49] and the association of risk factors for cardiovascular disease such as diabetes, hypertension, and obesity with cognitive changes [50]. In this study cohort, more AA participants have hypertension, heart failure, diabetes, and higher BMI than the White participants. The AA/MCI group also has the highest PSS score. These study results may reflect a potentially increased vulnerability to perceived stress in AA with MCI that could lead to cognitive impairment despite a lesser extent of Tau measurement.

Our findings potentially offer insight into the observed stress-AD link among AA through its associations with CSF AD biomarkers. Higher PSS scores are associated with higher Ptau/Aβ₄₂ ratios, which have clinical and diagnostic relevance based on recent evidence suggesting increased concordance of TAR and PTAR compared to Aβ₄₂ alone with neuritic plaque burden as detected by amyloid positron emission tomography [51]. This finding has further clinical and diagnostic significance as TAR and PTAR are established predictors of disease progression [52]. However, the cross-sectional study design limits the ability to dissect these associations further. Additional research into potential intermediate steps between perceived stress and CSF AD biomarkers in persons with MCI may help to clarify the relationship between perceived stress and AD risk.

Stress is recognized to affect multiple health domains, including cognition and related disparities [8]. The higher prevalence of AD and self-reported stress in AA as compared to Whites suggests that the exploration of the stress-AD relationship, including stress-reduction may have potential cognitive health benefits for AA [53]. Coping and problem-solving strategies can have beneficial effects on AA [54]. Stress-reduction methods can also positively impact the caregivers of persons with dementia [55]. The inclusion of perceived stress as a routine screening assessment during clinical care thus offers the possibility to identify individuals with increased risk for cognitive health problems.

This report has several limitations. The criteria for MCI in this investigation are based on ADNI criteria, which may be less precise than other neuropsychological criteria [56]. Despite the difference in diagnostic precision, both methods can detect MCI and the aim of the investigation is to explore evidence of a biological relationship between stress and CSF AD biomarkers. Although a potential biological link between stress and AD risk is presented, it does not elucidate possible underlying mechanisms and pathways. Further investigation into the potential underlying mechanisms is essential to unravel the relationship between perceived stress and AD risk. One potential mechanism that could explain the perceived stress-AD risk association is a stress-related change in vascular reactivity [57], which can impact cerebral hemodynamics that increases the risk of cognitive impairment [58, 59]. Stress-related inflammatory effects are also associated with adverse cognitive impacts as well [60]. Inflammatory mediators can stimulate the hypothalamic-pituitary-adrenal axis to release the stress hormone cortisol that has hippocampal effects leading to memory and cognitive impairment [61]. In addition to changes in hormonal and pro-inflammatory mediators, stress may cause epigenetic changes in the prefrontal cortex that are associated with adverse cognitive effects [62].

The cross-sectional study design is a limitation as it prevents longitudinal exploration of perceived stress and CSF AD biomarkers. The cross-sectional study design further precludes the determination of whether cognitive status and higher CSF AD biomarker concentrations are precursors or sequelae of higher PSS scores in this biracial cohort. Impaired cognition can increase stress, and potentially confound the association between higher PSS scores and CSF AD biomarkers in persons with MCI. However, our analysis did not detect a significant relationship between higher PSS scores and CSF AD biomarkers in the White/MCI group. Hence, impaired cognition alone may not fully explain the results of this investigation. The PSS questionnaire relies on recall of information, and recall bias is possible in persons with MCI. In our sample, the participants with MCI reported higher perceived stress. The PSS was designed to be sensitive to chronic perceived stress [12] and was validated in persons with MCI [32]. Recall bias is thus less likely to underestimate the actual stress levels in this group. Newer immunoassays are also available that may have a lower limit of detection than the ALZbio3 xMAP Luminex platform. However, prior studies have shown a strong correlation of the new platforms with the ALZbio close to 97% for Aβ₄₂ and 96% for both Tau and Ptau [63]. The impact of this issue might be limited since we compared all the participants on the same platform. Despite these limitations, the significant relationship between higher perceived stress and CSF AD biomarkers in AA with MCI impacts both the general understanding of AD in AA and the design of future interventions to reduce AD risk in this racial population.

In summary, this study demonstrates that self-reported perceived stress is associated with AD risk (Ptau and PTAR in CSF), especially in AA with MCI. Future investigations of biological pathways that connect high perceived stress with changes in CSF AD biomarkers among persons with evidence of clinical AD are needed. Identifying these mechanisms has the promise to influence research on AD prevention, racial disparity in neurodegeneration and cognitive aging, and may offer potential targets for intervention.

Footnotes

ACKNOWLEDGMENTS

This research was funded by the National Institutes of Health/National Institute on Aging (Grant No. NIA: RF1AG051633-01 and Grant No. R01-AG042127-06). Additional funding was received from a Diversity Supplement from the National Institute on Aging (Grant No. NIA: RF1AG051633-01S1) and the Alzheimer’s Association (AARGD-NTF-20-644587).

Authors’ disclosures available online ().

The supplementary material is available in the electronic version of this article: .

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