Prepandemic Alzheimer Disease Biomarkers and Anxious-Depressive Symptoms During the COVID-19 Confinement in Cognitively Unimpaired Adults.

BACKGROUND AND OBJECTIVES: Increased anxious-depressive symptomatology is observed in the preclinical stage of Alzheimer disease (AD), which may accelerate disease progression. We investigated whether ß-amyloid, cortical thickness in medial temporal lobe structures, neuroinflammation, and sociodemographic factors were associated with greater anxious-depressive symptoms during the COVID-19 confinement. METHODS: This retrospective observational study included cognitively unimpaired older adults from the Alzheimer's and Families cohort, the majority with a family history of sporadic AD. Participants performed the Hospital Anxiety and Depression Scale (HADS) during the COVID-19 confinement. A subset had available retrospective (on average: 2.4 years before) HADS assessment, amyloid [18F] flutemetamol PET and structural MRI scans, and CSF markers of neuroinflammation (interleukin-6 [IL-6], triggering receptor expressed on myeloid cells 2, and glial fibrillary acidic protein levels). We performed multivariable linear regression models to investigate the associations of prepandemic AD-related biomarkers and sociodemographic factors with HADS scores during the confinement. We further performed an analysis of covariance to adjust by participants' prepandemic anxiety-depression levels. Finally, we explored the role of stress and lifestyle changes (sleep patterns, eating, drinking, smoking habits, and medication use) on the tested associations and performed sex-stratified analyses. RESULTS: We included 921 (254 with AD biomarkers) participants. ß-amyloid positivity (B = 3.73; 95% CI = 1.1 to 6.36; p = 0.006), caregiving (B = 1.37; 95% CI 0.24-2.5; p = 0.018), sex (women: B = 1.95; 95% CI 1.1-2.79; p < 0.001), younger age (B = -0.12; 95% CI -0.18 to -0.052; p < 0.001), and lower education (B = -0.16; 95% CI -0.28 to -0.042; p = 0.008) were associated with greater anxious-depressive symptoms during the confinement. Considering prepandemic anxiety-depression levels, we further observed an association between lower levels of CSF IL-6 (B = -5.11; 95% CI -10.1 to -0.13; p = 0.044) and greater HADS scores. The results were independent of stress-related variables and lifestyle changes. Stratified analysis revealed that the associations were mainly driven by women. DISCUSSION: Our results link AD-related pathophysiology and neuroinflammation with greater anxious-depressive symptomatology during the COVID-19-related confinement, notably in women. AD pathophysiology may increase neuropsychiatric symptomatology in response to stressors. This association may imply a worse clinical prognosis in people at risk for AD after the pandemic and thus deserves to be considered by clinicians. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov Identifier NCT02485730.

Subjective cognitive decline and anxious/depressive symptoms during the COVID-19 pandemic: what is the role of stress perception, stress resilience, and ß-amyloid?

BACKGROUND: The COVID-19 pandemic may worsen the mental health of people reporting subjective cognitive decline (SCD) and therefore their clinical prognosis. We aimed to investigate the association between the intensity of SCD and anxious/depressive symptoms during confinement and the underlying mechanisms. METHODS: Two hundred fifty cognitively unimpaired participants completed the Hospital Anxiety and Depression Scale (HADS) and SCD-Questionnaire (SCD-Q) and underwent amyloid-ß positron emission tomography imaging with [18F] flutemetamol (N = 205) on average 2.4 (± 0.8) years before the COVID-19 confinement. During the confinement, participants completed the HADS, Perceived Stress Scale (PSS), Brief Resilience Scale (BRS), and an ad hoc questionnaire on worries (access to primary products, self-protection materials, economic situation) and lifestyle changes (sleep duration, sleep quality, eating habits). We investigated stress-related measurements, worries, and lifestyle changes in relation to SCD. We then conducted an analysis of covariance to investigate the association of SCD-Q with HADS scores during the confinement while controlling for pre-confinement anxiety/depression scores and demographics. Furthermore, we introduced amyloid-ß positivity, PSS, and BRS in the models and performed mediation analyses to explore the mechanisms explaining the association between SCD and anxiety/depression. RESULTS: In the whole sample, the average SCD-Q score was 4.1 (± 4.4); 70 (28%) participants were classified as SCD, and 26 (12.7%) were amyloid-ß-positive. During the confinement, participants reporting SCD showed higher PSS (p = 0.035) but not BRS scores (p = 0.65) than those that did not report SCD. No differences in worries or lifestyle changes were observed. Higher SCD-Q scores showed an association with greater anxiety/depression scores irrespective of pre-confinement anxiety/depression levels (p = 0.002). This association was not significant after introducing amyloid-ß positivity and stress-related variables in the model (p = 0.069). Amyloid-ß positivity and PSS were associated with greater HADS irrespective of pre-confinement anxiety/depression scores (p = 0.023; p < 0.001). The association of SCD-Q with HADS was mediated by PSS (p = 0.01). CONCLUSIONS: Higher intensity of SCD, amyloid-ß positivity, and stress perception showed independent associations with anxious/depressive symptoms during the COVID-19 confinement irrespective of pre-confinement anxiety/depression levels. The association of SCD intensity with anxiety/depression was mediated by stress perception, suggesting stress regulation as a potential intervention to reduce affective symptomatology in the SCD population in the face of stressors.

Sex, caregiver status and amyloid positivity predict increased anxiety and depression during the COVID-19‒related confinement

Background Anxiety and depression are more prevalent in women and caregivers and are associated with increased Alzheimer?s disease (AD) risk. We investigated multimodal predictors of increased anxiety/depression during the Covid19-related confinement in cognitively unimpaired (CU) older adults with an increased risk for AD with a special focus on sex/gender. Method We included 921 CU participants from the ALFA study (Table 1). Anxiety and depression (Hospital Depression and Anxiety Scale, HADS), perceived stress (Perceived Stress Scale, PSS) and stress resilience (Brief Resilience Scale, BRS) were measured during Covid19-related confinement. A subgroup completed the HADS (n=767) and underwent [18F]flutemetamol-PET imaging and sMRI (n=254) 2.4±0.8 years before confinement. Cross-sectional anxiety/depression measurements and change in anxiety/depression (delta score) from baseline to confinement were our primary outcomes of interest. We considered amyloid status (+/-) and cortical thickness (Cth) from the AD signature regions as imaging biomarkers. First, we investigated sex differences in the variables assessed during confinement. Second, we ran regression models to predict (i) cross-sectional anxiety/depression scores during confinement and (ii) change in anxiety/depression from baseline to confinement. Age, sex, education, APOE-ε4 status, caregiver status, stress related-variables and imaging biomarkers were considered as predictors. Result Fifteen percent of the participants were caregivers, 69% of which were women. Women showed increased stress perception relative to men (p=<0.001) ? notably, when they were caregivers (p=0.01). There were no sex-differences in stress resilience (p=0.5). In cross-sectional models, sex (women) and higher stress perception were independent predictors of greater anxiety/depression during confinement (Table 2a). Being a caregiver additionally predicted increase in anxiety/depressive symptomatology from baseline (Table 3a). Finally, in the subsample with biomarkers, amyloid positivity - but not Cth in the AD signature - contributed to predict anxiety/depression both cross-sectionally (Table 2b) and longitudinally (Table 3b) along with sex (women), caregiver status and stress perception. Conclusion Our results showed sex differences in caregiver status and stress perception during the Covid19-related confinement. Further, women, caregivers and those with higher self-perceived stress showed an increase in anxiety/depressive symptomatology. Amyloid pathology prior to confinement was associated with greater levels of anxiety/depression suggesting a role of amyloid pathology in anxiety/depressive symptomatology.

Subjective cognitive decline is associated with higher anxiety and depression during the COVID-19‒related confinement

Background Subjective cognitive decline (SCD) is often related to affective symptoms and both predict cognitive decline. We investigated whether SCD status predicted higher anxiety/depression during the Covid19-related confinement, along with amyloid positivity in cognitively unimpaired older adults. Method We included 205 participants from the ALFA+ study (Table 1). During the confinement, anxiety and depression (Hospital Depression and Anxiety scale, HADS), perceived stress (Perceived Stress Scale) and stress resilience (Brief Resilience Scale) were measured. Participants completed HADS, SCD-Questionnaire, and underwent a [18F]flutemetamol-PET scan on average 2.4 years before confinement (baseline). We ran linear analyses with (i) cross-sectional HADS scores during the confinement as well as (ii) change from baseline to confinement (delta scores) as dependent variables. SCD and amyloid status (+/-, defined with a Centiloid threshold of 12) and their interaction were considered as predictors, and demographics, APOE-ε4 status, and baseline HADS (for longitudinal analyses) as covariates. In a second step, perceived stress and stress resilience were considered in the models among covariates. Result Twenty-seven percent (n=56) of the participants were classified as SCD and 12.7% as amyloid positive. When main effects were tested, both SCD (p=0.03) and amyloid positivity (p=0.003) were associated with higher HADS scores during confinement (Table 2a). Further, a significant SCD*amyloid interaction was observed (p=0.001) such that only SCD participants with an amyloid positive scan showed higher HADS scores (p=0.001). SCD participants showed higher perceived stress than non-SCD participants (p=.044), but no differences were found in stress resilience (p=0.6). The inclusion of perceived stress and stress resilience as covariates reduced the SCD effect to a trend (p=0.06) but not the effect of amyloid (p=0.003). Longitudinal analyses with delta scores showed similar results for amyloid but not for SCD main effects (Table 2b). The amyloid*SCD interaction was also significant in longitudinal analyses (p=0.002) with amyloid status predicting an increase in HADS scores only in participants with SCD (p=0.003) (Fig. 1). Conclusion Having SCD and being amyloid positive is synergistically related to increased anxiety/depression during the Covid19-related confinement. Longitudinal studies are warranted to investigate the impact of higher confinement related anxiety/depression in the clinical prognosis of the SCD population.