Lifetime Stressful Events Associated with Alzheimer's Pathologies, Neuroinflammation and Brain Structure in a Risk Enriched Cohort.

OBJECTIVE: Along with the known effects of stress on brain structure and inflammatory processes, increasing evidence suggest a role of chronic stress in the pathogenesis of Alzheimer's disease (AD). We investigated the association of accumulated stressful life events (SLEs) with AD pathologies, neuroinflammation, and gray matter (GM) volume among cognitively unimpaired (CU) individuals at heightened risk of AD. METHODS: This cross-sectional cohort study included 1,290 CU participants (aged 48-77) from the ALFA cohort with SLE, lumbar puncture (n = 393), and/or structural magnetic resonance imaging (n = 1,234) assessments. Using multiple regression analyses, we examined the associations of total SLEs with cerebrospinal fluid (1) phosphorylated (p)-tau181 and Aß1-42/1-40 ratio, (2) interleukin 6 (IL-6), and (3) GM volumes voxel-wise. Further, we performed stratified and interaction analyses with sex, history of psychiatric disease, and evaluated SLEs during specific life periods. RESULTS: Within the whole sample, only childhood and midlife SLEs, but not total SLEs, were associated with AD pathophysiology and neuroinflammation. Among those with a history of psychiatric disease SLEs were associated with higher p-tau181 and IL-6. Participants with history of psychiatric disease and men, showed lower Aß1-42/1-40 with higher SLEs. Participants with history of psychiatric disease and women showed reduced GM volumes in somatic regions and prefrontal and limbic regions, respectively. INTERPRETATION: We did not find evidence supporting the association of total SLEs with AD, neuroinflammation, and atrophy pathways. Instead, the associations appear to be contingent on events occurring during early and midlife, sex and history of psychiatric disease. ANN NEUROL 2024;95:1058-1068.

Longitudinal association of apolipoprotein E and sleep with incident dementia.

INTRODUCTION: Few longitudinal studies have explored the association between apolipoprotein E gene (APOE) status, sleep disturbances, and incident dementia among middle-aged participants. METHODS: Cox regression analyses explored the association of sleep duration, insomnia, and daytime napping with incident all-cause dementia and their interaction with APOE genetic risk among 397,777 middle-aged adults. RESULTS: During a median of 10.8 years follow-up, sleeping more or fewer than 7 hours was associated with a higher dementia risk (hazard ratio [HR] for 5 vs 7 hours: 1.35, 95% confidence interval [CI] 1.11-1.64; HR for 9 vs 7 hours: 1.59; 95% CI 1.37-1.85) as was daytime napping (HR for often/all of the time vs never/rarely: 1.67; 95% CI 1.37-2.03). Stratified analyses revealed that the effects of sleep disturbances were similar across all APOE genetic risk groups. DISCUSSION: Short and long sleep duration and daytime napping in middle-aged individuals are associated with the development of dementia in later life. Sleep duration and quality are important for everyone regardless of their genetic risk by APOE genotype.

Development of a Psychological Intervention to Promote Meaningful Activity in People Living With Mild Dementia: An Intervention Mapping Approach.

BACKGROUND AND OBJECTIVES: Despite the importance of meaningful activity in mild dementia, only limited data are available on the development of interventions supporting people with mild dementia to engage in meaningful activity. In this article, we describe the development of an intervention that responds to this need. RESEARCH DESIGN AND METHODS: Intervention mapping (IM), an evidence-based approach, was used to develop STAYING ACTIVE (STAYing well and active-schedulINg meaninGful and enjoyAble aCTIvities to promote Vitality and wEll-being in mild dementia). The first step, a needs assessment, comprised a literature review, focus groups, and individual interviews with service users. Performance objectives of the intervention were formulated in Step 2, followed by the development of theory-based methods in Step 3. In Step 4, the new intervention was developed based on data collected in previous steps, existing interventions, and pilot testing. Qualitative data were analyzed using framework analysis. RESULTS: The needs assessment indicated that people with dementia and their carers view "staying active" as an important part of "enjoying life." Adapting to loss through compensation and receiving support were key facilitators of engaging in meaningful activity. Ecological, psychosocial, and activity-oriented theories guided the development of theory-based intervention strategies, which were based on awareness, skills, and addressing barriers of meaningful activity. DISCUSSION AND IMPLICATIONS: STAYING ACTIVE is grounded on theory, and service user experiences and aims at promoting meaningful activity in mild dementia. The IM framework may be useful in the development of future psychosocial interventions for people with dementia, facilitating transparency when efficacy is evaluated.

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.