Depression is a major modifiable risk factor for dementia, yet most prediction models treat it as a homogeneous exposure, despite evidence that risk varies among people with depression. This study aimed to identify key modifiers of the depression–dementia association to inform the development of tailored prediction models.
A narrative synthesis was conducted, incorporating (1) an umbrella review of nine meta-analyses examining the depression–dementia association; (2) a systematic review of depression-related medication use on dementia risk; and (3) findings from three Lancet Commission reports on dementia (2017, 2020, and 2024).
Seven key modifiers were identified that influenced the reliability and direction of risk estimates: demographic factors, assessment methods, depression severity, follow-up duration, depression timing and trajectory, the outcome predicted (e.g., all-cause vs dementia subtypes), and antidepressant use. Late-life and severe depression conferred the highest risk, with associations being stronger for vascular dementia than for Alzheimer's disease. Clinical diagnoses yielded higher risk estimates compared to symptomatic rating scales. Duration of follow-up was associated with contradictory directional effects. Antidepressant use was associated with increased dementia risk. However, class-specific analyses were inconclusive due to extreme heterogeneity. The Lancet Commission emphasized late-life and mid-life depression as key modifiable risk factors.
Multiple clinical, methodological, and temporal factors influence dementia risk estimates in individuals with depression. The findings support developing depression-specific dementia risk models that prioritize high-risk subgroups. Recommendations include distinguishing between symptom-based and clinical diagnostic approaches, addressing heterogeneity in timing and severity, modeling reverse causation, and validating models across diverse populations.
Social determinants of health (SDOH), infections, and Alzheimer's disease and related dementias (ADRD) are interconnected through complex pathways. Existing research establishes associations between SDOH and infections, between SDOH and ADRD, and between infections and ADRD. However, few studies examine how these three domains interact simultaneously. We propose five conceptual models linking these three concepts, including mediations, confounding, and indirect effects through intermediary processes. Empirical testing of these complex relationships requires different analytical strategies and data structures, such as population-based cohort studies with comprehensive data collection. We examine methodological considerations for population-based research, particularly four approaches for capturing infection exposures. Self-reported data are cost-effective but have limitations of recall bias and lack of pathogen-specific confirmation. Record linkage provides clinician-confirmed diagnoses but misses mild infections and is depends on coding accuracy. Laboratory measures offer objective biomarkers but cannot always pinpoint timing and require resource-intensive collection. Omics technologies enable systematic investigation of infection–brain health links but still have limitations in technical complexity, costs, standardization, and representation of disadvantaged populations. Future work requires integrating diverse data sources and analytical approaches, addressing gaps in historical infection exposure measurement and life-course SDOH assessment, and ensuring adequate representation of socioeconomically disadvantaged populations.
Introduction: Non-pharmacological interventions are increasingly relevant in neurocognitive disorders (NCDs) management. Cognitive training (CT) may benefit early stages, when functional resources allow targeted stimulation. However, its long-term effects and interaction with acetylcholinesterase inhibitors (AChEI) remain underexplored. This study aimed to investigate the 30-month efficacy of CT, alone or combined with AChEI, in older adults with mild NCD, considering the moderating role of cognitive reserve (CR) and individual characteristics.
Methods: A total of 108 individuals (mean age = 75.1 ± 6.5; 56.5% females) received either repeated CT alone (n = 69) or CT+AChEI (n = 39). Cognition was assessed at baseline and every 6 months using the Mini-Mental State Examination (MMSE) and Brief Neuropsychological Examination-2 (ENB-2). CR was measured with the Cognitive Reserve Index questionnaire (CRIq). Linear mixed models evaluated longitudinal changes, stratified by CR and sex.
Results: CT-only individuals showed greater and more consistent cognitive improvements over time compared to the CT+AChEI group (MMSE: β = 0.50, 95% CI: 0.04 to 0.96, p = 0.03). Improvements were also evident in specific measures tapping executive and memory functions. Participants with lower CR benefited most from CT (β = 0.86, 95% CI: 0.16 to 1.55, p = 0.02), while higher CR was associated with higher baseline and stability. Males showed more pronounced gains, particularly in the CT-only group.
Discussion: Sustained CT supports cognition in NCDs, particularly for those with lower CR. The combination with AChEI did not provide additional benefit and may reduce long-term effectiveness, warranting further investigation. Findings emphasize the importance of tailored, long-term approaches accounting for individual profiles.
Highlights: Cognitive training improved cognition over 30 months in mild NCDs.CT alone outperformed combined CT+AChEI treatment in long-term cognitive outcomes.Individuals with lower CR benefited most from CT.Males showed greater cognitive gains, particularly in the CT-only group.Long-term CT efficacy supports real-world applicability in early NCD care.
Introduction: Day-to-day variability of rest-activity patterns may have a multifaceted relationship with dementia risk, but empirical evidence is sparse.
Methods: We included 2332 dementia-free participants (79 ± 4.6 years, 58% female, 24% Black) who had ≥ 3 days of ZioXT accelerometer data from the Atherosclerosis Risk in Communities Neurocognitive Study in 2016 and 2017. Variability of physical activity (PA) volume was operationalized as median absolute deviation (MAD) of (1) daily average PA, (2) average PA during the most active 10 hours (M10), and (3) average PA during the least active 5 hours (L5). Variability of PA timing was defined as MAD of (1) the start time of the M10 interval and (2) the start time of the L5 interval. Participants were followed until incident dementia, death, last contact, or December 31, 2022. We used cause-specific Cox regression to estimate variability measures with incident dementia.
Results: After a median 5.2-year follow-up, 319 (13.7%) of individuals developed dementia. Higher MAD of daily average PA and M10 were associated with lower hazard of dementia (dose-response trend: P < 0.001), whereas higher MAD of L5 was associated with higher hazard of dementia (P = 0.046). Higher MAD of the start time of M10 was associated with higher hazard of dementia (P < 0.001), and a similar association was observed for MAD of the start time of L5 (P = 0.037). After further adjusting for daily PA volume, all associations persisted except for MAD of the start time of L5 interval. The findings were in general consistent across subgroup and sensitivity analyses.
Discussion: In this large older adult population, greater variability of daily PA volume, particularly during wake periods, and lower variability of PA timing, a marker of circadian phase, are associated with lower dementia risk. Research on the stability of interdaily rest-activity rhythms should consider potentially opposing relationships of types of PA variability with dementia risk.
This study assessed how medical exclusion criteria of a prevention Alzheimer's disease trial impact potential eligibility and sample characteristics.
Medical exclusion criteria from the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) trial were applied to N = 3695 participants from the population-based Health Retirement Study (HRS) with linked Medicare data. We determined the proportion of hypothetical eligibility. Multivariate Poisson regression was used to estimate associations between sociodemographic characteristics and eligibility.
Of the participants, 74.2% (N = 2742) were deemed ineligible. Accounting for all sociodemographic characteristics, older age, female gender, fewer years of education, lower net worth, and body mass index of 30+ was associated with a higher odds of being deemed ineligible. Ethnocultural identity and living arrangement were not associated with eligibility.
Our results suggest that certain sociodemographic factors may limit eligibility for a prevention Alzheimer's disease trial due to the presence of exclusionary medical conditions. This highlights the need to make trials more inclusive.
The locus coeruleus (LC) is a small nucleus located deep within the brainstem, serving as the brain's main source of noradrenergic neurons. Through its extensive projections, it plays a critical role in regulating cognitive processes and arousal. Although LC degeneration has been well documented in Alzheimer's disease and Parkinson's disease, its specific involvement in the pathophysiology of dementia with Lewy bodies (DLB) remains poorly understood.
This systematic review, conducted in accordance with the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines, explores the role of LC in the pathogenesis of DLB by synthesizing findings from human neuropathological and neuroimaging research and animal models of α-synucleinopathy.
Although studies directly examining the LC in DLB remain limited, particularly in human living patients, available evidence points to early and severe LC alterations in DLB and suggests that LC dysfunction may contribute to key clinical symptoms such as impaired arousal and anxiety.
A better understanding of the mechanisms driving LC dysfunction and neurodegeneration in DLB could facilitate the development of novel biomarkers and, ultimately, symptomatic therapies.
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