The Journal of Prevention of Alzheimer's Disease最新文献

Background: Soluble amyloid β_1-42 (Aβ₄₂) signals via the α7 nicotinic acetylcholine receptor to hyperphosphorylate tau in Alzheimer's disease (AD). Simufilam disrupts this pathogenic signaling by binding filamin A and disrupts its linkages with inflammatory receptors to reduce neuroinflammation. We assessed simufilam in two Phase 3 clinical trials in mild-to-moderate AD.

Methods: Participants were age 50-87 with Stage 4 or 5 CE, a mini-mental state exam (MMSE) ≥16 and ≤27 and a Clinical Dementia Rating Global Score (CDR-GS) of 0.5, 1 or 2. The criterion supporting AD pathology was plasma phosphorylated (p)-tau181 or prior amyloid PET. RETHINK randomized participants to simufilam 100 mg or placebo for 52 weeks. REFOCUS evaluated simufilam 50 and 100 mg versus placebo for 76 weeks. Co-primary endpoints were change from baseline on ADAS-Cog12 and ADCS-ADL. Sub-studies assessed exploratory plasma biomarkers and, in REFOCUS only, CSF and imaging biomarkers.

Results: Both trials failed to meet co-primary, secondary or exploratory biomarker endpoints. REFOCUS was terminated early, with 22% of participants still active in the trial. In the predefined mild subgroup in REFOCUS, simufilam was associated with slower cognitive decline than placebo through Week 64 (p = 0.019). This finding disappeared at Week 76 with 45% missing data and did not replicate in RETHINK. Favorable nominal exploratory post-hoc findings amongst participants with the highest half of screening plasma p-tau181 levels occurred in RETHINK but not REFOCUS. The plasma p-tau181 entry criterion did not reliably exclude amyloid PET negativity in the sub-study.

Conclusions: Simufilam did not meet co-primary or secondary endpoints in these Phase 3 trials. Simufilam was safe and well tolerated. Trials registered at clinicaltrials.gov: NCT04994483 and NCT05026177.

Background: Traumatic brain injury is an environmental risk factor that may accelerate the progression of Alzheimer's disease and behavioral and psychological symptoms of dementia in patients with mild cognitive impairment.

Objectives: To investigate whether traumatic brain injury in patients with mild cognitive impairment is associated with an increased risk of progression to Alzheimer's disease dementia and behavioral and psychological symptoms of dementia.

Design: A retrospective cohort study using the Korean National Health Insurance Service database.

Setting: National-level health data covering healthcare utilization, diagnoses, prescriptions, and procedures in South Korea from January 2012 to December 2021.

Participants: Patients diagnosed with mild cognitive impairment between January 1, 2013, and December 31, 2016, were followed until Alzheimer's disease dementia diagnosis, behavioral and psychological symptoms of dementia occurrence, death, or December 31, 2021. These patients were classified into two groups according to the presence of traumatic brain injury during the follow-up period.

Measurements: Age at the time of mild cognitive impairment diagnosis, sex, income level, the presence of several chronic conditions, presence of traumatic brain injury, progression of Alzheimer's disease dementia, and behavioral and psychological symptoms of dementia RESULTS: We assessed 452,718 patients (mean age: 67.16 years). Traumatic brain injury was significantly associated with an increased risk of Alzheimer's disease dementia progression (hazard ratio = 1.252, 95 % confidence interval: 1.206-1.301), particularly among patients aged <65 years (hazard ratio = 1.560, 95 % confidence interval: 1.391-1.749), and was linked to a higher risk of behavioral and psychological symptoms of dementia following Alzheimer's disease dementia diagnosis (hazard ratio = 1.300, 95 % confidence interval: 1.181-1.431).

Conclusions: Our results underscore the importance of traumatic brain injury prevention in patients with mild cognitive impairment for mitigating the progression and neuropsychiatric complications of Alzheimer's disease.

Background: The magnitude of cognitive change before and after incident heart failure (HF) is unclear. We investigated whether incident HF is associated with changes in cognitive function at the time of diagnosis and accelerated trajectory in cognitive decline in the subsequent years.

Methods: We used data from the Health and Retirement Study, a nationally representative survey of US adults aged 50 years or older. Participants underwent a cognitive assessment at baseline (wave 5, 2000), and at least 1 other time point (from wave 6 [2002] to wave 15 [2020]). The outcomes were change in global cognition, memory, and executive function. Outcomes were standardized into Z-scores, with higher scores indicating better cognitive performance. Linear mixed-effects models estimated changes in cognition at the time of HF (change in the intercept) and the rate of cognitive change over the years after HF (change in the slope), after adjusting for pre-HF cognitive trajectories and potential confounders.

Results: We included 12 850 adults (mean [SD] age, 66.1 [9.4] years; 61.8 % women). Over a median follow-up of 16 years (interquartile range: 8 to 20 years), 1457 participants had incident HF. The annual rate of cognitive decline before HF diagnosis among individuals with incident HF was similar to that of participants who remained HF-free throughout follow-up. However, incident HF was associated with subsequent decreases in global cognition (-0.073 SD [95 % CI -0.109 to -0.038]), memory (-0.070 SD [95 % CI -0.108 to -0.032]), and executive function (-0.054 SD [95 % CI -0.092 to -0.016]) around the time of the HF diagnosis. Moreover, individuals with incident HF vs those without HF demonstrated faster and long-term declines in global cognition (-0.011 SD/year [95 % CI -0.018 to -0.004]) and executive function (-0.008 SD/year [95 % CI -0.015 to -0.001]), but not in memory (-0.006 SD/year [95 % CI -0.013 to 0.001]) over the years after HF compared with pre-HF slopes.

Conclusions: Incident HF was associated with subsequent decreases in cognitive function at the time of diagnosis and accelerated cognitive decline over the following years.

Background: White matter hyperintensities (WMHs) represent a cardinal feature of cerebral small vessel disease (CSVD), yet iron dysregulation alterations within these lesions and their relationship to cognitive decline remains poorly understood.

Objectives: To characterize iron dysregulation in WMH using quantitative susceptibility mapping (QSM) and examine their relationship with CSVD severity and cognitive function.

Design: Cross-sectional study with longitudinal follow-up component.

Setting: Single-center study at Shandong Provincial Hospital Affiliated with Shandong First Medical University, China.

Participants: 299 participants recruited from January 2021 to September 2023, with 71 participants completing longitudinal follow-up (mean interval 20.6 months). Participants were categorized into early CSVD (0 points, n = 171), mild CSVD (1 point, n = 70), and severe CSVD (≥2 points, n = 58) groups based on total burden scoring.

Intervention: None (observational study).

Measurements: 3.0T MRI with quantitative susceptibility mapping and diffusion tensor imaging. Spatial analysis examined susceptibility values in WMH cores and perilesional zones (0-2 mm, 2-4 mm, 4-6 mm). Cognitive assessments included Montreal Cognitive Assessment (MoCA), Symbol Digit Modalities Test (SDMT), and other neuropsychological tests.

Results: WMH susceptibility values were significantly lower than normal-appearing white matter (-14.55 vs -7.77 ppb, P < 0.001) with progressive increases correlating with CSVD severity (P < 0.001). Cross-sectionally, higher WMH susceptibility values correlated with lower MoCA scores (r = -0.155, P = 0.045). Longitudinally, WMH susceptibility values predicted decline in information processing speed (SDMT: β = -0.247, P = 0.042). Spatial analysis revealed distinct patterns with perilesional regions showing intermediate susceptibility values.

Conclusions: Iron dysregulation alterations within WMH provide independent information about cognitive risk in CSVD. QSM emerges as a promising biomarker for monitoring cognitive trajectory and may facilitate early identification of patients at risk for cognitive decline.

Human cognition and behavior rely on the integration of large-scale neural networks that connect the cerebral cortex and subcortical structures. Emerging evidence suggests that alterations in the functional connectivity (FC) between the cortical and subcortical regions in Alzheimer's disease (AD) may influence the onset and progression of both cognitive and noncognitive symptoms at the group level. However, an individualized and longitudinal framework to capture deviations in subcortico-cortical FC from normative brain aging remains underexplored. We addressed this gap by leveraging large-scale longitudinal neuroimaging datasets and applying a normative modeling approach to characterize subcortical FC trajectories across the adult lifespan. First, we quantified individual deviations in the subcortical FC in individuals with cognitive impairment (CI) relative to a normative aging group using centile scores and tracked longitudinal changes across multiple follow-ups. We examined the relationship between changes in subcortical FC and clinical measures of cognitive function, including episodic memory, executive function, and language. Our findings revealed widespread decreases in the subcortical FC in individuals with CI, except in the limbic network, which diverged from the patterns observed in normal aging. These alterations are significantly associated with a decline in memory and executive functions. Collectively, our results may advance our understanding of AD-related connectopathy and provide a direction for profiling individualized longitudinal FC changes in individuals with CI. Furthermore, our results could inform individualized prognosis and targeted interventions.

Background: Predicting the transition from subjective cognitive decline (SCD) to mild cognitive impairment (MCI) is critical for dementia prevention.

Objective: Comprehensive assessment of MRI-based macro-/micro-structural and functional brain changes in SCD to develop an individualized model predicting transition to MCI.

Design, setting, and participants: Patients with SCD were screened from the ADNI, NACC, and OASIS-3 databases. 89 patients met the inclusion criteria and underwent structural magnetic resonance imaging (sMRI) and resting-state functional MRI (rs-fMRI). Over a 10-year follow-up, 49 patients progressed to MCI, while 40 remained stable.

Measurements: The VB-net automated brain segmentation, extracting hippocampal radiomics and whole brain subregion volume features. Brain functional features were extracted based on rs-fMRI. Cox regression was used to develop predictive models, which were independently validated with the testing set. The nomogram was constructed to estimate the probability of transition to MCI at 5-/7-/10-year. The nomogram's accuracy was assessed using calibration curves and concordance index (C-index), and clinical utility was evaluated through decision curve analysis.

Results: The model incorporating age, brain volume, functional, and radiomics features demonstrated the highest predictive performance for SCD progression in training (C-index: 0.962; 95 % CI: 0.95-0.98) and testing (C-index: 0.911; 95 % CI: 0.861-0.968) sets. A nomogram comprising 10 predictors was constructed to estimate individualized risk of progression to MCI at 5-/7-/10-year. The calibration curve showed good agreement between predicted and observed values. Decision curve analysis demonstrated the nomogram had substantial clinical value.

Conclusions: This multivariate model and nomogram could accurately predict the individual progression from SCD to MCI.

Background: Safety profiles of lecanemab, an anti-amyloid-β antibody for the treatment of early Alzheimer's disease (AD), remain uncertain and may vary between randomized controlled trials (RCTs) and real-world evidence (RWE) studies.

Objectives: This systematic review and meta-analysis aimed to evaluate the safety, tolerability, and acceptability of lecanemab based on findings from both RCTs and emerging RWE studies.

Methods: We systematically searched major databases and clinical trial registries from their inception to June 2025. Random-effects meta-analyses were performed to estimate the pooled incidence of key safety outcomes, including amyloid-related imaging abnormalities (ARIA), infusion-related reactions (IRRs), and treatment discontinuation (due to ARIA, adverse events [AEs], or any cause). The risk of ARIA according to the ApoE4 genotype was assessed via relative risk (RR). This study was registered with PROSPERO (No. CRD420251110679).

Results: A total of two RCTs and five RWE studies encompassing 1576 patients were included. The pooled ARIA incidence was 19% (95% CI: 16%-23%), which was significantly modulated by ApoE4 status (RR 1.45 for heterozygotes, 3.54 for homozygotes vs noncarriers) and the pooled symptomatic ARIA incidence was 3% (95% CI: 2%-4%). IRRs occurred in 26% (95% CI: 19%-34%), with heterogeneity reduced in patients receiving specific pre-infusion prophylaxis. The pooled rate of discontinuation due to AEs was 8% (95% CI: 5%-11%), with discontinuation due to ARIA occurring in 5% (95% CI: 3%-7%) of patients in RWE studies.

Conclusions: Lecanemab-related ARIA demonstrates a clear ApoE4 gene-dose effect, supporting routine ApoE4 genotyping before treatment. Standardizing pre-infusion prophylaxis may reduce variability in IRRs incidence, while prompt recognition and management of ARIA are critical for improving treatment tolerability. These findings provide important evidence to support the safe clinical use of lecanemab.

Alzheimer's Disease is a complex, chronic illness of increasing prevalence in the US and worldwide. The complexity of this illness, and its impact on caregivers make it an ideal candidate for navigation services. The development of billable navigation codes now make it possible to create a financially sustainable navigation program. We describe our initial experience with a brain health navigator program, partnering between primary and specialty memory care, in a large integrated healthcare system. While a number of challenges exist, and careful planning was required, we have successfully implemented a navigation program, enrolling greater than 100 patients in the initial 6 months. Patient and caregiver feedback has been highly positive. We have experienced no significant barriers to reimbursement and when accounting for incremental downstream revenue generation (e.g. MRI, labs), we are forecasting long-term financial sustainability and the opportunity for continued scaling over time.

Background and objectives: Multiple lifestyle and health factors could contribute to cognitive health, while not many studies examined the factors in a combined way, especially in Asian population. This study aims to examine the association of Life's Simple 7 (LS7) with cognitive function and its change in a multi-ethnic Asian population.

Methods: Longitudinal data were drawn from the Singapore Multi-Ethnic Cohort, involving 2601 participants (45-86 years). LS7 at baseline was calculated by summing seven metrics, and a higher LS7 (range: 0-7) score indicates a healthier lifestyle. Cognitive function was measured at two revisits with Mini-Mental State Examination (MMSE). Association of baseline LS7 with MMSE percentiles (10th, 30th and 50th) and its change over time were examined using linear quantile mixed model. Interactions between LS7 and age group, sex, ethnicity, education level and marital status were also explored.

Results: Higher LS7 was significantly associated with higher MMSE scores at 10th (β = 0.11, 95% CI 0.01, 0.20), 30th (β = 0.12, 95% CI 0.05, 0.19), and 50th (β = 0.07, 95% CI 0.03, 0.11) percentiles. These associations were particularly pronounced among currently unmarried individuals, participants aged 60 and above, those with education above primary school and Chinese ethnicity. No significant association was found between LS7 and MMSE change over time.

Discussion: Higher LS7 was significantly associated with better cognition particularly among older, unmarried individuals and participants with higher education or of Chinese ethnicity. These findings highlight the value of composite lifestyle scores for cognitive impairment risk modification in Asian populations.

Background: The potential improvement of cognitive function through folic acid (FA) supplementation in patients with vascular cognitive impairment (VCI) remains unclear, and no randomized controlled trials (RCTs) have been conducted specifically in populations with cerebral small vessel disease-related cognitive impairment (CSVD-CI).

Objective: This study aimed to explore the effects of FA supplementation on cognitive function and angiogenesis-related indicators in patients with CSVD-CI.

Design: Double-blinded, parallel group, randomized controlled trial, with a six-month follow-up period.

Setting: Department of neurology and neurosurgery in Shanxi, China.

Participants: 220 CSVD-CI patients.

Interventions: The intervention consisted of FA tablets (0.4 mg/tablet) administered orally at a dose of two tablets daily for six months, while the placebo tablets were identical in appearance and administration but lacked FA.

Measurements: The primary outcome was the Montreal Cognitive Assessment (MoCA) score at six months assessed in the intention-to-treat (ITT) population. Secondary outcomes included Mini-Mental State Examination (MMSE) score, Trail Making Test (TMT), Tinetti Performance Oriented Mobility Assessment (POMA), and five-level EuroQol five-dimensional questionnaire (EQ-5D-5 L).

Results: MoCA and MMSE scores improved significantly in the FA group compared to placebo (both P < 0.05). Additionally, the FA group had statistically significant increases in serum folate and decreases in serum homocysteine (Hcy) (both P < 0.001). Matrix metalloproteinase-9 (MMP-9) expression decreased significantly in the FA group compared with placebo (P < 0.05).

Conclusions: FA improved cognitive outcomes in CSVD-CI, accompanied by a reduction in serum Hcy levels and MMP-9 expression. Early FA supplementation could help prevent vascular-related cognitive decline in CSVD-CI patients.