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

Introduction: Hearing loss (HL) is a potential risk factor for Alzheimer's disease (AD), with animal studies suggesting a bidirectional relationship. This study examines whether HL links to changes in AD pathology and, whether AD biomarkers relate to subsequent HL progression.

Methods: Baseline Aβ42/Aβ40 and p-tau217 were measured using single-molecule arrays in 474 participants of the Rotterdam Study (mean age=62.37) between 2010-2016. HL was defined as the better-ear's pure-tone threshold average. After seven years, participants underwent amyloid PET; HL and p-tau217 were reassessed two years after PET.

Results: Baseline HL was not associated with amyloid PET positivity, Aβ42/Aβ40, or longitudinally with p-tau217. Likewise, HL progression did not predict PET outcomes. APOE4 carriership did not modify associations with Aβ PET. Similarly, baseline plasma biomarkers were also unrelated to longitudinal HL changes.

Conclusion: No bidirectional association was observed between HL and AD pathology, suggesting that HL may contribute to dementia through other pathways.

Alzheimer's disease (AD) is a growing public health concern in Asia, with an increasing prevalence driven by demographic shifts and rising life expectancy. The introduction of anti-amyloid monoclonal antibodies such as lecanemab and donanemab marks a pivotal transition from symptomatic management of AD to disease-modifying approaches, but their clinical use requires careful monitoring for amyloid-related imaging abnormalities (ARIA), a key safety consideration that presents either as vasogenic edema or as microhemorrhages and superficial siderosis. ARIA has been observed in varying frequencies across global and Asian clinical trial populations, underscoring the need for region-specific guidance. With our early clinical experiences in South Korea, Taiwan and Singapore serving as archetypes in Asia, we outline a framework for the detection and management of ARIA in Asian healthcare settings, accounting for disparities in imaging infrastructure, genetic factors, and clinician experience. Pre-treatment risk stratification, standardized imaging protocols, and severity-based treatment modifications are central to the framework, highlighting the critical role of multidisciplinary collaboration involving neurologists, geriatricians, psychiatrists, and radiologists in ensuring accurate detection and management of ARIA. Additionally, the paper highlights the role of pharmacovigilance, real-world evidence generation, physician education, and healthcare system preparedness in optimizing the safety and efficacy of anti-amyloid therapies in Asia. The proposed framework aims to ensure safe and effective use of anti-amyloid therapies while mitigating ARIA-related risks, thereby optimizing therapeutic outcomes for early AD in diverse healthcare settings across Asia.

Introduction: Functional impairment is central to dementia diagnosis, typically assessed through basic and instrumental activities of daily living (ADLs/IADLs) reported by participants or informants. However, it remains unclear which items and reporting sources best capture cognition-related functional impairment.

Methods: We analysed data from 1,050 adults aged ≥65 years in the English Longitudinal Study of Ageing Harmonised Cognitive Assessment Protocol. Self- and informant-reported ADL and IADL impairments were examined at overall and item levels. Associations with general and domain-specific cognition were estimated using linear regression, and with incident dementia over 6.7 years using Cox models, both adjusted for socioeconomic, lifestyle, and health factors.

Results: ADL and IADL impairment proportions were similar across self- and informant-reports, with modest concordance. Informant-reported, but not self-reported, impairments were consistently associated with poorer cognition across domains, particularly executive function (informant-reported ADL: β = -0.71 SD, 95% CI -0.89 to -0.53) and memory (informant-reported IADL: β = -0.46 SD, 95% CI -0.60 to -0.32), and higher dementia risk (ADL: HR = 3.13, 95% CI 1.23 to 7.96; IADL: HR = 5.00, 95% CI 2.40 to 10.43). The strongest associations were observed for managing money and tasks involving episodic or visuospatial memory, especially among individuals with intermediate education and when informants had higher education or daily contact.

Discussion: Informant-reported IADLs, particularly those involving financial management and memory, may be strong indicators of cognitive impairment and dementia risk. Emphasising these items and informant characteristics may improve population surveillance of dementia and inform outcome selection in preclinical dementia trials targeting early functional decline. These findings should be interpreted in the context of a population-based sample with attrition.

Research on Alzheimer's disease (AD) has traditionally focused on the brain. However, emerging evidence indicates that the liver acts as a silent partner in neurodegeneration. As a core hub for metabolic and immune regulation, the liver communicates bidirectionally with the brain via the liver-brain axis, participating in the regulation of various neurophysiological processes, including neurotransmitter regulation, feeding behavior, and cognition. This review summarizes how liver-derived hepatokines, inflammatory mediators, and metabolic products modulate brain function. We highlight that liver dysfunction disrupts the expression of critical molecules-including fibroblast growth factor 21, insulin-like growth factor 1, lipopolysaccharide, and lipocalin-2-thereby driving AD progression by impairing pathological protein clearance, activating neuroinflammation, exacerbating insulin resistance and oxidative stress, and disrupting lipid metabolism. We also discuss the therapeutic potential of targeting the liver-brain axis through lifestyle interventions (e.g., exercise and diet) and pharmacological approaches, to identify novel strategies to delay AD progression. In summary, we underscore the pivotal role of the liver-brain axis in AD pathogenesis and propose it as a promising target for early diagnosis and innovative therapies.

Background: The accurate identification of individuals at risk of Alzheimer's disease (AD) through blood-based biomarkers remains challenging.

Objectives: To evaluate the association between plasma amyloid-beta (Aβ)42/Aβ40 ratio and longitudinal amyloid deposition, clinical progression, brain atrophy and cognitive decline.

Design, setting and participants: This study extends the Fundació ACE Healthy Brain Initiative (FACEHBI) study (Barcelona, Spain), comprising 200 individuals with subjective cognitive decline (SCD) followed over five years.

Measurements: Aβ42/Aβ40 ratio was quantified using ABtest-MS, an antibody-free mass-spectrometry (MS) method. Survival analyses compared conversion risks to amyloid-PET positivity and mild cognitive impairment (MCI), in participants classified as low or high Aβ42/Aβ40, based on a cutoff of ≤ 0.241. Linear mixed-effect models evaluated associations of this biomarker with longitudinal changes in amyloid deposition, brain volume, and cognition.

Results: Low baseline Aβ42/Aβ40 was significantly associated with increased amyloid accumulation (β = 0.257, 95% confidence interval (CI) 0.177-0.336, P < 0.001), and with higher risk of conversion to Aβ-PET positivity (Hazard ratio (HR) = 2.84, 95% CI 1.14-7.04, P = 0.025) and to MCI due to AD (HR = 3.25, 95% CI 1.17-9.01, P = 0.024). It was also linked to decreased hippocampal (β = -1.183, 95% CI -2.154 to -0.211, P = 0.017) and cortical (β = -75.921, 95% CI -151.728 to -0.113, P = 0.050) volumes, and increased ventricular volume (β = 35.175, 95% CI 18.559-51.790, P < 0.001). Moreover, lower baseline levels of Aβ42/Aβ40 were weakly associated with greater worsening in Mini-Mental State Examination and complex associative memory.

Conclusions: Our findings suggest that the plasma Aβ42/Aβ40 ratio is associated with future amyloid accumulation, brain atrophy, and conversion to prodromal AD in individuals with SCD. This biomarker may help characterize individuals with a higher likelihood of progression and could support earlier and more personalized strategies.

Background: The joint effect of cardiovascular-kidney-metabolic (CKM) health and genetic susceptibility on dementia remains unclear.

Methods: This prospective cohort study utilized data from the UK Biobank. CKM syndrome was characterized by the presence of metabolic risk factors, cardiovascular disease, and chronic kidney disease. We employed Cox proportional hazards models to examine the association between CKM syndrome and dementia incidence, while also investigating the influence of genetic risk via polygenic risk score (PRS) and apolipoprotein E (APOE) ε4 status. We also examined the association between CKM syndrome and cognitive function via linear regression model.

Results: Among 331,731 participants (mean ± SD age, 56.53 ± 8.1 years; 156,762 [47.26 %] male), 4413 (1.33 %) developed dementia during a mean follow-up of 12.8 years. Advanced CKM syndrome correlated with higher risk of dementia; compared to stage 0, HRs for dementia were 1.19 (95 % CI 1.01-1.39, P = 0.036), 1.26 (95 % CI 1.09-1.45, P = 0.002), and 2.06 (95 % CI 1.77-2.39, P < 0.001) for stages 1, 2, and 3-4, respectively. Genetic susceptibility further strengthened this association, and the synergistic effect of CKM syndrome, dementia PRS, and APOE ε4 status surpasses the individual contributions of any single factor. These findings remained robust in a series of subgroups and sensitivity analyses. Individuals in the later stages of CKM syndrome demonstrated poorer performance on cognitive function tests.

Conclusions: Poor CKM health was independently associated with cognitive impairment and an increased risk of dementia. The association between CKM syndrome and risk of dementia could be further strengthened by genetic susceptibility.

Four studies now document reduced incidence of Alzheimer's disease (AD) or dementia diagnoses in aging individuals who report higher dietary intake of flavonols (or their glycosides) years prior to diagnosis vs those with lower intake. These effects are large, almost 50 %, for individuals at higher genetic risk for AD, providing a robust gene x environment interaction. They display a specific structure-activity relationship. These benefits are driven by modest-to-moderate differences in the quantity of flavonol (glycoside) consumed. These data contrast with the failure of late life supplementation with flavonol-rich ginko extract to alter progression to AD in groups of individuals who are not selected for genotype or dietary pattern. Studies of mouse AD models support benefits of the flavonol quercetin. In vitro and in vivo results add the receptor type protein tyrosine phosphatase PTPRD to the list of oxidative and other targets or mechanisms to which flavonol benefits are attributed. The magnitude of flavonol protection for individuals who would otherwise be especially vulnerable to AD, the ease of supplementation strategies with currently-available nutraceuticals and the opportunities for development of improved flavonol analogs all support further exploration of flavonol-based strategies for reducing the incidence of AD with aging.

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: 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.