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

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 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: The agreement between plasma Aβ42/40 and Aβ positron emission tomography (PET) is approximately 75 %, with ∼85 % of discrepancies due to positive plasma but negative PET results. It is unclear whether this reflects Aβ changes in plasma before PET-detectable.

Objectives: To assess the influence of Aβ42/40 positivity on risk of progression to Aβ PET positivity, and feasibility of using plasma Aβ42/40 tests to enrich a primary prevention trial.

Design: A prospective longitudinal cohort study.

Setting: Participants of Australian Imaging, Biomarkers and Lifestyle study (AIBL), Alzheimer's Disease Neuroimaging Initiative (ADNI), and Open Access Series of Imaging Studies 3 (OASIS3).

Participants: 507 cognitively unimpaired adults at baseline, with a baseline Aβ PET < 20 Centiloid (CL) and available longitudinal Aβ PET data.

Measurements: Baseline Aβ PET and plasma Aβ42/40 measurement by mass-spectrometry, followed by 1-6 additional Aβ PET scans every 1.5-3 years. Those < 5 CL were classified as PET- and 5-20 CL as PET_Low. Plasma -/+ was defined using the Aβ42/40 Youden's Index threshold (0.119), corresponding to Aβ PET status.

Results: At baseline, 283 were Plasma-/PET-, 97 Plasma+/PET-, 76 Plasma-/PET_Low, and 51 Plasma+/PET_Low. Among Plasma+/PET- individuals, 19 % progressed to PET+ (>20 CL), indicating a higher risk of progression, compared to Plasma-/PET- (HR: 3.90 [90 % CI: 2.00-7.61], p < 0.001). This elevated risk remained significant after matching the groups' baseline CL (3.43 [1.43-8.26], p = 0.010), or adjustment for age, sex, APOE ε4 and baseline CL (2.48 [1.22 - 5.07], p = 0.013). Plasma+/PET- individuals accumulated Aβ ∼8 times faster (1.14 CL/year) than Plasma-/PET- (0.15 CL/year, p < 0.001). Plasma+/PET- progressors became PET+ two years earlier than Plasma-/PET- progressors. Among the Plasma+/PET_Low individuals, 67 % progressed to PET+. Their progression was faster and earlier than in the Plasma-/PET_Low group (HR: 20.82 [11.28 - 38.42], p < 0.001 vs. 6.67 [3.51 - 12.65], p < 0.001; reference: Plasma-/PET-), largely driven by higher baseline CL in the Plasma+ group. In a primary prevention paradigm targeting high-risk PET_Low individuals, pre-screening with Aβ42/40 blood test reduced the number of PET scans by 49 %, compared to a PET-only strategy.

Conclusions: Cognitively unimpaired individuals with abnormal Aβ42/40 are at increased risk for future Aβ PET positivity. In the 5-20 CL subgroup, baseline CL is the main driver of this risk. Combining blood-based pre-screening with PET imaging may help efficiently enrich primary prevention trials.

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.

Alzheimer's disease (AD) is a heterogeneous neurodegenerative disease driven by pathological depositions of proteins that accumulate over decades. Compelling genetic and neurobiological evidence suggests that amyloid accumulation in the brain initiates and drives early-stage AD. Measurement of fibrillar amyloid has been pivotal to the development and approval of disease-slowing treatments. Various biomarkers of AD pathophysiology provide evidence of target engagement and downstream effects on disease progression, and their use as surrogate endpoints may help identify and expeditiously bring new treatments to patients. In clinical trials, a surrogate endpoint serves as a substitute for a direct measurement of a patient's clinical status, and its use can provide ethical, logistical, and economic advantages. Establishing biomarkers as surrogate endpoints involves evaluating scientific evidence through diverse statistical approaches to demonstrate their predictivity of clinical benefit. This article evaluated evidence supporting amyloid β plaque reduction as a surrogate endpoint in symptomatic AD by exploring regulatory considerations and guidelines for surrogate endpoints, examining the amyloid hypothesis and the current therapeutic landscape in AD, and presenting supporting evidence of surrogate endpoints from a recent clinical development program of AD.

Background: The global prevalence of dementia is rapidly expanding and is expected to triple by 2050. Approximately 45 % of dementia cases are estimated to be attributable to potentially modifiable risk factors. Identifying how these factors contribute to specific brain pathologies may improve strategies to reduce dementia incidence.

Objectives, design, setting: The aim of this study was to identify both non-modifiable and modifiable risk factors associated with longitudinal changes in white matter hyperintensities (WMH), amyloid-beta (Aβ) and tau. Data were acquired in the prospective observational Swedish BioFINDER-2 study between May 2017-January 2025. All participants underwent clinical assessments, questionnaires and at least two magnetic resonance imaging (MRI), Aβ Positron Emission Tomography (PET) and tau PET scans, respectively. Mixed-effects models were used to assess the associations between non-modifiable and modifiable risk factors and WMH (MRI), Aβ (PET) and tau (PET).

Participants: A total of 494 cognitively unimpaired participants were included, of whom 365 were amyloid-negative (CU Aβ-) and 129 were amyloid-positive (CU Aβ+).

Measurements and main outcomes: Non-modifiable (age, apolipoprotein E (APOE) ɛ4 genotype and sex) and modifiable risk factors (co-morbidities at baseline, such as hypertension and cardiovascular disease, BMI, and sleep duration) were analyzed with mixed-effects models, adjusted for age and sex, to predict longitudinal measurements of WMH, Aβ and tau.

Results: Mean age was 64.8 (SD 13.3) years and mean follow-up was 3.9 (SD 1.5) years. Predictors represent baseline data, both predictors and outcomes are on standardized scales. Linear mixed-effects models, adjusted for age and sex, showed that higher blood pressure (β = 0.02, 95 % CI :0.01-0.02), presence of hyperlipidemia (β = 0.03, 0.01-0.05), ischemic heart disease (β = 0.06, 0.03-0.09), smoking (β = 0.02, 0.00-0.03) and lower education (β = -0.01, -0.02- -0.01) were associated with a longitudinal increase in WMH. Presence of the APOE ε4 allele was linked to faster Aβ accumulation (β = 0.03, 0.02-0.04) and tau (β = 0.01, 0.00-0.03), but only to Aβ among Aβ+ positive participants. Higher depression score (β = 0.01, 0.00-0.01) and diabetes (β = 0.02, 0.00-0.04) were associated with faster Aβ accumulation. Lower BMI was associated with faster accumulation of tau (β = -0.01, -0.02- -0.01).

Conclusions: Modifiable risk factors of future dementia primarily affect accumulation of cerebral vascular pathology, although lower BMI was associated with tau accumulation and diabetes with Aβ accumulation.

O-GlcNAcase inhibitors (OGAi) have emerged as a promising therapeutic strategy in Alzheimer's disease (AD) by enhancing O-GlcNAcylation, which competes with tau phosphorylation and reduces tau aggregation. However, the Phase II clinical trial failure of ceperognastat, marked by accelerated cognitive decline in the treatment group, has raised significant safety concerns. Here, we examined the acute synaptic effects of three structurally distinct OGAi compounds-ceperognastat, ASN90, and MK8719-in mouse hippocampal slices. Electrophysiological recordings revealed suppression of both short- and long-term synaptic plasticity, including paired-pulse facilitation/depression and long-term potentiation. Immunohistochemical analysis confirmed disrupted synaptic protein levels (increased PSD-95, reduced Synaptophysin 1) and a biphasic shift in tau phosphorylation. These convergent findings suggest a class-wide synaptotoxic mechanism and call for a great caution in the development of disease-modifying therapies in AD. We argue that preclinical drug screening for synaptic functionality is essential in CNS-targeted therapeutic pipelines.

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: 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.