Journal of Alzheimer's Disease最新文献

Background: Disruption of circadian rest-activity rhythm (RAR) has been found in many neurological disorders. Objective: In this study, actigraphic data were collected and analyzed to identify the RAR pattern in the elderly with cerebral small vessel disease. Methods: 115 cerebral small vessel disease (CSVD) cases were recruited. The presence of lacune infarct, white matter hyperintensities, and cerebral microbleeds in magnetic resonance imaging (MRI) images were rated independently, as well as using a simple MRI score of 0-3 points. Each subject wore an Actigraph device in their nondominant hand for 4-7 days to collect raw data. RAR parameters were generated using both extended cosinor model (RAR α, RAR β, amplitude, acrophase, up-mesor, down-mesor, and pseudo-F statistic) and non-parametric methods (interdaily stability, intradaily variability, and relative amplitude). Results: Elder patients with a simple MRI score of 2-3 points showed a statistically lower amplitude compared with individuals with a simple MRI score of 0 points in the extended cosinor model. For the non-parametric method, elderly people with a simple MRI score of 1-3 points exhibited higher intradaily variability relative to those participants with a simple MRI score of 0 points. However, no differences were found regarding sleep quality among individuals with different simple MRI scores. White matter hyperintensities, lacune infarct, and cerebral microbleeds were independently associated with RAR β, RAR α, and intradaily variability, respectively. Conclusions: The RAR pattern was disturbed in elderly adults with CSVD. Abnormal RAR parameters were independently associated with CSVD MRI markers.

Seizures in people with Alzheimer's disease are increasingly recognized to worsen disease burden and accelerate functional decline. Harnessing established antiseizure medicine discovery strategies in rodents with Alzheimer's disease associated risk genes represents a novel way to uncover disease modifying treatments that may benefit these Alzheimer's disease patients. This commentary discusses the recent evaluation by Dejakaisaya and colleagues to assess the antiseizure and disease-modifying potential of the repurposed cephalosporin antibiotic, ceftriaxone, in the Tg2576 mouse model. The use of established epilepsy models in Alzheimer's disease research carries the potential to advance novel disease-modifying treatments.

Autophagy is a fundamental cellular process critical for maintaining neuronal health, particularly in the context of neurodegenerative diseases such as Alzheimer's disease (AD). This review explores the intricate role of the SNARE complex in the fusion of autophagosomes with lysosomes, a crucial step in autophagic flux. Disruptions in this fusion process, often resulting from aberrant SNARE complex function or impaired lysosomal acidification, contribute to the pathological accumulation of autophagosomes and lysosomes observed in AD. We examine the composition, regulation, and interacting molecules of the SNARE complex, emphasizing its central role in autophagosome-lysosome fusion. Furthermore, we discuss the potential impact of specific SNARE protein mutations and the broader implications for neuronal health and disease progression. By elucidating the molecular mechanisms underlying SNARE-mediated autophagic fusion, we aim to highlight therapeutic targets that could restore autophagic function and mitigate the neurodegenerative processes characteristic of AD.

Alzheimer's disease (AD) is the most common disease associated with cognitive dysfunction, which is closely associated with type 2 diabetes mellitus (T2DM) in clinical manifestations, pathological changes and prevention. Inhibition of dipeptidyl peptidase 4 (DPP-4) can lower blood glucose levels by stimulating insulin secretion. Besides, it can affect cognitive function through the neuroprotective effect of DPP-4 substrates, such as glucose-dependent insulin peptide and glucagon-like peptide-1, the proteolytic effect on amyloid-β and the protective effect on neuronal structure. This review discusses the relationship between cognitive impairment in T2DM and in AD, summarizes the effect of DPP-4 inhibitor (DPP-4i) on improving cognitive impairment in these two diseases based on the current studies. Given the lack of clinical randomized trials that evaluate the effect of DPP-4i on AD, this review is expected to provide preclinical evidence for DPP-4i as a potential therapy for the treatment and prevention of AD.

Background: Black adults have higher dementia risk than White adults. Whether tighter population-level blood pressure (BP) control reduces this disparity is unknown.

Objective: Estimate the impact of optimal BP treatment intensity on racial disparities in dementia.

Methods: A microsimulation study of US adults ≥18 across a life-time policy-planning horizon. BP treatment strategies were the Systolic Blood Pressure Intervention Trial (SPRINT) protocol, the Eighth Joint National Committee (JNC-8) recommendations, and usual care (non-intervention control). Outcomes were all-cause dementia, atherosclerotic cardiovascular disease (ASCVD), stroke, myocardial infarction, non-ASCVD death, global cognitive performance, and optimal brain health (being free of dementia, cognitive impairment, or stroke). Population-level and individual-level effects stratified by race were estimated.

Results: Optimal population-level implementation of a SPRINT-based BP treatment strategy, compared to usual care, would increase average annual dementia incidence in White, but not Black, adults (1% versus 0%), due to hypertensive individuals' greater survival, and reduce annual ASCVD events more in Black than White adults (13% versus 5%). Under a SPRINT-based strategy, individuals with hypertension gained more years lived without dementia, ASCVD, myocardial infarction, or stroke and more years lived in optimal brain health. A SPRINT-based strategy did not attenuate individual-level race disparities in outcomes, except stroke. Due to longer life expectancy, a SPRINT-based strategy did not substantially reduce lifetime dementia risk in either group. The JNC-8-based strategy had similar but smaller effects as the SPRINT-based strategy.

Conclusions: Our results suggest that tighter population-level BP control would not reduce population-level disparities in dementia between US Black and White adults.

Background: Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive impairment.

Objective: To elucidate the potential mechanisms of Sheng-Hui-Yi-Zhi (SHYZ) for the treatment of AD and explore the effective substances of SHYZ.

Methods: Liquid chromatography-mass spectrometry (LC-MS) was used to identify the active components of SHYZ. Network pharmacology was employed to predict the potential targets and pathways of SHYZ in the treatment of AD. SAMP8 mice were used as a model for AD and were treated with SHYZ. The Morris water maze was utilized to assess the learning and memory capabilities of mice. Additionally, the levels of TNF-α, IL-1β, and IL-6 in the brain hippocampus of mice were quantified using ELISA. The protein expression of PI3 K/p-PI3 K, AKT/p-AKT, MAPK38/p-MAPK38, and NFκB p65/p-NFκB p65 in the hippocampus was analyzed using Western blotting. Additionally, qRT-PCR was employed to assess the gene expressions of TNF-α, IL-1β, and IL-6 in the hippocampus.

Result: The network pharmacological prediction results showed that the treatment of AD with SHYZ was closely related to the inhibition of inflammatory response. Behavioral experiments revealed that SHYZ significantly reduced the time taken to escape, increased the number of times the platform was crossed, and prolonged the residence time in the target quadrant. Meanwhile, SHYZ treatment suppressed the expression of Aβ_1-42 protein and inflammatory factors. SHYZ significantly inhibited the expression of proteins of PI3 K, AKT, MAPK p38, and NF-κB p65.

Conclusions: SHYZ has been shown to effectively ameliorate learning and memory impairment in SAMP8 AD mice by inhibiting the expression of Aβ_1-42 and reducing the increase of inflammatory factors.

Background: While the preventive effects of green tea and coffee on cognitive decline have been demonstrated, their long-term effects on cognition remain unclear.

Objective: This study aims to investigate the effect of green tea and coffee consumption in middle age on the prevention of dementia.

Methods: This population-based cohort study included 1155 participants (aged 44-66 in 1995). Participants' consumption of green tea and coffee was assessed using questionnaires in 1995 and 2000. Their cognitive levels were neuropsychologically evaluated in 2025-2015. Logistic regression analyses were conducted with significant cognitive decline (defined as multi-domain cognitive decline and more severe conditions) as the dependent variable. Stratified analyses were also conducted by sex and age.

Results: Individuals who consumed 2-3 cups of green tea daily had a significantly reduced risk of cognitive decline (OR = 0.56, 95%CI: 0.35-0.91) after adjusting potential confounders. However, this effect was not significant with consumption of 4 or more cups. This protective effect was particularly observed in males (OR = 0.38, 95%CI: 0.19-0.76). A significant risk reduction was also observed in individuals consuming one or more cups of coffee daily (OR = 0.54, 95%CI: 0.34-0.84) in the older subjects (median age [53 years old] and older in 1995) in the same fully adjusted model, but not in the entire sample.

Conclusions: Our findings suggest that moderate green tea consumption in midlife may have a beneficial effect on preventing dementia, particularly in males. The effects of coffee consumption may be more advantageous for older individuals.

Background: High-density lipoprotein (HDL) modulates the blood-brain barrier and cerebrovascular integrity, likely influencing the risk of Alzheimer's disease (AD), neurodegeneration, and cognitive decline.

Objective: This study aims to identify HDL protein cargo associated with brain amyloid deposition and brain volume in regions vulnerable to AD pathology in older adults.

Methods: HDL was separated from the plasma of 65 non-demented participants of the Atherosclerosis Risk in Communities (ARIC) study using a fast protein liquid chromatography method. HDL cargo proteins were measured using a label-free, untargeted proteomic method based on mass spectrometry and data-independent acquisition. Linear regression with multiple imputations assessed the associations between each HDL cargo protein (log2-transformed) and brain amyloid deposition or temporal-parietal meta-ROI volume, adjusting for covariates.

Results: The mean (SD) age of the participants was 76.3 (5.4) years old, 53.8% (35/65) female, 30.8% (20/65) black, and 28.1% (18/64, 1 missing) APOE4 carriers. We found few HDL cargo proteins associated with brain amyloid deposition and considerably more HDL cargo proteins associated with temporal-parietal meta-ROI volume. Two HDL cargo proteins mostly associated with temporoparietal meta-ROI volume were fibrinogen B (FGB) and plasminogen (PLG). A doubling of FGB in HDL was associated with a greater temporoparietal meta-ROI volume of 1638 mm³ (95% CI [688, 2589]). In comparison, a doubling of PLG in HDL was associated with a lower temporoparietal meta-ROI of 2025 mm³ (95% CI [-3669, -1034]).

Conclusions: This study suggests that HDL cargo proteins associated with temporal-parietal meta-ROI volume are involved in complement and coagulation pathways.

Background: Medications for comorbid conditions may affect cognition in Alzheimer's disease (AD).

Objective: To explore the association between common medications and cognition, measured with the Mini-Mental State Examination.

Methods: Cohort study including persons with AD from the Swedish Registry for Cognitive/Dementia Disorders (SveDem). Medications were included if they were used by ≥5% of patients (26 individual drugs). Each follow-up was analyzed independently by performing 100 Monte-Carlo simulations of two steps each 1) k-means clustering of patients according to Mini-Mental State Examination at follow-up and its decline since previous measure, and 2) Identification of medications presenting statistically significant differences in the proportion of users in the different clusters.

Results: 15,428 patients (60.38% women) were studied. Four clusters were identified. Medications associated with the best cognition cluster (relative to the worse) were atorvastatin (point estimate 1.44 95% confidence interval [1.15-1.83] at first follow-up, simvastatin (1.41 [1.11-1.78] at second follow-up), warfarin (1.56 [1.22-2.01] first follow-up), zopiclone (1.35 [1.15-1.58], and metformin (2.08 [1.35-3.33] second follow-up. Oxazepam (0.60 [0.50-0.73] first follow-up), paracetamol (0.83 [0.73-0.95] first follow-up), cyanocobalamin, felodipine and furosemide were associated with the worst cluster. Cholinesterase inhibitors were associated with the best cognition clusters, whereas memantine appeared in the worse cognition clusters, consistent with its indication in moderate to severe dementia.

Conclusions: We performed unsupervised clustering to classify patients based on their current cognition and cognitive decline from previous testing. Atorvastatin, simvastatin, warfarin, metformin, and zopiclone presented a positive and statistically significant associations with cognition, while oxazepam, cyanocobalamin, felodipine, furosemide and paracetamol, were associated with the worst cluster.

Background: Past research suggests that ethnoracialized groups differ in their willingness to engage in preclinical Alzheimer's disease (AD) research overall. Studies indicated that participation willingness was affected by attitudes toward research and perceived invasiveness of biomarker collection techniques. However, comparative quantitative studies are few, and minoritized groups are under-included.

Objective: In a cross-sectional online survey, we sought to explore community-based adults' willingness to engage in preclinical AD biomarker testing, comparing their attitudes about research and different types of biomarker procedures.

Methods: We conducted an online survey with a diverse group of participants. African American (AA), American Indian/Alaska Native (AI/AN), Latinx (LTX), and Non-Hispanic White (NHW) adults aged 26-90 were asked about their research attitudes, biomarkers, and willingness to participate in specific biomarker test procedures (i.e., brain imaging via PET scanning, blood draws, and cerebrospinal fluid collection by lumbar puncture). We also assessed participants' perceived safety, burden, and distress for each of the three biomarker collection methods. To understand the association between research willingness and ethnoracial identity, we ran linear regression models for each procedure, adjusting for age, gender, educational attainment, and attitudes toward research.

Results: The AA group expressed greater willingness to engage in biomarker testing involving blood draws than the NHW group. The AI/AN group was significantly less willing to undergo lumbar puncture than the NHW group; this difference remained after adjusting for various sociodemographic factors and research attitudes.

Conclusions: Respondents' willingness to engage in preclinical AD biomarker research was affected by their perceptions about the testing collection procedure.