Journal of Alzheimer's Disease最新文献

Background: The growing aging population has led to an increase in the prevalence of Alzheimer's disease (AD) and osteoporosis (OP), both of which significantly impair quality of life. The comorbid nature of these conditions suggests a shared genetic etiology, the understanding of which is crucial for developing targeted therapies.

Objective: This study aims to explore the shared genetic etiology underlying AD and OP, using a system biology approach to identify potential therapeutic targets and natural compounds for treatment.

Methods: We employed Weighted Gene Co-Expression Network Analysis (WGCNA) with molecular docking strategies to uncover the genetic links between AD and OP. MT2A and CACNA1C were identified as key pleiotropic hub genes potentially linking AD and OP. Molecular docking was utilized to screen for compounds with therapeutic potential, leading to the identification of formononetin as a compound with significant binding affinity to these hub genes. Quantitative real-time PCR (qRT-PCR) validation was conducted to confirm the gene expression changes in disease models.

Results: Our study indicate that formononetin exhibits strong binding affinity to the identified hub genes, MT2A and CACNA1C. qRT-PCR validation confirmed the upregulation of these genes in disease models, which was mitigated upon treatment with formononetin, suggesting a reversal of disease markers.

Conclusions: This study advances our understanding of the genetic intersections between AD and OP and positions formononetin as a promising natural agent for further translational research. Formononetin's multi-target potential makes it a valuable candidate for managing these comorbid conditions, meriting further investigation and development as a therapeutic strategy.

Background: Spatial orientation is required for independent mobility in society. Deficits in spatial orientation can be an early symptom of Alzheimer's disease and other dementias, and there is a need for brief assessment tools to identify impairments.

Objective: The aim of this study was to evaluate the construct and known-group validity of our newly developed Spatial Orientation Screening (SOS) questionnaire.

Methods: We included 132 patients with subjective cognitive decline (n = 16), mild cognitive impairment (n = 32), or all-cause dementia (n = 84) from a memory clinic and a reference group of cognitively unimpaired older adults (n = 108). The patients and their next-of-kin answered the self- and proxy-rated versions of the 4-item SOS (0-8 points) and the 10-item Questionnaire of Everyday Navigational Ability (QuENA, 0-30 points). The patients also performed the Floor Maze Test (FMT) for performance-based spatial abilities.

Results: Mean ages (SD) of the patient and reference groups were 68.6 (±7.6) years and 73.7 (±6.7) years, respectively. Construct validity between self-rated versions of the SOS and QuENA was satisfactory with r_s= 0.66, between the proxy-rated versions r_s= 0.61, and between the proxy-reported SOS and FMT r_s= 0.49 (all p < 0.001). Known-group validity was also acceptable, with significantly higher median (IQR) SOS self-reported scores in patients 1.0 (2.0) compared to the reference group 0.2 (0.5) points, (p < 0.001). Informants reported more severe impairments compared to the patients' self-reports on both SOS and QuENA (both p < 0.001).

Conclusions: The SOS had satisfactory validity for use as a screening instrument for assessment of spatial orientation in memory clinic patients.

Background: Extracellular signal-regulated kinase 1 (ERK1) belongs to mitogen-activated protein kinases, which are essential for memory formation, cognitive function, and synaptic plasticity. During Alzheimer's disease (AD), ERK1 phosphorylates tau at 15 phosphorylation sites, leading to the formation of neurofibrillary tangles. The overactivation of ERK1 in microglia promotes the release of pro-inflammatory cytokines, which results in neuroinflammation. Additionally, elevated oxidative stress during AD stimulates the ERK1 pathway, leading to neuronal loss.

Objective: Because ERK1 signaling plays a significant role in tau phosphorylation, targeting ERK1 may be therapeutically beneficial by either preventing excessive activation of the signaling pathway or altering its pathway to enhance neuroprotective effects during AD.

Methods: This study employed structure-based virtual screening of phytoconstituents from the IMPPAT library. Subsequently, in-depth docking and molecular dynamics (MD) simulation studies were implemented to identify potential ERK1 inhibitors with desirable pharmacological properties.

Results: Silandrin and Hydroxytuberosone were found to be potential ERK1 inhibitors with higher affinity and specificity than the control molecule Tizaterkib. These compounds specifically bind to the ERK1 substrate binding pocket and interact with crucial residues. Finally, the elucidated compounds with ERK1 were evaluated using an all-atom molecular MD simulation to analyze structural dynamics, structural compactness, hydrogen bond dynamics, principal component analysis, and free energy landscape.

Conclusions: The study suggested that Silandrin and Hydroxytuberosone can further be exploited as potential lead molecules for therapeutic development against ERK1-mediated AD.

The motoric cognitive risk syndrome (MCR) is a novel and clinically relevant pre-dementia syndrome indicating a higher dementia risk (e.g., for Alzheimer's disease). Given that MCR prevalence is unknown in Germany, we conducted a cross-sectional study, in which 208 participants from Germany aged 50 and 82 years answered an online survey including questions to assess subjective MCR (sMCR). The adjusted sMCR prevalence was 25.3%. Adults with sMCR reported more diseases and showed negative associations with physical activity, sedentary behavior, and sleep, suggesting that lifestyle modifications can play a significant role in MCR prevention. Further research is required to complement our preliminary findings on sMCR prevalence in Germany.

Background: Blood-brain barrier (BBB) dysfunction is suggested to be a potential mediator between vascular risk factors and cognitive impairment, leading to vascular cognitive impairment. Objective: To investigate the relationships between age, sex, and vascular risk factors and BBB water permeability as well as their relationship with cognition. Methods: To measure BBB permeability, a novel arterial spin labelling MRI technique (ME-ASL) was applied to derive the time of exchange (Tex), arterial time transit (ATT), and cerebral blood flow (CBF). The association of potential risk factors, such as age, sex, body mass index (BMI), blood pressure (BP), and medical history, with these BBB parameters were assessed in 144 community-dwelling adults (median age 59 years, 57% females). The relationship between BBB permeability and cognitive performance measured by the Montreal Cognitive Assessment (MoCA) was also assessed. Results: We found that increased BMI was significantly associated with decreased CBF (β = -0.06). Systolic BP and diastolic BP showed significant associations with all ASL parameters; systolic BP was negatively correlated with Tex (β = -0.02) and CBF (β = -0.01) but positively with ATT (β = 0.02). Diastolic BP was negatively associated with Tex (β = -0.03) and CBF (β = -0.03) but positively with ATT (β = 0.03). MoCA scores had a borderline significant association with Tex (OR = 1.51) and a significant association with CBF (OR = 1.84), which became non-significant after adjusting for confounders. Conclusions: These outcomes underscore the potential of using ME-ASL, warranting further research to strengthen these findings.

Background: One of the hallmark pathological characteristics of Alzheimer's disease (AD) is amyloid-β (Aβ) accumulated in brain, which is mainly derived from the proteolytic processing of amyloid-β protein precursor (AβPP). The ubiquitin-proteasome system is able to reduce Aβ generation by ubiquitination and degradation of AβPP. Icariin (ICA), a flavonoid isolated from Epimedium brevicornum Maxim., has been reported that it could regulate the metabolism of AβPP and reduce the Aβ level in AD in vivo and in vitro models.

Objective: To investigate whether the effect of ICA on AβPP and Aβ is related to AβPP ubiquitination.

Methods: We used in vivo and in vitro models to observe the effect of ICA on AβPP ubiquitination as well as to investigate the effect of HMG-CoA reductase degradation protein 1 (HRD1), an E3 ubiquitin-protein ligase, on the processing of AβPP ubiquitination.

Results: This study showed that ICA improved the cognitive abilities of APP/PS1 AD mice in Morris Water Maze and Y-maze tests, upregulated HRD1 expression, subsequently elevated the total ubiquitination and K48-linked polyubiquitination of AβPP level, as well as increased AβPP degradation. Moreover, silenced HRD1 gene abolished the aforementioned effects of ICA. Furthermore, ICA decreased the location of AβPP in the early endosome, where AβPP is cleaved into Aβ, evidenced by reducing the co-localization of AβPP and early endosome antigen 1 (EEA1).

Conclusions: This study demonstrated that ICA increased AβPP degradation by upregulating HRD1 mediated ubiquitination.

Background: Physical activity and fitness are major targets in Alzheimer's disease (AD) preventive research. However, current research is heterogeneous and often disregards the relationship between these parameters and disease outcomes.

Objective: To assess the effects of physical activity and fitness on AD within the context of a multicomponent sports intervention.

Methods: 46 participants with early-stage AD (mean age 70 ± 7 years, 18 women, mean Montreal Cognitive Assessment (MoCA) score 19±5) were included in a six-month randomized controlled trial (Dementia-MOVE), participating in either a multicomponent sports intervention or a control condition with a psychoeducational program. The modulating effect of fitness and physical activity changes on AD outcome parameters such as cognition, function and cerebral brain structure from 3T-MRI were examined using multiple linear regression analyses.

Results: An increase in VO₂max was associated with assignment to the intervention group (p = 0.016), lower baseline fitness (p = 0.001), and an increased rate of physical activity (p = 0.046). Only in the intervention group, ΔVO₂max had a beneficial modulating effect on the MoCA score (p = 0.039), the executive functions (p = 0.017) and regional brain volumes of the temporal lobe, e.g., the hippocampus (p = 0.044). High daily step count was associated with preserved executive functions (p = 0.001), and caregivers' quality of life (p ≤ 0.001) in the overall sample.

Conclusions: Our results confirm that multicomponent exercise improves cardiorespiratory fitness in AD, which is associated with advantageous developments in cognitive performance and preservation of brain structure. These findings suggest that especially patients with comparably worse cognition and fitness benefit and should be encouraged for activity engagement.

Background: The amyloid cascade hypothesis still dominates in Alzheimer's disease (AD), and the acceleration of the clearance efficiency of amyloid-β (Aβ) has been always considered as an effective treatment option to slow the occurrence and progression of AD.

Objective: This study aims to explore the role of zkscan3 and its related pathways in AD of the microglia-mediated pathogenesis, and whether the combined effect of drugs can exert neuroprotective function.

Methods: N9 mouse microglia and HT-22 mouse hippocampal neurons were randomly divided into 6 groups, qRT-PCR technique was used to detect the gene expression level of zkscan3 and the genes related to lysosome generation and function. Fourteen C57 mice were randomly divided into two groups, and drug intervention model mice were randomly selected to establish from the AD group. Transmission electron microscope was used to detect the cell status and lysosome function in the hippocampus together with the other two groups.

Results: Compared with the AD model group, the gene expression of zkscan3 in the drug intervention group was downregulated, and the degree of neuronal injury in the hippocampus was reduced, the structure and number of synapses were improved, and the function of intracellular lysosome was enhanced.

Conclusions: Zkscan3 and its related genes play a vital role in the development of AD. CGRP and CHIT-1, as a combined intervention, imparts effects through zkscan3-related pathways to improve lysosomal function and exert certain neuroprotective effects.

Background: Recruitment registries are maximally effective when registrants are retained to the point of referral. The Research Attitudes Questionnaire (RAQ) has previously been shown to predict research participation behaviors, including Alzheimer's disease clinical trial completion.

Objective: To test the hypothesis that RAQ score is associated with retention behaviors in a local recruitment registry.

Methods: Using data from the UC Irvine Consent-to-Contact Registry, a recruitment registry that enrolls adults 18 years and older, we used logistic regression to quantify the association of RAQ score and the odds of first-year non-renewal. Covariates included demographic variables, comorbidities, and recruitment source. In longitudinal analyses, we used discrete proportional hazards and Cox proportional hazards models to quantify the relationship between RAQ score and time to non-renewal and time to active withdrawal, respectively.

Results: Among n = 4663 participants, we estimated that a 5-point higher baseline RAQ score was associated with a 15% lower odds of first-year non-renewal, after adjustment for potential confounding factors (OR: 0.85, 95% CI: (0.79, 0.92), p < 0.001). Older age and higher education were also associated with lower odds of non-renewal while Asian race, Hispanic ethnicity, and certain recruitment sources (e.g., doctor or friend referral) were associated with higher odds of non-renewal. Higher baseline RAQ and higher annually updated RAQ were both significantly associated with lower odds of non-renewal longitudinally. Age, education, and some recruitment sources, but not RAQ, were associated with active withdrawal.

Conclusions: Opportunities exist to identify predictors of registry retention behaviors and possible targets for intervention to improve related outcomes.

Background: In Alzheimer's disease (AD), tau and white matter lesion pathology are associated with clinical severity and subsequent decline, but their relative relationships with clinical assessments remain uncertain.

Objective: To examine cross-sectional and prognostic associations between baseline [¹⁸F]GTP1 tau positron emission tomography (PET) standardized uptake value ratio (SUVRs) and T1 white matter hypointensity (WMHypo) volumes with clinical indices.

Methods: We analyzed participants with biomarker-confirmed prodromal (n = 127) or mild (n = 233) AD with baseline [¹⁸F]GTP1 tau PET and MRI and longitudinal Clinical Dementia Rating-Sum of Boxes (CDR-SB), 13-item version of the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog13), Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), Mini-Mental Status Examination (MMSE), and Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) data.

Results: Higher baseline [¹⁸F]GTP1 SUVRs were independently associated with poorer baseline performance and faster rates of subsequent decline on all five clinical outcome measures. Higher baseline WMHypo volumes were independently associated with poorer baseline performance on the CDR-SB, ADAS-Cog13, RBANS, and MMSE and faster rates of subsequent decline on the CDR-SB and ADCS-ADL.

Conclusions: The independent associations of tau and white matter lesion pathology with clinical decline in AD suggest future prognostic models should include both imaging modalities.