Journal of Alzheimer's disease reports最新文献

Background: The relationship and mechanisms between body mass index (BMI) and cognition are complex and inconclusive. Additionally, the role of neuronal calcium dysfunction, reflected by cerebrospinal fluid (CSF) Visinin-like protein 1 (VILIP-1), in the mechanisms linked with BMI and Alzheimer's disease (AD) has not been investigated.

Objective: To investigate the relationship between CSF VILIP-1, BMI, and AD pathologies in non-demented elderly at early stages of AD.

Methods: Baseline CSF AD core biomarkers (amyloid-β₄₂ [Aβ₄₂], phosphorylated tau [P-tau], and total tau [T-tau]) were measured for 1201 non-demented participants, selected from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database, among whom 128 had measurements of CSF VILIP-1. Multivariate linear regression, causal mediation analyses, and linear mixed effects models were conducted to detect these associations.

Results: The average age of participants was 72.6. CSF VILIP-1 was decreased in A+/TN- (A-positive/T- and N- negative) group and elevated in A-/TN + (A-negative/T- or N-positive) and A+/TN + groups, as compared with A-/TN- group. In total participants, BMI was negatively related to CSF P-tau, T-tau, P-tau/Aβ₄₂ and T-tau/Aβ₄₂. Noticeable associations were also presented between CSF VILIP-1 and AD core biomarkers, but not with Aβ₄₂ after stratification by A/T/N scheme. Furthermore, the influences of BMI on CSF tau pathology were mediated by CSF VILIP-1. Higher baseline CSF VILIP-1 correspond to faster longitudinal cognitive decline.

Conclusions: Our findings indicated that CSF VILIP-1 changed dynamically and might be a key mediator in the associations between BMI and tau pathology, providing new insights into understanding the mechanisms underlying BMI-related cognitive deficits in non-demented elderly.

Familial cases of Alzheimer's disease (AD) with autosomal dominant transmission and early onset have a prevalence around 1%. Since only a small fraction of them has a monogenic inheritance due to APP, PSEN1, and PSEN2 genes, genetic studies are ongoing to unravel the missing heritability. By sequencing panels including multiple dementia-related genes, we identified a novel likely pathogenic mutation in SORL1 in a pedigree including five members affected by AD. This loss of function mutation may lead to a reduction of SORL1 receptor, worsening amyloidogenic burden. As the contribution of SORL1 mutations to heritability of AD is presently not well established, we think that it is very important to signal new familial (likely) pathogenic SORL1 mutations in order to define the actual genetic involvement of SORL1 in AD pathogenesis.

Background: The apolipoprotein E allele ε4 is the most well-known predisposing genetic risk factor for Alzheimer's disease (AD).

Objective: To identify AD genes in apolipoprotein E^-/- (ApoE^-/-) mice brains with confirmed entry of Porphyromonas gingivalis.

Methods: TaqMan™ Mouse AD arrays were performed on orally infected ApoE^-/- mice with confirmed P. gingivalis entry and compared with sham infected mice brains (N = 4) at 12- and 24-weeks post infection.

Results: Gene expression by qPCR demonstrated that in the P. gingivalis 12-weeks post oral infection, two genes were statistically significantly changed in their expression. These were cyclin dependent kinase 5 regulatory subunit 1 (Cdk5r1, 0.15 logfold change, p = 0.05) and Interleukin 1 alpha, (IL1a, -0.10 log fold change, p = 0.012). In the P. gingivalis 24-weeks post oral infection, three genes were statistically significantly changed in their expression. These were cholinergic receptor nicotinic alpha 7 subunit or Chrna7 (0.10 log fold change, p = 0.02), mitogen-activated protein kinase 1 or Mapk1 (0.10 log fold change, p = 0.05) and visinin like 1 or Vnsl1 (0.01 log fold change, p = 0.04). 87 out of 92 AD target genes demonstrated no difference between infected and sham mice brains.

Conclusions: Five genes, from a recognized AD panel had statistically significantly altered expression in the ApoE^-/- mouse AD model following P. gingivalis entry into the brain. This suggests the ApoE^-/- genetic variation may control the biological activity of specific genes relevant to inflammation and neuronal plasticity following P. gingivalis infection.

To investigate the role of neuroinflammation as mediator of amyloid-β-induced cortical activity changes in Alzheimer's disease (AD), we examined the relationship between cerebrospinal fluid (CSF) inflammatory cytokines (IL-1β, IL-2, IL-4, IL-6, IL-7, IL-8, IL-10, IL-12, IL-13, IL-17, TNF-α, IFN-γ, GM-CSF, G-CSF, MIP-1α, MCP-1) and electroencephalographic (EEG) abnormalities in a cohort of biologically defined AD patients (n = 55, M:F = 19:36, median age 73, Mini-Mental State Examination ≥ 22). We retrieved a positive association between IL-4 CSF levels and EEG background activity frequency; IL-7, IL-8, and IL-12 CSF levels were positively associated with the presence of interictal epileptiform discharges. Neuroinflammation accompanying AD pathology may enhance the amyloid's epileptogenic potential while also counteracting neurodegenerative damage.

Background: Neurological and psychological sequelae may persist after the infection of coronavirus disease 2019 (COVID-19). Depression and cognitive decline could increase the risk of Alzheimer's disease.

Objective: To estimate the impacts of COVID-19 on depressive symptoms and cognitive decline.

Methods: The data was from Beijing Research on Ageing and Vessel (BRAVE), which included all residents in the Xishan community. The first wave survey was performed from October to November 2019 (baseline) before the COVID-19 pandemic. The second wave survey was interrupted into two periods due to the introduction of the Ten New Measures, from October to November 2022 (no participants were infected) and from March to April 2023 (most participants were infected), providing an excellent opportunity to investigate the short-term impacts of COVID-19 on depressive symptoms and cognitive function with linear mixed models.

Results: Among a total of 1012 participants, the median (interquartile range, IQR) age at baseline was 60.00 (56.00, 65.00) years, with 374 (36.96%) men and 479 participants COVID-19 infected. Compared with uninfected participants, the infected did not suffer pronounced depressive symptoms (β = -0.047; 95% CI -0.204 to 0.110) and accelerated declines in global cognition (β = 0.116; 95% CI -0.001 to 0.234) from wave 1 to wave 2. Sensitive analyses shared generally consistent findings.

Conclusions: The impacts of COVID-19 infection on depressive symptoms and cognitive decline were not significant among participants in the BRAVE cohort. Further research is needed to investigate the long-term impacts on neurological and psychiatric symptoms.

Background: Cognitive impairments have been reported among disadvantaged populations.

Objective: We aimed to ascertain how demographic factors are associated with cognitive performance in individuals enrolled in a local substance abuse recovery program.

Methods: In total, 106 participants were included in the study. Besides demographic information, vital signs and cognitive function, measured by Mini-Mental State Examination (MMSE) or Montreal Cognitive Assessment (MoCA), were collected from each participant. Welch's t-test and regression analysis were used to analyze how different demographic factors are associated with cognitive assessment scores.

Results: The mean age of African American (AA) participants (n = 43) were 48.35 ± 1.65 years, which are older than that for the White participants of 38.95 ± 1.36 (n = 63) years. Compared to the AA participants, the White participants had a larger variance in attained education levels. The average MMSE scores were 27.09 ± 0.40 for AA participants, which is lower than that for the White participants of 28.52 ± 0.33 (p < 0.05). The average MoCA scores were 23.71 ± 0.54 for AAs, which is lower that for the White participants of 26.65 ± 0.44 (p < 0.001). The AA and White participant groups had cognitive impairment rate of 18.6% and 6.35%, respectively. The regression analysis indicates age and education are two significant predictors for the cognitive performance difference between the two racial groups.

Conclusions: Significant disparities in cognitive performance exist between two racial groups of enrolled in a local substance abuse recovery program. The older age and lower levels of attained education in AA participants can explain the poorer cognitive function than the White participants.

Background: Late-onset Alzheimer's disease (LOAD) has been associated with alterations in the morphology of multiple brain structures, and it is likely that disease mechanisms differ between brain regions. Coupling genetic determinants of LOAD with measures of brain morphology could localize and identify primary causal neurobiological pathways.

Objective: To determine causal pathways from genetic risk variants of LOAD via brain morphology to LOAD.

Methods: Mediation and Mendelian randomization (MR) analysis were performed using common genetic variation, T1 MRI and clinical data collected by UK Biobank and Alzheimer's Disease Neuroimaging Initiative.

Results: Thickness of the entorhinal cortex and the volumes of the hippocampus, amygdala and inferior lateral ventricle mediated the effect of APOE ε4 on LOAD. MR showed that a thinner entorhinal cortex, a smaller hippocampus and amygdala, and a larger volume of the inferior lateral ventricles, increased the risk of LOAD as well as vice versa.

Conclusions: Combining neuroimaging and genetic data can give insight into the causal neuropathological pathways of LOAD.

Background: Alzheimer's disease (AD) is a chronic neurodegenerative disease and the most prevalent form of dementia. Fenugreek seeds possess anti-inflammatory and antioxidant effects, making them valuable therapeutic agents in managing neurodegenerative diseases.

Objective: This study aimed to investigate the primary biological pathways and specific mechanisms underlying the protective effects of fenugreek in preventing mice of AD by employing bioinformatics and experimental verification.

Methods: We administered fenugreek extract as an intervention in mice model of AD and then assessed their cognitive ability and histopathological changes. We predicted the key target genes associated with fenugreek action on AD and the main biological pathways using the bioinformatics method. Furthermore, we observed the different expression of target genes by western blot (WB).

Results: The bioinformatics analysis revealed a strong correlation between fenugreek and AD. The behavioral experiments confirmed that fenugreek improved the behavioral and cognitive dysfunction in mice with AD. The histopathology revealed significant changes that fenugreek can inhabit Nissl bodies. Western blot experiments confirmed that fenugreek exerted statistically significant modulatory effects on the levels of inflammatory proteins [interleukin-6 (IL-6), IL-10, and IL-1β] and oxidative stress-related proteins (amyloid-β protein precursor, apolipoprotein E, and presenilin 1).

Conclusions: This study suggested that fenugreek might be involved in the AD pathway and effectively prevented the progression of AD through significant anti-inflammatory and antioxidant effects.

Background: Whether there is a cognitive load-dependent brain activation pattern in the pre-Alzheimer's disease phase is unknown. Multimodal system provides a powerful technical tool.

Objective: We evaluated brain activity patterns under different cognitive loads in patients with mild cognitive impairment.

Methods: Functional near-infrared spectroscopy signals and electroencephalography signals were acquired from the mild cognitive impairment group (MCI, n = 20) and the healthy control group (HC, n = 24) under four cognitive loads. We analyzed the respective brain activity features and performed correlation analyses.

Results: (1) During the encoding phase, both the left occipital (p _cond= 0.05, p _group< 0.01) and left temporal (p _cond= 0.02, p _group= 0.03) skewness condition effects and between-group effects were significant. (2) As the cognitive load increased, the clustering coefficients and local efficiencies were significantly lower for the HC group. (3) The left occipital and left temporal activation skewness in the MCI group were significantly correlated with left occipital electrical features, whereas the left occipital activation intensity and skewness were significantly correlated with left occipital electrical features in HC group.

Conclusions: The pattern of brain activity in MCI depends on cognitive load. Left occipital and left temporal may be important brain regions for evaluating MCI and need to be focused on in the future.

Background: Observational studies indicate a complex relationship between coagulation factors and Alzheimer's disease (AD). However, the current findings are inconsistent, and it remains uncertain whether a causal relationship exists.

Objective: This study utilizes a Mendelian randomization analysis to investigate the causal relationships between blood levels of coagulation factors and AD risk.

Methods: Eleven coagulation factors with valid instrumental variables available were evaluated. Two independent cohorts of European ancestry with AD genome-wide association study (GWAS) summary statistics were used: UK Biobank (UKB, N = 472,868) and the International Genomics of Alzheimer's Project (IGAP, N = 63,926). We primarily conducted Mendelian randomization (MR) analyses using the Inverse variance weighted (IVW). Meanwhile, the MR-Egger intercept test is used to detect horizontal pleiotropy, the Residual Sum of Squares observed (RSSobs) is used to assess the model's goodness of fit, and the leave-one-out analysis is employed for sensitivity analysis.

Results: Using IVW analysis, the UKB database shows positive correlations of Protein C (PC, p = 0.002), Activated Partial Thromboplastin Time (aPTT, p = 0.019), and coagulation factor X (FX, p = 0.032) with AD, and a negative association for coagulation factor XI (FXI, p = 0.021). The IGAP database mirrors these findings for PC and FXI but not for the others. Leave-one-out analysis showed an anomaly after a single single nucleotide polymorphism (SNP) driving, yet the overall results remained stable.

Conclusions: This study demonstrates that elevated levels of PC, FX, and aPTT, along with reduced levels of FXI, are causally associated with an increased risk of AD. These findings might pave the way for the diagnosis and treatment of AD.