Journal of Alzheimer's disease reports最新文献

Background: The relationship between alpha 2-macroglobulin (A2M) gene and Alzheimer's disease (AD) has been widely studied across populations; however, the results are inconsistent.

Objective: This study aimed to evaluate the association of A2M gene with AD by the application of meta-analysis.

Methods: Relevant studies were identified by comprehensive searches. The quality of each study was assessed using the Newcastle-Ottawa Scale. Allele and genotype frequencies were extracted from each of the included studies. Odds ratio (OR) with corresponding 95% confidence intervals (CI) was calculated using a random-effects or fixed-effects model. The Cochran Q statistic and I² metric was used to evaluate heterogeneity, and Egger's test and Funnel plot were used to assess publication bias.

Results: A total of 62 studies were identified and included in the current meta-analysis. The G allele of rs226380 reduced AD risk (OR: 0.64, 95% CI: 0.47-0.87, pFDR = 0.012), but carrier with the TT genotype was more likely to develop AD in Asian populations (OR: 1.56, 95% CI: 1.12-2.19, pFDR = 0.0135). The V allele of the A2M-I/V (rs669) increased susceptibility to AD in female population (OR, 95% CI: 2.15, 1.38-3.35, pFDR = 0.0024); however, the II genotype could be a protective factor in these populations (OR, 95% CI: 0.43, 0.26-0.73, pFDR = 0.003). Sensitivity analyses confirmed the reliability of the original results.

Conclusions: Existing evidence indicate that A2M single nucleotide polymorphisms (SNPs) may be associated with AD risk in sub-populations. Future studies with larger sample sizes will be necessary to confirm the results.

Background: Clinical guidelines recommend incorporating non-cognitive markers like mild behavioral impairment (MBI) and sleep disturbance (SD) into dementia screening to improve detection.

Objective: We investigated the longitudinal associations between MBI, SD, and incident dementia.

Methods: Participant data were from the National Alzheimer's Coordinating Center in the United States. MBI was derived from the Neuropsychiatric Inventory Questionnaire (NPI-Q) using a published algorithm. SD was determined using the NPI-Q nighttime behaviors item. Cox proportional hazard regressions with time-dependant variables for MBI, SD, and cognitive diagnosis were used to model associations between baseline 1) MBI and incident SD (n = 11,277); 2) SD and incident MBI (n = 10,535); 3) MBI with concurrent SD and incident dementia (n = 13,544); and 4) MBI without concurrent SD and incident dementia (n = 11,921). Models were adjusted for first-visit age, sex, education, cognitive diagnosis, race, and for multiple comparisons using the Benjamini-Hochberg method.

Results: The rate of developing SD was 3.1-fold higher in older adults with MBI at baseline compared to those without MBI (95% CI: 2.8-3.3). The rate of developing MBI was 1.5-fold higher in older adults with baseline SD than those without SD (95% CI: 1.3-1.8). The rate of developing dementia was 2.2-fold greater in older adults with both MBI and SD, as opposed to SD alone (95% CI:1.9-2.6).

Conclusions: There is a bidirectional relationship between MBI and SD. Older adults with SD develop dementia at higher rates when co-occurring with MBI. Future studies should explore the mechanisms underlying these relationships, and dementia screening may be improved by assessing for both MBI and SD.

Background: Alzheimer's disease pathology and vascular burden are highly prevalent and often co-occur in elderly. It remains unclear how both relate to cognitive decline.

Objective: To investigate whether amyloid abnormality and vascular burden synergistically contribute to cognitive decline in a memory clinic population.

Methods: We included 227 patients from Maastricht and Aachen memory clinics. Amyloid abnormality (A+) was defined by CSF Aβ₄₂ using data-driven cut-offs. Vascular burden (V+) was defined as having moderate to severe white matter hyperintensities, or any microbleeds, macrohemorrhage or infarcts on MRI. Longitudinal change in global cognition, memory, processing speed, executive functioning, and verbal fluency was analysed across the A-V-, A-V+, A+V-, A+V+ groups by linear mixed models. Additionally, individual MRI measures, vascular risk and vascular disease were used as V definitions.

Results: At baseline, the A+V+ group scored worse on global cognition and verbal fluency compared to all other groups, and showed worse memory compared to A-V+ and A-V- groups. Over time (mean 2.7+ - 1.5 years), A+V+ and A+V- groups showed faster global cognition decline than A-V+ and A-V- groups. Only the A+V- group showed decline on memory and verbal fluency. The A-V+ group did not differ from the A-V- group. Individual MRI vascular measures only indicated an independent association of microbleeds with executive functioning decline. Findings were similar using other V definitions.

Conclusions: Our study demonstrates that amyloid abnormality predicts cognitive decline independent from vascular burden in a memory clinic population. Vascular burden shows a minor contribution to cognitive decline in these patients. This has important prognostic implications.

Background: Understanding the mechanisms whereby genetic variants influence the risk of Alzheimer's disease (AD) may provide insights into treatments that could reduce AD risk.

Objective: Here, we sought to test the hypothesis that a single nucleotide polymorphism (SNP) associated with AD risk, rs2070902, influences splicing of FCER1G exon 2.

Methods: AD and non-AD brain samples were analyzed for FCER1G expression by genotyping, immunohistochemistry, immunofluorescence, and qPCR.

Results: The protein encoded by FCER1G, FcRγ, is robustly expressed in microglia in both AD and non-AD brain. The FCER1G isoform lacking exon 2 (D2-FCER1G) was readily detectable. Moreover, the proportion of FCER1G expressed as this isoform was increased in brains with high AD neuropathology. However, the proportion of FCER1G expressed as the D2-FCER1G isoform was not associated with rs2070902 genotype.

Conclusions: In summary, the proportion of FCER1G expressed as the D2-FCER1G isoform is increased with AD neuropathology but is not associated with rs2070902.

Background: Alzheimer's disease (AD) is a complex neurodegenerative disorder whose etiology involves multiple genetic and environmental factors. Sphingomyelin (SM) is a type of sphingolipid found in cell membranes, and recent evidence suggests a potential link between SM and AD. However, the nature of this relationship remains unclear.

Objective: To elucidate the potential causal relationship between SM levels and the risk of developing AD using a two-sample Mendelian randomization approach.

Methods: The study utilized data extracted from the genome wide association study database. The primary analysis method was the inverse variance weighted (IVW) method, which was supplemented by weighted median, weighted mode, and MR Egger methods. The study specifically investigated the bidirectional causal relationship between SM and AD, evaluating odds ratios (OR) with a 95% confidence interval (95% CI).

Results: Elevated levels of SM were found to be a risk factor for AD, as shown by IVW(MRE) [OR: 1.001, 95% CI: 1.000 to 1.002; p = 0.020 < 0.05], IVW(FE) [OR: 1.001, 95% CI: 1.001 to 1.002; p = 3.36e-07 < 0.05], and MR Egger. Conversely, AD was demonstrated to lead to an increase in SM levels [IVW(MRE): OR: 5.64e+08, 95% CI: 1.69e+05 to 1.89e+12; p = 1.14e-06 < 0.05], with consistent findings across the IVW(FE), MR Egger, weighted median, and weighted mode methods.

Conclusions: The study establishes a bidirectional positive correlation between SM and AD. Increased SM levels are associated with a higher risk of developing AD, and the presence of AD can further elevate SM levels, potentially exacerbating the disease's progression.

Background: Dementia with Lewy bodies (DLB) is a progressive neurodegenerative disease with various clinical symptoms. Limited data have described the clinical subtypes of DLB.

Objective: We aimed to compare clinical subtypes of DLB according to initial symptoms and to study the effect of Apolipoprotein E (APOE) gene in DLB.

Methods: We included DLB patients classified into three groups based on initial symptoms: non-motor onset (cognitive and/or psychiatric) (NMO-DLB), motor onset (parkinsonism and/or gait disorders) (MO-DLB), and mixed onset (non-motor and motor symptoms) (MXO-DLB). Clinical and APOE genotype associations and survival were analyzed.

Results: A total of 268 patients were included (NMO-DLB = 75%, MXO-DLB = 15.3%, MO-DLB = 9.7%). Visual hallucinations were more frequent (p = 0.025), and attention was less commonly impaired in MXO-DLB (p = 0.047). When adjusting with APOE ɛ4 status (APOE genotype performed in 155 patients), earlier falls and frontal lobe syndrome were more common in MXO-DLB (p = 0.044 and p = 0.023, respectively). The median MMSE decline was 2.1 points/year and the median FAB decline was 1.9 points/year, with no effect of clinical subtypes. Median survival was 6 years. It was similar in DLB subtypes (p = 0.62), but shorter for patients with memory symptoms at onset (p = 0.04) and for males (p = 0.0058).

Conclusions: Our study revealed a few differences between DLB clinical subtypes. APOE ɛ4 appears to be associated with earlier falls and a higher prevalence of frontal syndrome in MXO-DLB. However, DLB clinical subtypes did not impact on survival. Nevertheless, survival analysis identified other poor prognosis factors, notably inaugural memory impairment and male gender.

Background: One of the most popular ways to address cognitive decline is cognitive training. The fact that cognitive deterioration is permanent is one of the main issues. This issue might be resolved by preventive cognitive training when it is acute. As a result, this study aims to design and assess how well stroke patients respond to hierarchical, multi-dimensional preventative cognitive training.

Objective: To describe the study design of this center implementation trial.

Methods: Participants in the study will be recruited from a hospital in China and randomly assigned to the intervention group or the usual care group. Interventions will include four-week hierarchical multi-dimensional preventive cognitive training through a WeChat program. for Primary outcome measures will be the Montreal Cognitive Assessment, Mini-Mental State Examination, and Post-Stroke Cognitive Impairment (PSCI) Incidence. The secondary outcome measure will include the Hamilton Depression Scale, Hamilton Anxiety Scale, Modified Barthel Index, and National Institutes of Health Neurological Deficit Score. Outcomes will be measured at baseline, 12 weeks, and 24 weeks from the baseline.

Results: We expect that the hierarchical multi-dimensional preventive cognitive training program will be easy to implement, and the cognitive function, cognitive psychology, ability of daily living will vary in each setting.

Conclusions: The results will provide evidence highlighting differences in a new strategy of cognitive training through the WeChat program, which allows the home-based practice, puts forward an advanced idea of preventive cognitive training in the acute stage, and has the highest effectiveness of reducing cognitive impairment, and Alzheimer's disease.

Background: Tauopathies are a subset of neurodegenerative diseases characterized by abnormal tau inclusions. Recently, we have discovered a new, human specific, tau isoform termed W-tau that originates by intron 12 retention. Our preliminary data suggests this newly discovered W-tau isoform might prevent aberrant aggregation of other tau isoforms but is significantly downregulated in tauopathies such as Alzheimer's disease.

Objective: To accurately predict, examine, and understand tau protein structure and the conformational basis for the neuroprotective role of W-tau.

Methods: A tridimensional deep learning-based approach and in vitro polymerization assay was included to accurately predict, analyze, and understand tau protein structure and the conformational basis for the neuroprotective role of W-tau.

Results: Our findings demonstrate: a) the predicted protein tridimensionality structure of the tau isoforms raised by intron retention and their comparison with the other tau isoforms; b) the interaction of W-tau peptide (from W-tau isoform) with other tau isoforms; c) the effect of W-tau peptide in the polymerization of those tau isoforms.

Conclusions: This study supports the importance of the structure-function relationship on the neuroprotective behavior of W-tau inhibiting tau fibrillization in vitro.