Journal of Alzheimer's Disease最新文献

BackgroundThe extent to which plasma biomarkers of Alzheimer's disease and neurodegeneration capture domain-specific cognitive performance across diverse populations remains unclear.ObjectiveTo determine whether plasma phosphorylated tau181 (p-tau181) and neurofilament light (NfL) are independently associated with cognitive domains, and whether associations differ across non-Hispanic White (NHW), non-Hispanic Black (NHB), and Hispanic participants.MethodsWe analyzed 3023 community-dwelling older adults from the Health and Aging Brain Study-Health Disparities (38.4% NHW, 22.6% NHW, 38.9% Hispanic). We used linear regressions to test associations between plasma biomarkers and cognitive domains (memory, executive function, processing speed, language), adjusting for age, sex, education, and apolipoprotein ε4 carriership. We fit models including both p-tau181 and NfL to assess their independent associations, evaluate biomarker × racial/ethnic interactions, and test p-tau181 × NfL interactions within each racial/ethnic group.ResultsAmong NHW participants, higher p-tau181 and NfL were associated with poorer memory, executive function, processing speed, and language. In NHB participants, p-tau181 was associated with memory, showed attenuated associations for language, and demonstrated similar associations with executive function and processing speed as observed in NHW participants. In Hispanic participants, p-tau181 was associated with memory and processing speed but was nonsignificant for executive function and language, and NfL showed significant but attenuated associations across all domains. Higher p-tau181 and NfL were jointly associated with slower processing speed only in NHW and NHB participants.ConclusionsPlasma p-tau181 and NfL were associated with multiple cognitive domains, with the strongest effects in NHW participants and attenuated associations in NHB and Hispanic individuals.

BackgroundMesenchymal stem cell (MSC)-based therapy has emerged as a promising alternative treatment for Alzheimer's disease (AD) but is limited by low cell survival rates and complex handling.ObjectiveThe present study explored the therapeutic potential of subcutaneous transplantation of MSC spheroids in a mouse AD model.MethodsWe prepared uniform size MSC spheroids with good stemness properties, and performed three consecutive subcutaneous treatments with MSC spheroids on early-stage AD APP/PS1 mice (6 months old), with each injection administered one month apart. Following treatment, behavioral experiments were conducted to evaluate learning and cognitive functions. Additionally, positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) were utilized to assess cerebral glucose metabolism and neuronal functional connectivity. Subsequently, brain tissue sections were prepared and stained to evaluate amyloid plaque deposition, levels of inflammation, and other pathological changes.ResultsAPP/PS1 mice treated with MSC spheroids demonstrated better performance in cognitive behavioral tests compared to the AD model group. Imaging studies showed that brain glucose metabolism was higher in the MSC spheroids-treated group than in the AD model group, with enhanced functional brain connectivity. Moreover, pathological analysis revealed that MSC spheroids treatment resulted in a reduced amyloid-β plaque burden and attenuated inflammatory phenotypes in AD mice. MSC spheroids also protected neurons from apoptosis and restored synaptic plasticity.ConclusionsOur study suggests that subcutaneous transplantation of MSC spheroids reduced key pathological changes in AD by improving brain glucose metabolism and alleviating inflammation.

BackgroundHippocampal synaptic dysfunction driven by toxic amyloid-β oligomers (AβO) is an early event in the progression of neurodegeneration and cognitive decline in Alzheimer's disease (AD). Non-invasive photobiomodulation therapy (PBM) is a promising intervention that has been shown to reduce amyloid and tau pathology, improve synaptic function, and preserve hippocampal neurogenesis in animal models of AD. Nano-pulsed laser therapy (NPLT) is a type of PBM therapy using pulsed 808 nm near-infrared laser light and optoacoustically generated ultrasound waves to stimulate deeper brain structures than would be accessible by traditional PBM therapy. We hypothesize that NPLT can effectively modulate hippocampal neurogenesis to induce resilience against AD.ObjectiveTo assess resilience of hippocampal neurons derived from NPLT-treated neural stem cells (NSC) against AβO toxicity.MethodsWe use NPLT to stimulate adult hippocampal neural stem cells (NSC) then induce neuronal differentiation in vitro and assess the mature neurons for AβO binding capacity and mitochondrial toxicity, and gene expression changes after NPLT.ResultsWe found that neurons differentiated from NPLT-treated NSC are resilient against AβO binding and mitochondrial toxicity, and show increased expression of genes associated with autophagy and proteostasis.ConclusionsOur findings support the hypothesis that NPLT modulation of hippocampal neurogenesis can be an effective non-invasive approach to induce resilience against AD toxic oligomers.

BackgroundKnowledge of comorbidities among diverse populations with mild cognitive impairment (MCI) and Alzheimer's disease (AD) is important in clinical trials and real-world clinical practice.ObjectiveThe objective of this study was to evaluate the prevalence of comorbidities prior to and after diagnosis with MCI/AD in the real world.MethodsThis retrospective cohort study used insurance claims and electronic health records from Optum's de-identified Market Clarity Data. MCI, AD, and comorbidities were determined using diagnosis codes and, in some cases, specific medications. Controls were matched 1:1 to individuals with MCI/AD.ResultsAmong individuals with MCI/AD diagnoses (mean ages 66 and 76, respectively), the most prevalent comorbidities prior to and after MCI/AD diagnoses were cardiovascular disease, hypertension, and diabetes. Individuals with MCI had a higher prevalence of stroke before diagnosis compared with controls.ConclusionsAmong all demographic groups, comorbidities are highly prevalent and need recognition when caring for individuals with MCI/AD. This applies to all sex and race/ethnicity stratifications examined in this study, although the frequency of comorbidities experienced by different groups varied.

BackgroundIndividuals with mild cognitive impairment (MCI) are at an increased risk of developing Alzheimer's disease. Anatomical and functional brain alterations associated with this condition are still elusive.ObjectiveThis study explored the cognitive correlates of cortical thickness, white matter (WM) volume, and resting-state connectivity among people with MCI.MethodsA total of 56 older participants (aged 51 to 92 years) with amnestic MCI were recruited. Cognitive abilities were measured using the Trail Making Task, the Stroop Color-Word Test, the Forward and Backward Digit Span test, and computerized n-back tasks. Morphometry was used to measure cortical thickness and WM volume from 3 T MR images, while functional connectivity was measured using resting-state fMRI and calculated using Independent Component Analysis. Voxel-wise regressions were used to test associations between cognitive scores and brain measures.ResultsWorse working memory updating (n-back) performance was associated with lower cortical thickness of the left middle temporal gyrus. Additionally, at a lower demand, working memory performance was linked to frontoparietal network (FPN) intrinsic connectivity, while WM volume within the anterior segment of the left arcuate fasciculus and default mode network (DMN) resting-state connectivity were relevant when the demand was higher. Lower DMN connectivity was also associated with worse conflict monitoring (Stroop) performance (all cluster-corrected ps < 0.05).ConclusionsThe findings highlight the relevance of the perisylvian region to working memory updating and conflict monitoring in people with MCI.

BackgroundThe role of histone deacetylase 6 (HDAC6) in neurodegenerative diseases, particularly Alzheimer's disease (AD), has attracted significant research interest. Peroxiredoxin 2 (Prx2), a key antioxidant enzyme and HDAC6 substrate, plays a neuroprotective role against oxidative stress-mediated apoptosis.ObjectiveThis study systematically investigates the neuroprotective mechanism of the HDAC6-Prx2 axis in both cellular and transgenic AD models.MethodsAn AD model was established by bilateral hippocampal microinjection of Aβ_1-42 oligomers in mice. The assessments of mice or their brain samples were included behavioral tests, immunofluorescence, western blot, NADP+/NADPH ratio, and oxidative stress assays. HDAC6-mediated acetylation of Prx2 was confirmed via co-immunoprecipitation, and the specific site was identified.ResultsThe disruption of the HDAC6-Prx2 interaction can significantly alleviate the apoptosis of hippocampal neurons in AD mice and salvage learning/memory deficits. Inhibiting HDAC6 can increase the acetylation level of Prx2 K196, thereby enhancing its antioxidant activity. Acetylated Prx2 inhibits the excessive production of reactive oxygen species (ROS), which is mechanically linked to HDAC6-dependent neuronal apoptosis This pathway mechanistically links HDAC6 activity to oxidative stress-induced apoptosis. HDAC6-mediated deacetylation of Prx2 K196 was shown to exacerbate oxidative damage and cognitive decline.ConclusionsThe study identifies a novel pathway where HDAC6 inhibition elevates Prx2 K196 acetylation, breaking the vicious cycle of ROS and apoptosis. Dual targeting of HDAC6 activity and Prx2 acetylation status represents a promising therapeutic strategy for AD.

BackgroundAccumulating evidence indicates that helicobacter pylori (HP) is related to Alzheimer's disease (AD).ObjectiveTo investigate the roles of HP on the pathogenesis of AD involving gut-brain axis dysfunction and blood-brain barrier (BBB) disruption.MethodsTotal 62 AD patients were categorized into AD with HP (AD-HP) and AD with no (AD-nHP) groups. Demographic and cognitive data were collected, and HP infection was confirmed by ¹³C-urea breath test. The levels of BBB variables, neuroinflammatory factors, and AD biomarkers in cerebrospinal fluid (CSF) were measured using enzyme-linked immunosorbent assay. Gut microbiota and metabolites were profiled by 16S ribosomal ribonucleic acid gene sequencing and gas chromatography-mass spectrometry. Correlations and linear regression among above variables were analyzed.ResultsAD-HP group exhibited impaired overall cognition and cognitive domains of immediate and short-term memory and language, and elevated CSF levels of matrix metallopeptidase (MMP) 9, vascular endothelial growth factor (VEGF), interferon-γ, and phosphorylated tau (P-tau) 181. Overall cognitive score was positively correlated with amyloid-β₄₂ and negatively with P-tau181 levels in CSF. Positive correlations were observed between P-tau181 and soluble triggering receptor expressed on myeloid cells 2, between P-tau231 and chitinase-3-like protein, and between P-tau231 and BBB variables (receptor for advanced glycation endproducts, MMP9, zsonula occludens-1, and claudin-5). In AD-HP group, there was a unique dysbiosis pattern of gut microbiota and metabolites, and HP was particularly associated with the reduced gut 23-nordeoxycholic acid methyl ester and elevated CSF VEGF level (all p < 0.05).ConclusionsHP infection exacerbates gut dysbiosis, promotes BBB disruption, intensifies neuroinflammation, accelerates AD pathology, and aggravates cognitive decline.

For years, the understanding of Alzheimer's disease (AD) has been shaped by the amyloid hypothesis, which suggests that pathological markers like amyloid-β (Aβ) and phosphorylated tau are the primary drivers of the disease. This hypothesis has guided the development of major treatment strategies, including monoclonal antibodies targeting Aβ. However, most of these treatments have failed to produce clinically significant results, highlighting the urgent need for a new therapeutic approach. It is now evident that AD is a complex, multifactorial disease that develops over decades, ultimately leading to Aβ and tau accumulation. Therefore, addressing the underlying causes of these depositions is crucial. One well-supported yet underrecognized theory is the infection hypothesis, which links infections to AD pathology. Despite substantial scientific evidence, this perspective has faced significant resistance. In this review, we describe how chronic infections contribute to AD by triggering neuroinflammation and Aβ accumulation. We also explore the barriers to accepting the infection hypothesis and the steps necessary for its integration into drug development and early-stage treatment strategies. Persisting with an amyloid-centric approach will only exacerbate the societal burden. Embracing the infection hypothesis could transform AD research, diagnosis, and treatment, bringing new hope to millions.

BackgroundDementia is a major global public health challenge, and gaps in public knowledge and stigma impede timely diagnosis and inclusive care. The Dementia Friends program is a brief community intervention to improve dementia knowledge and attitudes, but its effectiveness outside the UK, including Israel, is under-evaluated.ObjectiveThis study examined whether participation in the Israeli Dementia Friends program was associated with changes in dementia-related knowledge and stigma. In addition, we assessed whether perceived susceptibility, familiarity with dementia, and self-perception as a change agent were linked to these changes.MethodsA pre-post research design included 820 participants at baseline (Time 1) and 205 at a three-month follow-up (Time 2). Participants completed questionnaires on subjective and objective dementia knowledge, stigma (emotional reactions and discriminatory behavior), perceived susceptibility, and perceiving oneself as a change agent. Data was analyzed using t-tests, analyses of variance (ANOVA), and regression analyses.ResultsSignificant increases were found in subjective (p = 0.005) and objective (p = 0.019) dementia knowledge, with improved positive emotional reactions (p = 0.012). Negative emotional reactions decreased (p = 0.05), but discriminatory behavior showed no significant change (p = 0.75). Higher education was most strongly associated with increases in knowledge, and reductions in perceived susceptibility were associated with decreases in negative emotional reactions and discriminatory behavior.ConclusionsProgram participation was associated with higher dementia knowledge and more positive emotional responses, though discriminatory behaviors persisted. More comprehensive strategies beyond education are needed to fully address stigma.

BackgroundSedentary behavior is common in older adulthood and is associated with poor health outcomes. Less is known about how sedentary behavior relates to cognition in older adulthood and how it relates to increased risk for cognitive decline associated with Alzheimer's disease (AD).ObjectiveWe sought to examine these associations in a large, population-based cohort of community-dwelling older adults residing in a Rust Belt region of the United States.MethodsA subset of the population-based Monongahela-Youghiogheny Healthy Aging Team (MYHAT) participants (n = 193) completed 7 days of wrist-accelerometry following comprehensive neuropsychological assessment. Cross-sectional linear regression models related sedentary time to domains of cognition. Models were adjusted by age, sex, education, and APOE4 carrier status and moderate to vigorous physical activity (MVPA). The interaction between sedentary behavior and APOE4 genotype on cognition was also examined.ResultsGreater sedentary behavior was associated with worse executive function (β = -0.06, p = 0.01) and memory (β = -0.06, p = 0.05) performance. These results were attenuated when adjusting for MVPA. No significant interactions between sedentary time and APOE4 carrier status were observed, although estimation results applying the delta method on regression coefficients suggested the associations were stronger in APOE4 non-carriers when compared to APOE4 carriers.ConclusionsHigher levels of sedentary behavior were associated with worse performance in cognitive domains implicated in AD. Public health initiatives and precision-based medicine approaches to reduce sedentary behavior in a population-based cohort of older adults may be important AD prevention measures. Results support the importance of reducing sedentary time.