Alzheimer's Research & Therapy最新文献

Background: Alzheimer's disease and related dementias are major public health challenges, with the apolipoprotein (APOE) ε4 allele being a significant genetic risk factor. Cardiometabolic risk factors such as diabetes, hypertension, dyslipidemia, obesity, and tobacco use are also linked to cognitive impairment. The objective of this study was to (1) characterize both independent and interactive associations of racial/ethnic group (Non-Hispanic White (NHW), Non-Hispanic Black (NHB) and Hispanic), APOE ε4 genotype, and multiple cardiometabolic risk factors with performance across four cognitive domains. Secondarily, we aimed to quantify the hypothetical population-level cognitive gains that could result from eliminating each modifiable risk factor within each racial/ethnic group.

Methods: We analyzed baseline data from 3,833 HABS-HD participants (1,348 NHW; 1,065 NHB; 1,420 Hispanic; mean age 65.3 ± 8.6 years; 62.0% female). APOE genotype, consensus-determined cardiometabolic status, and harmonized cognitive domain scores (episodic memory, executive function, processing speed, language) were obtained. Multivariable linear regressions assessed independent effects of race/ethnicity, APOE ε4 carriage, and each cardiometabolic factor on domain-specific z-scores, adjusting for age, sex, and education (Bonferroni-corrected). Interaction terms tested effect modification by race/ethnicity. Counterfactual population intervention models estimated the mean cognitive gain from hypothetically eliminating each modifiable risk factor within each racial/ethnic group.

Results: NHB Hispanic, and NHW participants prevalences were APOE ε4 (32.2%, 27.4%, 17.6%), diabetes (26.1%, 35.0%, 13.9%), hypertension (79.0%, 63.6%, 58.2%), obesity (56.8%, 50.3%, 38.5%), and tobacco dependence (12.9%, 7.5%, 3.9%). In adjusted models, NHB and Hispanic ethnicity, APOE ε4, diabetes, hypertension, and tobacco dependence each independently predicted lower performance across all four cognitive domains (adjusted p < .001), whereas obesity showed domain-specific positive associations. No race × risk-factor interactions remained significant after correction. In intervention models, hypothetically eliminating diabetes and hypertension yielded the largest predicted improvements, especially in executive function and language, with the greatest gains projected among NHB and Hispanic racial ethnic group.

Conclusions: Cardiometabolic health markedly contributes to racial ethnic differences in cognitive aging beyond APOE ε4 effects. Population-level interventions targeting diabetes and hypertension could narrow NHB and Hispanic cognitive deficits, informing precision public-health strategies for dementia prevention.

Background: Amyloid PET/CT is essential for quantifying amyloid-beta (Aβ) deposition in Alzheimer's disease (AD), with the Centiloid (CL) scale standardizing measurements across imaging centers. However, MRI-based CL pipelines face challenges: high cost, contraindications, and patient burden. To address these challenges, we developed a deep learning-based CT parcellation pipeline calibrated to the standard CL scale using CT images from PET/CT scans and evaluated its performance relative to standard pipelines.

Methods: A total of 306 participants (23 young controls [YCs] and 283 patients) underwent 18 F-florbetaben (FBB) PET/CT and MRI. Based on visual assessment, 207 patients were classified as Aβ-positive and 76 as Aβ-negative. PET images were processed using the CT parcellation pipeline and compared to FreeSurfer (FS) and standard pipelines. Agreement was assessed via regression analyses. Effect size, variance, and ROC analyses were used to compare pipelines and determine the optimal CL threshold relative to visual Aβ assessment.

Results: The CT parcellation showed high concordance with the FS and provided reliable CL quantification (R² = 0.99). Both pipelines demonstrated similar variance in YCs and effect sizes between YCs and ADCI. ROC analyses confirmed comparable accuracy and similar CL thresholds, supporting CT parcellation as a viable MRI-free alternative.

Conclusions: Our findings indicate that the CT parcellation pipeline achieves a level of accuracy similar to FS in CL quantification, demonstrating its reliability as an MRI-free alternative. In PET/CT, CT and PET are acquired sequentially within the same session on a shared bed and headrest, which helps maintain consistent positioning and adequate spatial alignment, reducing registration errors and supporting more reliable and precise quantification.

Background: Synaptic dysfunction, which occurs before the formation of amyloid plaques (Aβ) and neurofibrillary tangles (NFTs), is strongly associated with cognitive deficits and represents major early clinical features of Alzheimer's disease (AD). Abnormal NMDAR signaling emerges as a noticeable feature of synaptic dysfunctions in AD. Nonetheless, the underlying mechanisms of NMDAR dysfunctions remain unclear.

Methods: 3xTg-AD mice were injected with AAV-IRF1. Cognitive function was assessed using behavioral tests, while biochemical and immunofluorescence analyses were conducted to evaluate the protein levels of IRF-1, OGA, subunits of NMDAR, O-GlcNAcylation of NMDAR subunits, and internalization of NMDA receptors. Synaptic alterations in the hippocampus were detected by electrophysiology and Golgi staining.

Results: In the present study, we demonstrate that Interferon Regulatory Factor-1 (IRF-1), which is deficient in the brain of individuals with Alzheimer's disease (AD), negatively regulates the O-GlcNAcylation levels of GluN1 through transcriptional regulation of the human OGA gene. Furthermore, IRF-1 may influence trafficking of NMDARs, thereby affecting dendritic spine density and synaptic plasticity, and ultimately improving the learning and memory of 3xTg-AD mice.

Conclusion: Our results indicate that IRF1 can improve the cognitive function of 3xTg-AD mice by regulating the O-GlcNAcylation of GluN1, offering evidence that IRF-1 could serve as a novel therapeutic target for treating synaptic dysfunction in Alzheimer's diseases.

Alzheimer's disease (AD) is a devastating neurodegenerative disorder, with no effective treatment currently available. Recently, non-pharmacological therapy, especially gamma frequency stimulation has shown promising therapeutic effects in Alzheimer's disease (AD) mouse models. Electric field (EF) is a non-invasive biophysical approach for neuronal protection. However, whether EF is beneficial in AD neuropathology remains unknown. In this study, we exposed the P301S tauopathy mouse model to EF at gamma frequency on the head. We demonstrated that EF treatment significantly improved the cognitive impairments in the P301S mice. This was accompanied by reduced tau pathologies, suppressed microglial activation, neuroinflammation and oxidative stress in the tauopathy mouse brain. Moreover, EF treatment induced cell-specific responses in neural cells, with neurons being more susceptible, followed by microglia and oligodendrocytes. EF also had favorable effects on synaptic protein in neurons, inflammatory response and complement signaling in microglia, and myelination in oligodendrocytes. This study provides strong evidence that EF at gamma frequency may have great potential to be a novel therapeutic intervention for P301S by attenuating neuropathology and offering neuroprotection.

Background: Tau protein aggregates are a key pathological hallmark of Alzheimer's disease (AD) and are closely associated with cognitive decline and neurodegeneration. It is proposed that tau aggregates faithfully propagate throughout the brain by self-templating their disease-associated conformation onto natively-folded tau monomers, thereby inducing their aggregation and incorporation into growing fibrils. As such, the inhibition or modulation of tau seeding and aggregation represents a viable therapeutic strategy for AD and other tauopathies.

Methods: We have recently developed seed amplification assays (SAA) for the detection and amplification of small quantities of misfolded protein aggregates in various neurodegenerative diseases. In this article, we adapted the SAA technology to amplify the process of tau aggregation and seeding in AD brain samples. Using the Tau-SAA we screened two chemical libraries: one comprising over 20 suspected aggregation inhibitors and the other comprising over 200 FDA-approved, blood-brain barrier-permeable compounds from a commercial chemical library. We also performed secondary in vitro assays to confirm the activity of selected hits as well as determining the IC50 of the most active compounds.

Results: Our Tau-SAA detects the presence of tau seeds even after a 100-million-fold dilution of the initial inoculum. Examination of 26 postmortem brain samples from AD and control cases confirmed that our assay is specific for AD brain tau seeds. Screening of 220 compounds showed that approximately 57% of suspected aggregation inhibitors and ~ 3% of CNS-penetrant compounds inhibited over 75% of AD brain-templated tau aggregation.

Conclusions: In conclusion, our data suggests that Tau-SAA readily detects the presence of tau seeds in AD brains but not in controls, and that by amplifying AD brain tau seeds, the assay may serve as a valuable primary drug screening platform.

Background and objectives: The relationship between APOE4 status and plasma biomarkers previously shown to be related to Alzheimer's risk have not been carefully examined among Mexican Americans. This research is needed to elucidate disparities within the Alzheimer's field by evaluating key genetic factors in an underrepresented population. The present study deepens our understanding of the interaction between biological and genetic factors for these populations with greater incidence of Alzheimer's disease (AD) and helps address whether APOE4 confers similar risk of AD in Mexican Americans as previously reported in Non-Hispanic Whites.

Methods: Cross-sectional data consisting of 792 Mexican American and 785 Non-Hispanic White participants from the Health & Aging Brain Study - Health Disparities (HABS-HD) with available plasma biomarkers and APOE4 genotype profiles were included in the present study. Linear regression models were used to test our hypotheses. APOE4-Race/ethnicity interaction term tested whether the biomarker levels differed between ethnic groups. Analyses were adjusted for age, gender, and education. Further analyses explored whether biomarker levels differed by APOE4 carrier status within racial/ethnic groups.

Results: Among 1577 participants (59.5% women; mean age 66.4 ± 8.74 years), significant differences were observed across race/ethnic and APOE4 groups. Mexican Americans were younger (p < 0.001), had a higher proportion of women (p = 0.001), fewer years of education (p < 0.001), and lower MMSE scores (p < 0.001). Biomarker differences between Mexican Americans and Non-Hispanic Whites included variations in Aβ42/Aβ40 (p = 0.03) and p-tau181 (p < 0.001), but not in total tau, TNF-α, or NfL levels (all p > 0.12). Race/ethnicity-APOE4 interactions were significant for Aβ42/Αβ40, p-tau181, and total tau (all p < 0.05) but not for NfL or TNF-α. APOE4 associations with Aβ42/Aβ40 and p-tau181 were significant in NH White participants (all p < 0.001) but not among Mexican Americans.

Conclusion: These findings will significantly contribute to understanding potential differences in the role of APOE4 and AD plasma biomarkers among Mexican Americans. This research has the potential to enhance preventive care and early diagnosis for populations with a higher incidence of AD.

Background: Existing evidence highlights associations between sleep behaviors and dementia risk; however, the impact of adhering to a healthy sleep pattern on dementia risk remains unclear.

Methods: Of 406,364 UK Biobank participants aged 40-64, we excluded those who had withdrawn, had incomplete sleep data, or had dementia at baseline, yielding a final sample of 333,014. Participants were enrolled between 2006 and 2010, with follow-up extending from recruitment to dementia diagnosis, death, loss to follow-up, or the censoring date (December 2022), whichever came first. Incident dementia was identified using hospital inpatient and death records, along with primary care data, with cases diagnosed at a mean age of 70.0 years (standard deviation [SD]: 5.6). Sleep-related questionnaire items from the UK Biobank were summarized into five sleep behaviors: sleeping 7-8 h daily, early chronotype, absence of frequent insomnia, no snoring, and no frequent daytime sleepiness. Each behavior meeting the healthy criterion was assigned one point, resulting in a total range from 0 to 5, with higher scores indicating better adherence to a healthy sleep pattern. Cox proportional hazards models were used to assess the association between healthy sleep patterns and dementia risk, adjusting for demographics, lifestyle factors, and medical history. A subset of 33,401 participants underwent brain magnetic resonance imaging (MRI) scans during the 9.4-year median period between sleep assessment and imaging. The imaging analysis included total brain volume, gray matter volume, white matter volume, hippocampal volume, and white matter hyperintensities (WMH).

Results: During a median follow-up of 13.8 years, 3,035 incident dementia cases were recorded, including 1,304 Alzheimer's disease (AD) cases and 597 vascular dementia (VD) cases. A higher adherence to a healthy sleep pattern was associated with a lower dementia risk. Each 1-point increase in the healthy sleep score corresponded to a 7% reduction in dementia risk (Hazard Ratio [HR] = 0.93, 95% Confidence Interval [CI]: 0.89-0.96). Compared to participants with a score of 0-1, those with a score of 5 had a significantly lower risk of dementia (HR = 0.75, 95% CI: 0.61-0.92). Benefits were more pronounced in adults aged 40-55 years than those aged 56-64 years (p for interaction < 0.001). Adherence to a healthy sleep pattern was associated with increased grey matter volume and decreased WMH volume (all p < 0.05). Mediation analysis indicates that preserving grey and white matter integrity partially mediated the dementia-risk-lowering benefit (p < 0.05).

Conclusions: Adherence to a healthy sleep pattern is associated with both a reduced risk of dementia and greater white matter integrity, underscoring the role of improving overall sleep behaviors to support brain structure and lower dementia risk.

Introduction: Quantification of amyloid plaques (A), neurofibrillary tangles (T₂), and neurodegeneration (N) using PET and MRI is critical for Alzheimer's disease (AD) diagnosis and prognosis. Existing pipelines face limitations regarding processing time, tracer variability handling, and multimodal integration.

Methods: We developed petBrain, a novel end-to-end processing pipeline for amyloid-PET, tau-PET, and structural MRI. It leverages deep learning-based segmentation, standardized biomarker quantification (Centiloid, CenTauR, HAVAs), and simultaneous estimation of A, T₂, and N biomarkers. It is implemented in a web-based format, requiring no local computational infrastructure and software usage knowledge.

Results: petBrain provides reliable, rapid quantification with results comparable to existing pipelines for A and T₂, showing strong concordance with data processed in ADNI databases. The staging and quantification of A/T₂/N by petBrain demonstrated good agreements with CSF/plasma biomarkers, clinical status and cognitive performance.

Discussion: petBrain represents a powerful open platform for standardized AD biomarker analysis, facilitating clinical research applications.

Background: Impaired phonological short-term memory is a core feature of the logopenic variant of primary progressive aphasia (lvPPA), but it is not clear whether a core phonological processing deficit is also present.

Methods: We asked three questions: (i) beyond short-term memory impairment, do lvPPA patients have an impairment within phonology itself?; (ii) is their performance in working memory and naming reflective of this phonological impairment?; and (iii) is their repetition performance related to structural and functional differences in key language-dominant regions? We compared non-word and word repetition and short-term memory performance in patients with typical Alzheimer's disease (tAD), lvPPA per consensus criteria, and others who previously satisfied definitions of lvPPA but had progressed with multi-domain cognitive impairments (lvPPA+).

Results: Bayesian analyses revealed no group differences in phonological tasks of word and non-word repetition. We found very strong evidence for an effect of self-reported hearing loss on word and non-word repetition, but not multi-syllabic word/phrase repetition. A comparison of phonological versus working memory and naming tasks produced either no evidence or evidence for no correlation. Beyond the expected grey matter reductions in patients relative to controls, there was anecdotal evidence for an association between non-word repetition and functional connectivity between dorsal premotor and posterior superior temporal gyrus regions in patients.

Conclusions: Our results indicated that, in the absence of self-reported hearing loss, patients did not exhibit impairments in tasks tapping "pure" phonological processing. Our results suggest that instead of having a core phonological impairment, lvPPA patients have a working memory/buffering impairment.