Alzheimer's Research & Therapy

Understanding tau pathology progression across the Alzheimers disease (AD) continuum is critical for diagnosis and stratification. This study examined how age of onset and disease stage influence regional tau deposition using [{superscript 1}F]RO948-PET, and its relationship with plasma biomarkers, cognition, and cortical atrophy. In total, 57 participants underwent tau-PET, MRI, blood sampling, and neuropsychological testing: 39 patients with MCI (A{beta}-/A{beta}+) or AD, and 18 cognitively normal controls. The MCI A{beta}+ and AD groups were further divided into early-onset (EOAD, <65y) and late-onset (LOAD, >65y) subgroups. MCI A{beta}+ patients showed early tau accumulation in medial-temporal regions, extending to inferior-temporal cortex. MCI-EOAD exhibited more advanced neocortical tau binding, while MCI-LOAD showed intermediate lateral temporal involvement. In AD, EOAD patients had higher parietal tau burden than LOAD. Plasma biomarkers (p-tau181, p-tau217, p-tau231, GFAP, NFL) were elevated in MCI A{beta}+ and AD. Plasma p-tau217 showed strong correlations with tau-PET in medial and inferior temporal regions, with weaker correlations in neocortical areas. EOAD showed non-linear tau-PET/p-tau217 associations, contrasting with LOADs linear pattern. Tau-PET was negatively correlated with global cognition and executive function, while p-tau217 better reflected early episodic memory decline. Both tau measures correlated with cortical thinning, especially in the entorhinal cortex. These findings highlight [{superscript 1}F]RO948-PETs sensitivity in detecting early tau pathology and superiority in capturing individual differences in tau burden, particularly in advanced stages where plasma biomarkers plateaued. Tau-PET demonstrated superior resolution of disease progression and individual variability, reinforcing its value as a prognostic biomarker and a critical tool for patient stratification in clinical trials. One Sentence Summary[{superscript 1}F]RO948 tau-PET detects early tau pathology and onset-related patterns, outperforming plasma biomarkers in tracking Alzheimers progression.

Alzheimers disease (AD) is acknowledged as one of the most common types of dementia. Various brain regions were found to associated with AD pathology. Precuneus and fusiform gyrus are two notable regions whose role has been implicated in cognitive function. However, a thorough investigation was lacking to link these regions with AD pathology. In this study, we conducted a comprehensive radiomic based investigation using magnetic resonance imaging (MRI) scans to link precuneus and fusiform gyrus with AD pathology. We obtained T1 weighted MR scans of AD (n=133), MCI (n=311) and CN (n=195) subjects from ADNI database at three different time points (i.e., 0, 6 and 12 months). Then, we conducted statistical analysis to compare these features among AD, MCI and CN subjects. We found significant decline in gray matter volume (GMV) and cortical thickness of both precuneus and fusiform gyrus in AD as compared to the MCI and CN subjects. Further, we utilized these features to develop machine learning classifiers to classify AD from MCI and CN subjects and achieved accuracy of 97.78% and 94.41% respectively. These results strengthen the connection of precuneus and fusiform gyrus with AD pathology and opens a new avenue of AD research.

BackgroundPositron emission tomography (PET) imaging has greatly improved the diagnosis and monitoring of Alzheimers disease (AD). The recently developed neuroinformatic field is expanding analytical and computational strategies to study multimodal neuroscience data. One approach is integrating PET imaging and omics to provide new insights into AD pathophysiology. MethodsHippocampal and blood transcriptomic data of cognitively unimpaired (CU) and cognitively impaired (CI) individuals were obtained from Gene Expression Omnibus (GEO) databases and the Alzheimers Disease Neuroimaging Initiative (ADNI). We used the differentially expressed genes (DEGs) from these datasets to implement a modular dimension reduction approach based on Gene Ontology (GO) and reverse engineering of transcriptional networks centered on transcription factors (TF). GO clusters and regulatory units of TF were selected to undergo integration with [18F]Fluorodeoxyglucose ([18F]FDG)-PET images using voxel-wise linear regression models adjusted for age, gender, years of education, and APOE {varepsilon}4 status. ResultsThe GO semantic similarity resulted in 16 GO clusters enriched with overlapping DEGs in blood and the brain. Voxel-wise analysis revealed a strong association between the cluster related to the regulation of protein serine/threonine kinase activity and the [18F]FDG-PET signal in the brain. The master regulator analysis showed 61 regulatory units of TF significantly enriched with DEGs. The voxel-wise analysis of these regulons showed that zinc-finger-related regulatory units had the closest association with brain glucose metabolism. ConclusionWe identified multiple biological processes and regulatory units of TF associated with [18F]FDG-PET metabolism in the brain of individuals across the aging and AD clinical spectrum. Furthermore, the prominent enrichment of protein serine/threonine kinase activity-related GO cluster and the zinc-finger-related regulatory units highlight the potential gene signatures associated with changes in glucose metabolism due to AD pathology.

Microglial activation is an early phenomenon in Alzheimers disease (AD) that may occur prior to and independently of amyloid-{beta} (A{beta}) aggregation. Recent studies in transgenic animal models suggest that the apolipoprotein E {varepsilon}4 (APOE{varepsilon}4) allele may be a culprit of early microglial activation in AD. However, it is unclear whether the APOE{varepsilon}4 genotype is associated with microglial reactivity in the living human brain. Here, we tested whether APOE{varepsilon}4 carriership is associated with microglial activation in individuals across the aging and AD spectrum. We studied 118 individuals who had positron emission tomography (PET) for A{beta} ([18F]AZD4694), tau ([18F]MK6240), and microglial activation ([11C]PBR28), as well as clinical, genetic, and magnetic resonance imaging data. We found that APOE{varepsilon}4 carriership was associated with increased microglial activation mainly in early Braak-staging regions within the medial temporal cortex, and this effect of APOE{varepsilon}4 was independent of A{beta} and tau deposition. Furthermore, microglial activation mediated the A{beta}-independent effects of APOE{varepsilon}4 on downstream tau accumulation, neurodegeneration, and clinical impairment. Interestingly, the physiological distribution of APOE mRNA expression, obtained from the Allen Human Atlas, predicted the patterns of APOE{varepsilon}4-related microglial activation in our population, suggesting that the deleterious effects of APOE{varepsilon}4 occur at the level of gene expression. These results support a model in which the APOE{varepsilon}4 has A{beta}-independent effects on AD pathogenesis by activating microglia in brain regions associated with early tau deposition. Our findings provide a rationale for the development of novel AD therapies targeting the interplay between ApoE and neuroinflammation.

This manuscript presents a study with recruited volunteers that comprehends three sorts of events present in Alzheimers Disease (AD) evolution (structural, biochemical, and cognitive) to propose an update in neurodegeneration biomarkers for AD. The novel variables, K, I, and S, suggested based on physics properties and empirical evidence, are defined by power-law relations between cortical thickness, exposed and total area, and natural descriptors of brain morphology. Our central hypothesis is that variable K, almost constant in healthy human subjects, is a better discriminator of a diseased brain than the current morphological biomarker, Cortical Thickness, due to its aggregated information. We extracted morphological features from 3T MRI T1w images of 123 elderly subjects: 77 Healthy Cognitive Unimpaired Controls (CTL), 33 Mild Cognitive Impairment (MCI) patients, and 13 Alzheimers Disease (AD) patients. Moreover, Cerebrospinal Fluid (CSF) biomarkers and clinical data scores were correlated with K, intending to characterize health and disease in the cortex with morphological criteria and cognitive-behavioral profiles. K distinguishes Alzheimers Disease, Mild Cognitive Impairment, and Healthy Cognitive Unimpaired Controls globally and locally with reasonable accuracy (CTL-AD, 0.82; CTL-MCI, 0.58). Correlations were found between global and local K associated with clinical behavioral data (executive function and memory assessments) and CSF biomarkers (t-Tau, A{beta}-40, and A{beta}-42). The results suggest that the cortical folding component, K, is a premature discriminator of healthy aging, Mild Cognitive Impairment, and Alzheimers Disease, with significant differences within diagnostics. Despite the non-concomitant events, we found correlations between brain structural degeneration (K), cognitive tasks, and biochemical markers.

Alzheimers disease (AD) is a brain disease characterized by deposition of insoluble amyloid-{beta} plaque, intraneuronal neurofibrillary tangles, and cognitive dysfunction. AD can be characterized as early-onset or late-onset based on age and genetic factors. For early-onset, these genetic factors can include amyloid precursor protein (APP), presenilin-1 (PSEN1), and presenilin-2 (PSEN2). For late-onset, these can include apolipoprotein E e4 (APOE4), and the R47H variant of triggering receptor expressed on myeloid cells 2 (TREM2). Mouse models incorporating these risk factors provide critical knowledge for studying AD pathology and preclinical studies for drug development. However, these transgenic mice depend on early-onset genetic mutations and are deficient in certain AD features that are present in late-onset. Here, we developed innovative non-linear and feature selection procedures for our cross-species translation framework, Translatable Components Regression (TransComp-R), to identify transcriptomic features in mouse models predictive of human late-onset AD pathobiology. We used the cross-species computational translatability links of TransComp-R to perform computational high-throughput drug screening and identified multiple repurposable drugs for AD treatment that targeted the sleep-wake cycle. We tested these predictions in an orthogonal, prospective cohort of human subjects treated with an orexin receptor antagonist, suvorexant. We correlated conserved protein-level biomarkers from our cross-species transcriptomics model with significant reductions in phosphorylated tau in cerebrospinal fluid collected from humans treated with suvorexant. This study demonstrates the power of computational methods like TransComp-R to enhance the utility of murine disease models for discovering new therapeutic approaches for AD. One Sentence SummaryCross-species translation modeling across different mouse models reveals sleep-relevant drug mechanisms as potentially therapeutic for Alzheimers disease.

Alzheimers disease (AD), the most prevalent neurodegenerative disorder globally, has emerged as a significant health concern, particularly due to the increasing aging population. Recently, it has been revealed that extracellular vesicles (EVs) originating from neurons play a critical role in AD pathogenesis and progression. These neuronal EVs can cross the blood-brain barrier and enter peripheral circulation, offering a less invasive means for assessing blood-based AD biomarkers. In this study, we analyzed plasma EV-derived messenger RNA (mRNA) from 82 subjects, including individuals with AD, mild cognitive impairment (MCI), and healthy controls, using next-generation sequencing (NGS) to profile their gene expression for functional enrichment and pathway analysis. Based on the differentially expressed genes identified in both MCI and AD groups, we established a diagnostic model by implementing a machine learning classifier. The refined model demonstrated an average diagnostic accuracy over 98% and showed a strong correlation with different AD stages, suggesting the potential of plasma EV-derived mRNA as a promising non-invasive biomarker for early detection and ongoing monitoring of AD.

BackgroundMany of earlier studies reporting the frequency of preclinical Alzheimers disease (AD) among cognitive normal (CN) individuals have based on the clinical study cohort from Western countries, and it has not been validated whether the frequency of preclinical AD in Asian country cohort may differ from that in Western countries. MethodsWe conducted meta-analysis of earlier literature and original data of 4 Japanese cohort study (i.e., AMED-Preclinical, Brain/Minds Aging Imaging Study, J-ADNI, and A4 study screening conducted in Japan), among which we incorporated cognitive normal (CDR = 0) clinical study participants who were examined their amyloid status by amyloid-PET or CSF. ResultsIn total, among the reviewed 658 Japanese CN participants from 10 different groups, 103 turned out to be amyloid positive, and the estimated overall frequency of preclinical AD (of any stage) was 17.2% (95% CI: 12.0 - 23.0%) with a high statistical heterogeneity of I2 = 64%. In meta-regression, being the Japanese cohort was barely significantly associated with the lower frequency of preclinical AD (p = 0.048). ConclusionsOur study suggested that currently there is no robust evidence to support the lower frequency of preclinical AD in clinical study settings of Japan than that of Western countries.

Alzheimers disease (AD) is a multifactorial disease that exhibits cognitive deficits, neuronal loss, amyloid plaques, neurofibrillary tangles and neuroinflammation in the brain. We developed a multi-scale predictive modeling strategy that integrates machine learning with biophysics and systems pharmacology to model drug actions from molecular interactions to phenotypic responses. We predicted that ibudilast (IBU), a phosphodiesterase inhibitor and toll-like receptor 4 (TLR4) antagonist, inhibited multiple kinases (e.g., IRAK1 and GSG2) as off-targets, modulated multiple AD-associated pathways, and reversed AD molecular phenotypes. We address for the first time the efficacy of ibudilast (IBU) in a transgenic rat model of AD. IBU-treated transgenic rats showed improved cognition and reduced hallmarks of AD pathology. RNA sequencing analyses in the hippocampus showed that IBU affected the expression of pro-inflammatory genes in the TLR signaling pathway. Our results identify IBU as a potential therapeutic to be repurposed for reducing neuroinflammation in AD by targeting TLR signaling.

Objective: Deep cervical lymphatic-venous anastomosis (LVA) has shown promise in treating Alzheimer's disease (AD), yet no preoperative tool exists to identify potential responders. We developed and evaluated a novel A {beta} PET based scoring system that quantifies regional amyloid burden according to anatomical proximity to the meningeal lymphatic vessels (MLVs) to predict treatment response. Methods: We retrospectively enrolled 58 AD patients who had undergone upper cervical LVA. Eleven regions of interest (ROIs) adjacent to the superior sagittal and straight sinuses were scored based on anatomical proximity to MLVs (higher = closer) and functional relevance to AD (functional score = 1 for AD-related ROIs), yielding a regional assigned score (RAS). Standardized uptake value ratios (SUVRs) were obtained for each ROI. The total SUVR (Stotal) was calculated as {sum}(SUVR x RAS) over all ROIs, and S4+5 was defined as the same sum restricted to ROIs with RAS 4 or 5. These scores, along with baseline demographic characteristics, were evaluated for their ability to predict treatment response using LASSO-logistic regression and receiver operating characteristic (ROC) curve analysis. Results: Forty-one patients (70.7%) were responders. At baseline, responders had significantly higher SUVR of the associative visual cortex (SAVC) (1.68{+/-}0.26 vs. 1.53{+/-}0.12, P=0.0394) and higher S4+5 (32.69{+/-}4.45 vs. 30.14{+/-}3.07, P=0.0358) than non-responders. In univariate analysis, S4+5 was the only significant predictor (OR=1.183, 95% CI: 1.005-1.391, P=0.0433); SAVC was borderline significant (OR=16.654, 95% CI: 0.999-277.63, P=0.0501), while SUVR of the posterior cingulate cortex (SPCC) and Mini-Mental State Examination (MMSE) showed only weak trends (P=0.0714 and P=0.0889, respectively). In the multivariable model, MMSE was independently associated with treatment response (adjusted OR = 1.43, 95% CI: 1.06-1.93, P = 0.022); with SPCC and SUVR of the superior parietal cortex (SsPL) reaching marginal significance (P=0.055 and P=0.051, respectively). The apparent AUC was 0.920, decreasing to a Bootstrap-corrected AUC of 0.780 (95% CI: 0.708-0.884) after optimism correction (optimism = 0.139). The Brier score was 0.097. The covariates-only model yielded a corrected AUC of only 0.574, confirming the incremental value of PET DOI data. Conclusion: This exploratory study introduces a novel A{beta} PET scoring system grounded in MLV anatomy that, combined with baseline MMSE, demonstrates modest predictive potential for LVA response in AD. The findings warrant validation in larger, multicenter cohorts.

Epigenetic dysregulation has been widely reported in patients of Alzheimers disease (AD) and epigenetic drugs are gaining particular interest as a potential candidate therapy target. However, it is less clear how epigenetic dysregulation contributes to AD development. In this work, we performed regulatory divergence analysis using large-scale AD brain RNA-seq data and reported a widespread existence of regulatory degeneration among AD patients. It seems that transcription factor (TF)-mediated regulations get weakened or lost during AD development, resulting in disruption of normal neuronal function, especially including protein degradation, neuroinflammation, mitochondria and synaptic dysfunction. The regulatory degeneration burden (RDB) is well correlated with the detrimental clinical manifestations of AD patients. Studies of epigenetic marks, including histone modification, open chromatin accessibility and three TF binding sites supported the existence of regulatory degeneration. It suggested that epigenetic dysregulation contributed to regulatory degeneration, which also explained the consequence of epigenetic dysregulation. Among the epigenetic regulators, HDAC1 was proposed as a potential participator in such a process. Overall, our computational analysis suggested a novel causal mechanism of AD development and proposed HDAC1 as a drug target to treat AD.

Patients with Alzheimers disease (AD) and clinically overlapping neurodegenerative diseases are classified molecularly using the A/T/N classification system. Apart from fluid biomarkers and structural MRI, the three-dimensional A/T/N system incorporates characteristic features from {beta}-amyloid-PET (A), tau-PET (T), and FDG-PET (N). We evaluated if dynamic features of tau-PET with [18F]PI-2620 allow assessment of A/T/N in individual patients using a single imaging session. Cortical tissue clearance (K2a) of [18F]PI-2620 was validated as a surrogate of the {beta}-amyloid status against {beta}-amyloid-PET and cerebrospinal fluid (CSF) A{beta}42/40 ratio, demonstrating remarkable positive (91.5%) and negative (95.1%) predictive values at an AUC of 0.99 (P<0.0001). K2a outperformed cortical tau burden as a surrogate for {beta}-amyloid status in 47 participants with a clinical diagnosis of probable AD (3/4-repeat(R)-tauopathy) and 82 {beta}-amyloid-negative patients with primary 4R-tauopathies. Perfusion-like [18F]PI-2620 images (R1) were validated as a surrogate marker for neuronal injury, exhibiting strong quantitative and visual correlations with FDG-PET and early-phase {beta}-amyloid-PET, as well as with volumetric MRI and CSF total tau levels. Composite quantitative A/T/N indices facilitated personalized staging along temporal disease trajectories. Our results suggest that [18F]PI-2620 imaging has the potential to facilitate the assessment of region and stage dependent PET-based A/T/N during a single dynamic PET session. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=114 SRC="FIGDIR/small/25320240v1_ufig1.gif" ALT="Figure 1"> View larger version (43K): org.highwire.dtl.DTLVardef@25229forg.highwire.dtl.DTLVardef@3ff0eorg.highwire.dtl.DTLVardef@5df95forg.highwire.dtl.DTLVardef@19eef09_HPS_FORMAT_FIGEXP M_FIG C_FIG

IntroductionMultiple studies have reported variations in inflammatory levels in blood of Alzheimers disease (AD), although further research is needed to identify discriminatory biomarkers for AD diagnosis. MethodsA prospective comparative paired study of a group of AD patients compared to normal controls (NC) was carried out in a multicenter study, where age and sex ratio were homogenized to avoid bias. The cohort comprised 39 patients with a diagnosis of AD (64.1% women; mean age 74.8{+/-}0.8 years) and 27 matched NC (66.7% women; 74.8{+/-}0.8 years). The diagnosis of AD was performed by neurologists using the Mini-Mental State Examination test (MMSE) and classical markers in cerebrospinal fluid (CSF) and/or amyloid-PET. We investigated the discriminatory potential of 13 serological parameters in blood, consisting of seven interleukins (IL-3, IL-4, IL-5, IL-6, IL-8, IL-12p40, and IL-15) and other 6 serological inflammatory markers (EGF, GM-CSF, IP-10, sCD40L, PDGF-AB/BB, and RANTES). Additionally, six sociodemographic variables were examined. Apolipoprotein E (APOE) genotype was also determined. ResultsThe results revealed an inverse association between educational level, number of languages spoken, and physical activity, with the risk of AD. An enrichment of the APOE4 isoform was observed in AD (28 out of 39 AD vs 3 out of 24 NC). All circulating inflammation markers were lower in AD patients than in NC (except for IP-10 and sCD40L, while Il-3 and GM-CSF were undetectable in both groups), with statistically significant differences detected in IL-8, IL-12p40, and PDGF-AB/BB (AD/NC ratios of 0.56, 0.59, and 0.81, respectively). IL-8 was decreased specifically in APOE4 carriers (carriers/non-carriers ratio of 0.73), and in amyloid-positive cases (positives/NC ratio of 0.46), whereas IL-12p40 and PDGF-AB/BB showed positives/NC ratios of 0.56 and 0.83, respectively. DiscussionSerum levels of IL-8, IL-12p40, and PDGF-AB/BB were significantly reduced in AD patients. Additionally, IL-8 decrease was associated with APOE4-carriers and amyloid-positive cases.

Aortic dissection (AD), a life-threatening cardiovascular emergency, continues to impose high mortality due to insufficient therapeutic options, as monotherapy targeting angiotensin II type 1 receptor (AT1R) demonstrates limited clinical efficacy. Utilizing single-cell RNA sequencing, we identified integrin {beta}3 as a critical driver of AD progression, with expression levels positively correlated with disease severity. Histopathological validation in human AD specimens and a murine angiotensin II (AngII)-infusion model confirmed marked upregulation of integrin {beta}3 activation. Pharmacological blockade of integrin {beta}3 with Cyclo(-RGDfK) significantly attenuated aortic pathogenesis in vivo, reducing dissection incidence and aortic degeneration. Mechanistically, AngII-mediated AT1R activation induced formation of a receptor complex with integrin {beta}3, triggering its conformational activation. Transcriptomic profiling revealed that activated integrin {beta}3 potentiates vascular endothelial dysfunction by binding glycogen synthase kinase 3{beta} (GSK3{beta}), which stabilizes {beta}-catenin via a non-canonical Wnt signaling axis. This pathway drives endothelial barrier disruption, hallmarks of aortic wall destabilization in AD. Our findings unveil a previously unrecognized synergy between AT1R and integrin {beta}3, implicating aberrant Wnt/{beta}-catenin signaling as a nexus of endothelial injury in AD pathogenesis. These results advocate for a paradigm-shifting dual-therapeutic strategy concurrently targeting AT1R and integrin {beta}3 to restore vascular homeostasis, offering a mechanistically grounded approach to mitigate this lethal disease. This work bridges critical gaps in understanding AD pathophysiology and provides a transformative framework for precision therapeutics.

BackgroundAlzheimers disease (AD) is the most common neurodegenerative disorder, the NLRP3 inflammasome has been shown to play a pivotal role in the pathogenesis of AD, and with increasing attention to its involvement in AD. Therefore, we applied bibliometric methods to describe the current research status of the NLRP3 inflammasome in AD. This study aims to analyze the research trends and hotspots in this field from 2013 to 2024, providing valuable insights for AD research. MethodsWe have selected research on the NLRP3 inflammasome in Alzheimers disease from the Web of Science Core Collection, with the time range from January 1, 2013, to November 30, 2024, and exported all publications in plain text format. Visualization analysis was performed using CiteSpace 6.4.R1, VOSviewer 1.6.20, and Scimago Graphica 1.0.46. ResultsA total of 759 publications related to the NLRP3 inflammasome in Alzheimers disease were included in this study. The number of annual publications showed a general upward trend. The top three countries in terms of publication volume were China, the United States, and Italy. The University of Manchester was the institution with the highest number of publications. The author with the most publications was Michael Heneka, while the most cited author was Eicke Latz. The International Journal of Molecular Sciences published the highest number of articles and was also the most frequently cited journal. The most common keywords included Alzheimers disease, NLRP3 inflammasome, neuroinflammation, A{beta}, and microglia. ConclusionThe primary research hotspots in this field focus on the role of NLRP3 in AD pathology, its potential as a therapeutic target, and strategies to modulate neuroinflammation through targeting the NLRP3 inflammasome. Future research should further investigate the interactions between NLRP3 and other molecular pathways, assess its clinical therapeutic potential, and provide new insights and strategies for the early diagnosis and treatment of AD.

BackgroundFluoroethylnormemantine (FENM), a new Memantine (MEM) derivative, prevented amyloid-{beta}[25-35] peptide (A{beta}25-35)-induced neurotoxicity in mice, a pharmacological model of Alzheimers disease (AD) with high predictive value for drug discovery. Here, as drug infusion is likely to better reflect drug bioavailability due to the interspecies pharmacokinetics variation, we analyzed the efficacy of FENM after chronic subcutaneous (SC) infusion, in comparison with IP injections in two AD mouse models, A{beta}25-35 -injected mice and the transgenic APP /PSEN1{partial}E9 (APP/PS1) line. MethodsIn A{beta}25-35-treated mice, FENM was infused at 0.03-0.3 mg/kg/day during one week after A{beta}25-35 injection. For comparison, FENM and MEM were administered IP daily at 0.03-0.3 mg/kg. In 10-month-old APP/PS1 mice, FENM was administered during four weeks by daily IP injections at 0.3 mg/kg or chronic SC infusion at 0.1 mg/kg/day. Memory deficits, spatial working memory and recognition memory, were analysed. Markers of neuroinflammation, apoptosis, oxidative stress, and amyloid burden in APP/PS1 mice, were quantified. Markers of synaptic plasticity such as PSD-95 and GluN2A/B/D subunits expression in hippocampus homogenates or synaptosomes were quantified in A{beta}25-35-treated mice and synaptic long-term potentiation (LTP) in hippocampal slices was analysed in APP/PS1 mice. ResultsDeficits in spontaneous alternation and object recognition in A{beta}25-35 mice were prevented by infused FENM at all doses tested. Similar effects were observed with the daily FENM or MEM treatments. Animals infused with 0.1 mg/kg/day FENM showed prevention of A{beta}25-35-induced neuroinflammation, oxidative stress and apoptosis. FENM infusion restored A{beta}25-35-induced alterations in synaptosomal PSD-95, GluN2A and P-GluN2B levels. GluN2D levels were unchanged whatever the treatment. In APP/PS1 mice, FENM infused or administered IP alleviated spontaneous alternation deficits, neuroinflammation, increases in A{beta}1-40/A{beta}1-42 and hippocampal LTP alteration. ConclusionThese data confirmed the neuroprotective potential of FENM in the pharmacological A{beta}25-35 and transgenic APP/PS1 mouse models of AD, with a superiority to MEM, and showed that the drug can be efficiently infused chronically.

Alzheimers disease (AD) and vascular dementia (VaD) are two of the commonest causes of dementia worldwide. While AD is characterized by amyloid plaque and neurofibrillary tangle formation, and VaD is characterized by cerebrovascular disease (CeVD), these pathophysiological processes frequently coexist, leading to mixed AD+VaD dementia (MIX). At present, it is unclear which of the multiple gene expression changes observed in MIX brains are driven by AD versus VaD processes. In this study, postmortem neocortical tissues of AD (n=9), VaD (n=9), and MIX (n=10), together with age-matched controls (CTRL, n=10), underwent transcriptome profiling in conjunction with pathway analyses using an established exon-microarray platform. Transcriptome profiling showed that up- and down-regulated genes are mainly associated with vascular dysfunction and neurodegeneration, respectively. VaD manifested the least number of differentially expressed genes (DEG) amongst the diagnostic groups, showing similar but relatively less pronounced changes in common dementia-associated pathways. MIX shared high similarities with AD in gene expression profiles and dysregulated canonical pathways, with additional, MIX-specific DEG and dysregulated pathways suggestive of additive or emergent deleterious effects from AD and cerebrovascular pathologies. Our study provided a genome-wide overview of the gene expression landscape for AD, VaD and MIX, enabling the identification of common and disease-specific pathophysiological processes which inform further studies into the complex interactions between AD and CeVD.

The blood-brain barrier (BBB) is a highly selective permeability barrier that safeguards the central nervous system (CNS) from potentially harmful substances while regulating the transport of essential molecules. Its dysfunction is increasingly recognized as a pivotal factor in the pathogenesis of Alzheimers disease (AD), contributing to the accumulation of amyloid-{beta} (A{beta}) plaques. We propose an AD therapeutic strategy targeting the BBB low-density lipoprotein receptor-related protein 1 (LRP1). We show that a multivalent scaffold with LRP1-specific peptide modulates the A{beta} transport at the BBB. We show via detailed experimentation on AD model mice that this intervention markedly reduces A{beta} deposits and prevents cognitive decline. This study marks a new approach to drug design, combining multivalent targeting with the regulation of membrane trafficking through advanced molecular engineering. Crucially, the therapeutic effects emerge from the multivalent nature of our proposed system. Furthermore, our findings underscore the paramount significance of the BBB in AD pathogenesis, particularly emphasizing the critical role of LRP1-mediated A{beta} clearance in mitigating disease progression.

Alzheimer's disease is characterized by progressive cognitive decline and early cerebrovascular dysfunction, including impaired neurovascular coupling (NVC) and reduced cerebral blood flow (CBF). Tau pathology is a major driver of these deficits, yet therapeutic strategies targeting tau-induced neurovascular dysfunction remain limited. The M1 muscarinic acetylcholine receptor (M1 mAChR) is a promising therapeutic target because of its critical role in cognition. We previously demonstrated that pharmacological activation of M1 mAChR improves cognitive function and neuronal survival in amyloid-based Alzheimer's disease mouse models through sex-specific mechanisms. However, whether M1 mAChR activation restores tau-mediated NVC deficits remains unknown. P301S mice were used as a model of tauopathy. Cognitive function was evaluated using the novel object recognition and Morris water maze tests, and NVC was assessed by measuring whisker stimulation-induced changes in CBF using laser speckle contrast imaging. Following baseline measurements, mice received an acute intraperitoneal injection of VU0486846, a selective M1 mAChR positive allosteric modulator (3 mg/kg), and CBF responses were reassessed over time. P301S tau mice exhibited impaired recognition and spatial memory functions, associated with reduced whisker stimulation-induced increase in CBF, indicative of impaired NVC response, while acute treatment with VU0486846 reversed these changes in NVC. This rescuing effect of VU0486846 was observed earlier in female tau mice compared to males, suggesting a sex-biased effect of M1 mAChR modulation. These findings demonstrate that M1 mAChR positive allosteric modulation reverses tau-induced neurovascular dysfunction, supporting M1 mAChR activation as a promising disease-modifying approach for Alzheimer's disease. The earlier improvement observed in females further suggests that therapeutic efficacy is influenced by biological sex.

Staging the severity of Alzheimers disease pathology using biomarkers is central to early detection and therapeutic trial design. In this cross-sectional study, we standardized amyloid and tau PET data across multiple cohorts to characterize the frequency of amyloid and tau PET-based stages across the clinical continuum. We examined amyloid and tau severity in 10,396 participants (mean [SD] age, 71.9 [7.1] years) with amyloid PET imaging and a subset (n = 3,295) with tau PET imaging. Clinical stage was defined using cohort-specific criteria and categorized as cognitively unimpaired (n = 7,764), mild cognitive impairment (n = 1,480), or dementia (n = 1,152). Amyloid positivity was defined as [&ge;]25 centiloids and amyloid severity was staged using centiloids bins (e.g., <10, 10-24, 25-49, 50-74, 75-99, [&ge;]100). Tau PET severity was staged using a hierarchical Braak staging schema (e.g., T-, T12+, T34+, T56+), and combined with amyloid status to operationalize PET-based Alzheimers disease biological stages (e.g., Stage A: A+T-; Stage B: A+T12+; Stage C: A+T34+; Stage D: A+T56+). The cumulative probabilities of PET-based stages were estimated using ordinal logistic regression models. In cognitively unimpaired individuals, the frequency of amyloid levels [&ge;]10 centiloids increased with age. Similarly, amyloid levels [&ge;]25 centiloids increased with age in mild cognitive impairment. Overall, elevated amyloid ([&ge;]25 CL) was more likely with increasing age among non-demented individuals. By contrast, this age association was attenuated in dementia where severe amyloid burden (e.g., [&ge;]100 CL) was most common. In the tau PET subsample (n = 3,295), there was a three-way interaction between amyloid, age, and clinical impairment on likelihood of tau severity. Both higher amyloid and greater clinical impairment were associated with increased tau severity; however, the strength and direction of these associations varied with age. At lower amyloid levels, the odds of tau severity increased with older age among cognitively unimpaired and mild cognitive impairment. Conversely, at higher amyloid levels, the odds of higher tau severity (e.g., T56+) decreased with older age in mild cognitive impairment and dementia. A similar age-related pattern was observed in the frequency of biological stages (n = 1,154), where Stage D (e.g., A+T56+) was most frequent in younger individuals with dementia. These findings underscore the dual importance of amyloid and tau PET severity as biomarkers for staging and characterizing Alzheimers disease progression. They also demonstrate the feasibility of applying PET-based staging frameworks for the diagnosis of Alzheimers disease across multiple tracers and cohorts.