Journals
2025 EN
Bondonno Catherine P. · Pokharel Pratik · Erichsen Dorit Wielandt
+16 more
Abstract INTRODUCTION Dietary nitrate, through conversion to nitric oxide, which supports vascular and nervous system function, may lower dementia risk but may also form neurodegenerative N ‐nitrosamines, depending on the nitrate source. METHODS We investigated associations between source‐specific nitrate and nitrite intake and incident and early‐onset dementia (<65 years) in 54,804 dementia‐free participants from the Danish Diet, Cancer and Health Cohort Study over ∼27 years. Nitrate and nitrite intakes were derived from food frequency questionnaires and nitrate and nitrite databases. RESULTS Higher plant‐sourced nitrate intake was non‐linearly associated with lower rates of incident dementia (fifth vs first quintile hazard ratio 95% confidence interval: 0.90 [0.83, 0.98]), while increased risk was seen for higher intakes of animal‐sourced, additive‐permitted meat‐sourced, and tap water‐sourced nitrate. Similar associations were seen for source‐specific nitrite intake and were more pronounced for early‐onset dementia. No clear effect modification was observed. DISCUSSION These findings highlight the importance of nitrate source in dementia risk and warrant further investigation. Highlights Plant nitrate is associated with a lower risk of incident and early‐onset dementia. Animal and tap water nitrate are associated with an increased risk of dementia. Encouraging consumption of plant‐based nitrate sources may lower risk of dementia.
Journals
2025 EN
La Joie Renaud · Cummings Jeffrey L. · Dage Jeffrey L.
+12 more
Abstract Following regulatory approval of anti‐amyloid beta (Aβ) therapies, a better characterization of patients receiving these treatments is needed to guide clinical management and inclusion in future trials. This Alzheimer's Association‐convened workgroup proposes a terminology, treatment‐related amyloid clearance (TRAC), to reflect alterations in disease pathophysiology based on biomarker evidence for clearance of Aβ deposits. TRAC designates biomarker‐defined pharmacodynamic changes, rather than direct neuropathological evidence, and applies to individuals with (1) pretreatment biomarker confirmation of cerebral Aβ deposition, (2) treatment with an Aβ‐targeting therapy, and (3) a follow‐up biomarker test indicative of partial or full clearance of Aβ deposits. The workgroup currently recommends defining TRAC using amyloid‐positron emission tomography (PET) and emphasizes the role of quantitative measurements for defining the degree of clearance. This framework is expected to be adapted over time in response to rapidly evolving biomarker and clinical advances and with the accumulation of real‐world data on patients receiving anti‐Aβ therapies. Highlights TRAC identifies patients with biomarker evidence for clearance of amyloid deposits. TRAC is currently defined using amyloid‐PET. Full TRAC means that PET levels dropped below predetermined positivity threshold. Partial TRAC means that PET levels dropped significantly but remain above threshold. This framework is meant to guide future research on patients receiving treatment.
Journals
2025 EN
Wu Yiyang · Travaglini Kyle J. · Gabitto Mariano
+9 more
Abstract INTRODUCTION We investigated sex‐specific gene expression associations with the neuropathology and cognitive manifestation of Alzheimer's disease (AD) leveraging single‐nucleus transcriptomic datasets including 2.84 million nuclei from the dorsolateral prefrontal cortex (DLPFC). METHODS We delineated the full scope of sex‐specific transcript associations, differential gene expression, signaling pathway, and cell–cell communication network changes in eight major DLPFC cell types. RESULTS Nine female‐specific associations were identified and replicated, involving ADGRV1 , OR3A3 , IFI27L1 , LYRM1 , STAP2 , TSTD2 , PDYN , and TMEM50B . We observed the preponderance of protective female‐specific associations in neurons. Sex‐specific genes were enriched in the immune‐, inflammation‐, and damage‐related stress‐response pathways. Six ITGB1‐mediated microglia‐specific incoming signals that may contribute to female‐specific risk of Aβ accumulation were also highlighted. DISCUSSION Our study highlights the transcriptome‐wide, single‐cell landscape of sex‐specific molecular associations with AD neuropathology and cognitive decline, while identifying and replicating several female‐specific gene associations in neurons to help direct future mechanistic studies. Highlights Single‐nucleus transcriptomic association analysis identified 2660 sex‐specific associations involving 2110 genes with four AD endophenotypes. The majority of female‐specific associations link to better endophenotype outcomes were from neurons. Nine female‐specific associations were replicated, including ADGRV1 and OR3A3 with Aβ; IFI27L1 , LYRM1 , STAP2 , and TSTD2 with tau; PDYN with global cognition; and TMEM50B with longitudinal cognitive trajectory. Sex‐specific effect genes were enriched in the immune‐, inflammation‐, and damage‐related stress‐response pathways. Six ITGB1‐mediated microglia‐specific incoming signals may play roles in female‐specific risk for Aβ accumulation.
Journals
2025 EN
Fish Lauren A · Canchi Saranya · Telpoukhovskaia Maria
+24 more
Abstract Background Development of effective drugs for Alzheimer's Disease (AD) is challenging, likely due in part to poor recapitulation of AD in animal models. We developed the genetically diverse AD‐BXD mouse model, a panel of reproducible strains that exhibit variation in age at onset and extent of cognitive decline observed in human AD. Using multi‐modal data (genomic, protein, behavior) from this model, we have uncovered new genes and pathways mediating cognitive resilience to AD. For example, we recently reported a resilience gene expression signature in excitatory intratelencephalic neurons (Telpoukhovskaia et al., 2023, bioRxiv ). Method To uncover novel, conserved gene expression signatures and neuronal subtypes associated with AD resilience, we integrated frontal cortex AD‐BXD single‐nuclei transcriptomic data ( N = 56) with a larger human dataset ( N = 465, ROSMAP, Green et. al, 2024, Nature) to generate translationally relevant mouse cell annotations. After integration and annotation of the mouse data with the human cell taxonomy, we conducted differential gene expression (DE) analysis on mouse excitatory and inhibitory neuronal subclasses using animals’ performance on a fear conditioning task as a continuous cognitive resilience covariate (negative binomial mixed models accounting for subject‐ and cell‐level overdispersion with Nebula). Result In benchmarking experiments, we confirmed that the continuous cognitive metric confers higher statistical power than a conventional categorical resilience covariate while retaining most DE genes found using the categorical covariate. In the current analysis, we identified DE genes in excitatory and inhibitory neuronal subtypes, with the largest number of DE genes found in layer 2/3 excitatory neurons (markers LINC00507, GLRA3, RORB). Several of the DE genes from this cluster have already been studied in the context of neurodegeneration. SCG5, the only DE gene found in both an excitatory and an inhibitory neuronal cluster, was also recently shown to be associated with AD risk. Conclusion We identified a transcriptomic signature associated with cognitive resilience in a genetically diverse AD mouse model. Ongoing work aims to interrogate resilience gene expression signatures and cell types that are conserved across mice and humans. Downstream analyses will include unbiased drug target nomination and drug repositioning analyses to prioritize promising genes, pathways, and drugs for preclinical validation.
Journals
2025 EN
Reid Danielle M. · Cook Noah · Yang Chenyu
+16 more
Abstract Background To elucidate sex differences in Alzheimer's disease (AD), we conducted the largest‐to‐date sex‐stratified genome‐wide association study (GWAS) of AD. To further increase power and identify sex‐specific, potentially druggable AD causal proteins, we performed proteome‐wide association studies (PWAS) integrating GWAS with proteogenomic (i.e., protein quantitative trait locus [pQTL]) brain and cerebrospinal fluid (CSF) datasets. Method Sex‐stratified and sex‐heterogeneity AD GWAS were conducted in European ancestry individuals using a 3‐stage design, followed by fixed‐effects meta‐analysis (Figure 1A). PWAS were conducted via FUSION, combining sex‐stratified AD GWAS with sex‐matched and non‐sex‐stratified protein‐specific variant weights, respectively (Figure 2A). Significant findings in European ancestry were evaluated for sex heterogeneity consistency with admixed African ancestry AD GWAS (improved sex heterogeneity p ‐value upon fixed‐effects meta‐analysis) and PWAS (sample‐size weighted Z‐score combination improved in matching sex and non‐significant Z‐score [P>0.05] in opposite sex). Result GWAS identified 1 sex‐heterogeneous, 14 female‐specific, and 5 male‐specific loci, with 13 out 20 total loci (65%) showing consistent sex heterogeneity in African ancestry data, and 5 out of 20 being novel AD risk loci (Figure 1B‐C). Brain and CSF AD PWAS identified 66 and 19 genes significantly associated with AD in females, respectively, whereas 23 and 17 were identified for males. Upon filtering for sex‐specificity, 34 (52%) female and 4 (21%) male‐specific genes were identified (Figure 2B). Out of 38 total sex‐specific genes, 27 were present in 22 novel AD loci, and 23 out of 30 total unique loci (77%) showed persistent sex heterogeneity upon integration with African ancestry data (Figure 2B). The brain contributed 33 genes, of which 7 were uniquely observed through sex‐matched PWAS (Figure 2C). There were few overlapping significant sex‐stratified proteins between brain and CSF; however, 4 out of 5 overlapping proteins displayed concordant effect directions (Figure 2D). Conclusion Sex‐stratified GWAS and PWAS identified 20 and 30 sex‐specific AD loci/genes, respectively, with high sex heterogeneity accordance in exploratory African‐admixed AD GWAS and PWAS. To provide validation and help prioritize probable causal genes at novel, significant GWAS/PWAS loci, colocalization analyses were performed with various QTL datasets (data not shown). These findings enhance our understanding of AD pathogenesis and risk, which may inform drug target development relevant to sex‐specific personalized medicine.
Journals
2025 EN
Callizot Noelle · Rouvière Laura · Botto Catherine
+3 more
Abstract Background The co‐occurrence of multiple protein aggregates, or even hybrid aggregates, is very often observed in many neurodegenerative diseases, corroborating their molecular cross‐links. Despite the emergence of studies indicating crossovers between Amyloid β (Aβ), hyperphosphorylated Tau protein (pTau) and alpha‐synuclein (αSyn), a thorough understanding of their mechanistic coupling and subsequent pathogenicity is still lacking. It is well known that there are molecular interactions between these different proteins, and in particular between αSyn and pTau and Aβ. However, there is little evidence of a direct link between the formation of one and the appearance of the other. The close links between these proteins on their appearance was studied. Method Primary cultures of hippocampal and dopaminergic neurons both were injured with Aβ oligomers or αSyn PFF. Mitochondrial and lysosomal stress were carefully studied. At different timing accumulation of toxic protein was observed (by ICC and protein analysis). In vivo, aged mice (18 month old) were injured with Aβ or αSyn PFF by stereotaxic injection. Up to 6 weeks after the lesion, appearance of toxic proteins was following in different brain areas (SNpc, hippocampal area, amygdala, striatum). Result We observed a strong correlation between toxic αSyn aggregates and pTau accumulation. Similarly, aggregated αSyn was found after Aβ injections into the hippocampus. Appearance of these various toxic aggregates was always preceded by strong oxidative stress and by lysosome defects. Conclusion These results demonstrate the complexity of the relationships between these different proteins. We demonstrated that not only physical interaction are existing, but that each induced formation of the others leading to neuronal death.
Journals
2025 EN
Legrand Axel · Delatour Benoit · Linard Morgane
+2 more
Abstract Background Alphaherpesviruses, including Herpes Simplex Virus Type 1 (HSV‐1) and Varicella‐Zoster Virus (VZV), are human neurotropic viruses with a high prevalence worldwide. The relationships between neurotropic Herpesviruses and Alzheimer's disease (AD) have been repeatedly emphasized. Our project is based on the hypothesis that neuro‐invasion of alphaherpesviruses, especially of HSV‐1, could trigger or contribute to the formation of early lesions in AD. Method To test our hypothesis, we use a multidisciplinary approach based first on two different animal models for studying the neuropathological consequences of HSV‐1 infection: the cotton‐rat model and the mouse model. Animals were infected in the upper lip and sacrificed at different time points after infection. Histological analyses were conducted to detect viral proteins, microglia, Aß and pTau deposits by immunostaining. Various stains were used to highlight tissue damage. Viral RNAs (lytic or latent phase of HSV‐1) were detected by in situ hybridization (RNAscope). Biochemical assays of Aß/ Tau proteins were performed using the Meso Scale Discovery technology. Another aspect of the project analyses the Shatau cohort, a cohort of human individuals (AD and non demented cases) for which we have serological data for HSV‐1 and VZV, in vivo measurements of Locus Coeruleus integrity, neuroimaging markers of brain accumulation of Aß and pTau proteins, and AD biomarkers in cerebrospinal fluid. Result In the different animal models of peripheral HSV‐1 infection we were able to evidence a neuro‐invasion characterized by the presence, in the brainstem, of viral proteins, lytic/latent viral genomes and neuroinflammatory status. In addition, we detected, by immunohistochemistry and biochemical dosages, evidence of abnormal deposition of Aß and hyperphosphorylated tau proteins evocative of AD. Our results in the analysis of the Shatau cohort indicate that, as hypothesized, anti‐viral antibody titrations are increased in AD vs non‐demented control patients. In addition, VZV titers appear surprisingly to be associated with AD biomarkers for the reduction of the Locus Coeruleus integrity and increased in CSF biomarkers, while association with HSV‐1 titers are weaker or absent. Conclusion Our results strengthen the hypothesis of a causal connection between infection and neuro‐invasion of alphaherpesviruses and AD neuropathologies.
Journals
2025 EN
Ciccotosto Giuseppe D · Bijlsma Elly · Dashper Stuart G
+1 more
Abstract Background We have previously shown that repeated oral inoculation of mice with bacteria that cause the chronic oral disease periodontitis resulted in brain infiltration and induction of Alzheimer's disease (AD)‐like pathology. Here, we examined whether purified bacterial membrane vesicles (BMVs) from the oral pathobiont Porphyromonas gingivalis or oral commensal Neisseria oralis could enter the brain and cause pathology, without the need for an infection of the brain. Methods Three experimental groups of 36 female C57BL/6 mice, were injected intravenously with 10 µg of purified BMVs from P. gingivalis or N. oralis , or an equal volume of vehicle alone (Control), through the tail vein on Days 1, 5, 8 and 11. Six mice from each group were killed on Days 2, 6, 12, 26, 40 and 55, then PBS perfused before their brains dissected. Immunohistochemistry analyses of 3 hemibrains per group, per timepoint, were probed for the presence of the BMVs, neuronal damage, neuroinflammation, AD‐like pathology and immune system activation. Result BMVs from both P. gingivalis and N. oralis were found within the brains after one injection. Detection of P. gingivalis MV positive cells peaked at two timepoints, at Days 6 and 26, whereas detection of N. oralis MV positive cells peaked at Day 26, 2 weeks after the final intravenous injection. By Day 55, the detection of cells positive for both BMVs had decreased to levels consistent with the BMVs being removed from the brains. There were similar levels of neuronal degeneration, Il‐6 and IL‐1β in the hippocampus between the three groups of mice over time, but only P. gingivalis MVs were able to induce microgliosis and astrogliosis in the hippocampus. There were no amyloid plaques detected in the brains, but phosphorylated Tau peaked significantly at Day 26 in the mice that received BMVs. Conclusion BMVs from both N. oralis and P. gingivalis entered the brain from the bloodstream but caused different host responses. Upon cessation of BMV injection, the BMVs were naturally removed from the brain over time, suggesting that treatment of the source of the BMVs, namely periodontitis, would reduce exposure to brain pathology causing agents.
Journals
2025 EN
Ajalo Catherine · Andai David · Shah Jasmit
+16 more
Abstract Background Sleep disturbances are increasingly linked to Alzheimer's disease (AD) . Short sleep duration impairs memory whilst longer duration is linked to neuroinflammation and underlying neuropathology. Sleep health remains understudied in Africa, limiting insights into its role in dementia risk. Thus, we examined relationships between subjective sleep quality and memory complaints, focusing on dementia; and highlighting implications of self‐reported sleep in African populations. Method Participants ( n = 263; mean age 54.97; 60.1% female) from the Brain Resilience Kenya (BRK) and AD‐Detect Kenya studies were included and categorized into four groups: Dementia cases ( n = 32, mean age 71.7), AD‐Detect and BRK Cognitively unimpaired controls ( n = 201), and Oncology patients (breast/prostate cancer, n = 23). Self‐reported sleep was assessed using the 6‐item RU‐SATED questionnaire, measuring: Regularity; Uninterrupted Sleep; Satisfaction; Alertness; Timing; Efficiency; Duration (total score range: poor (0) – excellent (12)). Self‐reported cognitive concerns were compared against RU‐SATED score. Logistic regression models were used to examine relationships between memory performance (binary outcome) and predictors across groups: RU‐SATED score, age, biological sex, education level and study group. Result Dementia cases had the highest memory complaints (90.6%, n = 29) versus AD‐Detect controls (46.8%, n = 36), BRK controls (46.6%, n = 61), and oncology patients (47.8%, n = 11). Surprisingly, dementia cases recorded the highest mean RU‐SATED score (9.03, SD 1.94), followed by oncology patients (8.52, SD 2.84), AD‐Detect controls (7.71, SD 2.25), and BRK controls (7.49, SD 2.47). No significant correlation emerged between self‐reported sleep quality and memory complaints. However, regression analysis (χ²(10) = 58.80, p < 0.001) identified age as a strong predictor of memory complaints (OR = 1.07, p < 0.001), with each additional year increasing complaint likelihood by 7%. Males were 56% less likely than females to report memory complaints (OR = 0.44, p = 0.005). Sleep data measured via actigraphy will be presented. Conclusion Preliminary findings suggest reporter bias in dementia patients with memory impairments, highlighting the need for gold‐standard objective ascertained sleep data. In LMICs like Kenya, where sleep health data is scarce, reliance on self‐reported assessments may introduce inaccuracies. Future studies should leverage objective measures (e.g., actigraphy, polysomnography) and informant verification to improve reliability, informing dementia risk reduction strategies in underrepresented populations.
Journals
2025 EN
de Haro Maria · Fadel Omar El · Stephens Morgan Catherine
+4 more
Abstract Background Genomic and transcriptomic analyses have identified molecular pathways dysregulated in Alzheimer's disease (AD). However, their roles in disease remain largely unknown due to limited in vivo validation. YAP1, a downstream effector of the Hippo pathway, has been shown to be dysregulated in AD and sequestered into amyloid aggregates. Additionally, studies have shown that suppressing Hippo kinase activity improves outcomes in AD animal models (PMIDs: 31980612, 35525373, 38760516). This study explores the interaction between the Hippo pathway and Tau, examining how its dysregulation contributes to AD pathogenesis and providing new mechanistic insights into the therapeutic potential of targeting the Hippo pathway. Method We analyzed brain transcriptomes from Alzheimer's disease (AD) patients (bulk and single‐nucleus) and AD mouse models. Additionally, whole‐exome sequencing data from ADSP revealed differential mutational burdens in Hippo pathway genes between AD cases and controls. To validate and characterize the interaction between the Hippo pathway and Tau, we employed behavioral, biochemical, and histopathological assays in vivo and in human NPCs. Result Genomic analyses of AD suggest an increased mutational burden in Hippo pathway genes compared to controls, while transcriptomic data indicate dysregulation consistent with pathway activation. These in silico findings were validated in vivo. We demonstrate that Hippo pathway modulation can suppress Tau‐mediated neuronal dysfunction in Drosophila. Additionally, knockdown of several Hippo pathway genes reduces Tau protein levels in both Tauopathy fly and human NPC models. Furthermore, Tau and YAP1 co‐immunoprecipitate in human NPCs and brains from aged P301S mice. Conclusion Our findings reveal aberrant Hippo pathway activation and increased mutations in AD. Modulating pathway components reduces Tau toxicity and lowers Tau levels, highlighting the Hippo pathway as a potential diagnostic and therapeutic target.