bluuebunny/crossref_metadata_2025 huggingface dataset:
Preliminary Insights from a Multi‐Ancestry TWAS in Alzheimer’s Disease in African and European Populations
Authors: Sun Xinyu , Mews Makaela , Wheeler Nicholas R. , Benchek Penelope , Reitz Christiane , Naj Adam C. , Below Jennifer Elizabeth , Kunkle Brian W. , Griswold Anthony J. , Bush William S.
Published: January 2025

Background

Recent advances in Alzheimer’s Disease (AD) research have emphasized the importance of recruiting from diverse populations. Notably, African‐descent individuals have an almost doubled risk of developing AD compared to European‐descent individuals. Transcriptome‐wide association studies (TWAS) have advanced the analysis of non‐coding variants by integrating gene expression with GWAS data. The newly developed Multi‐ancEstry TRanscriptOme‐wide analysis (METRO) method leverages gene expression data from multiple ancestries, enhancing TWAS power. Addressing this knowledge gap, our study utilized METRO, incorporating both African and European expression and genotype data from the Multi‐Ancestry Genomics, Epigenomics, and Transcriptomics of Alzheimer’s (MAGENTA), to identify AD‐associated genes in each population.

Method

Quality control (QC) on genotype data included filtering SNPs with MAF>0.05 and removing samples with outlier global principal components (PCs). Post‐QC, 199 African and 236 European samples from MAGENTA, with both whole‐blood expression and genotype data, were retained. cis‐eQTL analysis was performed for each protein‐coding gene within a 500kb region, adjusting for age, sex, PCs, and PEER factors. We obtained African American AD GWAS statistics from Kunkle et al. 2021 (n = 8,006) and European AD GWAS statistics from Douglas et al. 2021, excluding 23andMe and UKBB samples (n = 398,058). High‐coverage 1kGP WGS data served as the linkage disequilibrium (LD) reference panel for GWAS statistics. METRO analysis utilized both ancestries’ summary‐level eQTL and GWAS statistics.

Result

We identified 276 statistically significant genes using European‐descent individuals after Bonferroni correction. In contrast, no significant genes were found using African‐descent individuals, except within the APOE locus. Excluding APOE locus genes, gene‐set enrichment analysis using DisGeNET revealed enrichment in AD and related dementia pathways among the top 10 pathways. Among the 246 significant genes, excluding APOE locus, identified in individuals of European‐descent, 131 exhibited the same gene‐trait association direction in individuals of African‐descent.

Conclusion

The multi‐ancestry TWAS identified 276 genes potentially associated with AD, particularly in pathways related to the disease. These findings may enhance our understanding of AD genetic risk. The limited sample size in African‐descent AD GWAS may explain the lack of significant gene identification beyond the APOE locus. Future studies with more diverse populations are essential for discovering novel AD‐related genes in underrepresented groups.
Cross‐species protein interactome network‐based analysis of GWAS and human brain quantitative trait loci (x‐QTL) data identifies risk genes and drug targets for Alzheimer’s disease
Authors: Xu Jielin , Zhou Yadi , Hou Yuan , Pieper Andrew A. , Cheng Feixiong , Leverenz James B
Published: January 2025

Background

The emerging tools of protein‐protein interactome network offer a platform to explore not only the molecular complexity of human diseases, but also to identify risk genes and drug targets. Integration of the genome, transcriptome, proteome, and the interactome networks are essential for such identification, including Alzheimer’s disease (AD), Parkinson disease (PD), and Amyotrophic lateral sclerosis (ALS)

Method

In this study, we performed multi‐modal analyses of cross‐species protein interactome networks and human brain functional genomics data to identify risk genes and drug targets for neurodegenerative diseases. We presented a multi‐view topology‐based deep learning framework to identify disease‐associated genes for cross‐species interactome (TAG‐X). We re‐constructed comprehensive protein‐protein interactome networks for human, Drosophila melanogaster (fruit fly), Caenorhabditis elegans (worm), and Saccharomyces cerevisiae(yeast), by assembling high quality binary protein‐protein interactions (PPI). The fundamental premise of TAG‐X is that AD risk genes exhibit distinct functional characteristics compared to non‐risk genes and, therefore, can be distinguished by their aggregated human brain‐specific functional genomic features from various quantitative trait loci (x‐QTL), including expression QTL (eQTL), protein QTL (pQTL), splicing QTL (sQTL), methylation QTL (meQTL), and histone acetylation QTL (haQTL).

Result

After integration genome‐wide association studies (GWAS) and x‐QTL data into the interactome networks via TAG‐X, we found that unique integration of fly, worm and yeast interactome networks boosted performance in risk gene prediction compared with the human protein‐protein interactome across AD (e.g., fly: NDUFAF6, CHRNA2; worm and yeast: TOMM40), PD (e.g., fly: SCARB2; worm: AGAP1; yeast: SLC2A13, BCKDK) and ALS (e.g., fly: SOD1; worm: SARM1; yeast: VCP, PRDX6). We found that human brain‐specific PPI network presented the strongest potential for AD risk gene discovery (e.g., AD: ACE, BIN1, INPP5D,MS4A4A, SYK; PD: SNCA, LRRK2, DGKQ; ALS: SCFD1, G2E3). Furthermore, interactome network‐predicted genes are significantly enriched in known drug targets and are significantly enriched in disease‐related pathobiological processes.

Conclusion

In summary, we presented a cross‐species protein interactome network methodology that utilizes functional genomic and GWAS findings to identify disease risk genes and drug targets for AD and other neurodegenerative diseases if broadly applied. Functional observations of candidate targets and genes are warranted in the future.
Differentially expressed genes and biological processes shared by alternative and mouse models of Alzheimer’s disease
Authors: Pereira Flávia Suelen De Oliveira , Carello‐Collar Giovanna , Ryssina Vitória Vitalina Margarita , Ávila Daiana Silva , de Bastiani Marco Antônio , Zimmer Eduardo R.
Published: January 2025

Background

Replacement, Reduction, and Refinement (3R) guidelines propose the use of alternative models to study human diseases. These models have high homology and are less onerous compared to rodents, which dominate Alzheimer’s disease (AD) research. However, it is still necessary to investigate whether evolutionary components are conserved among AD models cross‐species. Thus, we aimed to determine similar and different core molecular programs and biological processes in alternative and mouse models of AD.

Methods

We searched the Gene Expression Omnibus (GEO) repository for available RNa‐sequencing studies of alternative (Caenorhabditis elegans, Drosophila melanogaster, and Danio rerio) and mouse (Mus musculus) models of amyloidosis. The following datasets were selected for alternative (GSE198684, GSE109489, GSE158233) and mouse (GSE186710 and GSE144746) models of AD. According to the species, we selected the brain (hippocampus), head, or whole body as samples. Data was downloaded using the GEOquery package and the differentially expressed genes were defined as having FDR‐ adjusted p‐value < 0.05. Using the R Studio and Cytoscape software, we grouped DEGs into clusters of gene ontology for biological processes (GOBPs) according to their function.

Results

A greater number of DEGs were shared between D. rerio and mouse models of amyloidosis when compared to other species (Figure 1). By comparing alternative models, C. elegans has more DEG‐intersections with D. melanogaster than with D. rerio (Figure 1). Regarding biological processes, more overlap of GOBPs was found between D. melanogaster and M. musculus (Figure 2). C. elegans, despite having present DEGs in common with D. rerio and M. musculus, did not share GOBP terms with these vertebrates, but only with D. melanogaster (Figure 2). The shared biological processes conserved among the species were classically associated with AD pathology, such as protein misfolding response, immune and inflammatory systems, neurotransmission, and metabolic processes (Figure 3).

Conclusions

The findings suggest that alternative models share transcriptomic similarities with mouse models of amyloidosis. Thus, these models may serve to accelerate the understanding of amyloid‐related pathophysiological processes and the development of innovative therapeutics in AD.
Pupil dilation during visual search is sensitive to plasma pTau181 levels in cognitively healthy older adults
Authors: Festa Elena K , Heindel William C , Marangi Camille A. , Zou Jingjing , Galasko Douglas R. , Salmon David P. , Jacobs Diane M.
Published: January 2025

Background

Pathological changes of Alzheimer’s disease (AD) occur in the locus coeruleus (LC) years before clinical symptoms. This may affect LC activity that can be indexed by changes in pupil dilation. AD also disrupts connections between related but functionally distinct cortical areas leading to visual feature binding deficits. Thus, feature binding in individuals with preclinical AD may require additional cognitive effort that engages LC activity. Pupil dilation during conjunctive visual search may therefore be a particularly sensitive marker of preclinical AD.

Method

Sixty‐three cognitively unimpaired older adults from the UCSD Alzheimer’s Disease Research Center (51% men; overall mean age = 78.4 years, education = 17.5 years, and MoCA score = 25.9), performed a conjunctive visual search task while their pupil diameter was continuously recorded. There were 108 trials in which the participant searched for a target stimulus (a black dot moving up‐and‐down) among distractor stimuli that shared target features (white dots moving up‐and‐down and black dots moving left‐and‐right). Search displays contained 1, 3, or 5 stimuli with a target present on half of the trials. Reaction time and accuracy in detecting presence of a target were recorded. Plasma levels of the AD biomarker pTau181 were determined by the National Centralized Repository for Alzheimer’s Disease using Quanterix (v2). Plasma pTau181>4.09 pg/mL was considered AD positive.

Result

AD positive (n = 19) and AD negative (n = 44) groups did not differ on age, education, sex, or MoCA scores. Despite similar behavioral performance in visual search, the groups displayed striking differences in pupillary responses across conditions. Both groups showed more pupil dilation with increasing display size, consistent with the application of cognitive effort. However, only the AD‐positive group showed significantly greater pupil dilation in the target‐present than target‐absent condition. This selective pupil modulation in the AD‐positive group may reflect greater demands associated with maintaining the search template in working memory or with performing template‐matching processes to guide attention.

Conclusion

Results suggest early functional changes in the LC noradrenergic system are detectable in biomarker‐positive cognitively healthy older adults. Pupillary responsivity under task‐induced conjunction search conditions may serve as a particularly sensitive marker of preclinical AD.
Digital Cognitive Screening Outcomes in Older Women at the Annual Well Woman Visit
Authors: Rizer Sandra , Joyce Jillian L. , Dargie Samantha A. , Chapman Silvia , Libon David J. , Mora Laura , Tom Sarah E. , Marder Karen , Rosser Mary , Cosentino Stephanie
Published: January 2025

Background

Mild cognitive impairment, a precursor to Alzheimer’s disease and related disorders (ADRD), is widely underdiagnosed. Routine screenings are key for identifying older adults with emerging neurodegenerative disease. As women have increased risk of ADRD and often use their gynecologist as their primary care physician, the annual well woman visit offers a critical opportunity to screen older women for ADRD. This study aimed to examine objective cognitive outcomes using a novel digital screening tool easily deployed in clinical settings.

Method

Women 50 and older were invited to participate in the current study at the time of their annual visit to the Columbia University Integrated Women’s Health Center. Participants completed a brief tablet‐based cognitive screener, the Core Cognitive Evaluation (CCE), developed by Linus Health. The CCE includes an immediate and delayed three‐word recall (3 points) and clock drawing (2 points) for a maximum of 5 points (Normal>3, Borderline 2‐3, Impaired<2), based on both core and error/process variables. A continuous 100‐point clock score is also produced with eight indices.

Result

Of 130 eligible participants, 71(55%) agreed to participate in the study (see Table 1 for demographics). Continuous clock scores ranged from 16 to 100 (Mean(SD) = 73.15(21.2)). As described in Table 2, 62% participants scored in the Normal range, 37% in the Borderline range and 1% in the Impaired range. After a delay, 76% of participants recalled all or more of the words initially recalled. Lower scores were observed in clock drawing than delayed word recall, with spatial reasoning being the lowest the clock index score on average. See Figure 1 for clock indices.

Conclusion

The majority of women obtained Normal CCE scores while 38% performed in the Borderline or Impaired range. By capturing subtle information about the process used to complete cognitive tasks, tablet‐based testing offers a sensitive means of detecting cognitive changes. Future work is needed to evaluate screener outcomes in relation to comprehensive neuropsychological testing and cognitive change over time. A limitation of this study is the sociodemographic homogeneity of the participants. Future work aims to expand into gynecology settings with more diverse patient populations.
Plasma high‐density lipoprotein levels is associated with preserved hippocampal volume in Alzheimer`s disease individuals without vascular co‐pathology
Authors: Rodrigues Matheus Scarpatto , Oliveira Markley Silva , Lussier Firoza Z , Ferreira Pamela C.L. , Povala Guilherme , Bauer‐Negrini Guilherme , Felix Cynthia , Abbas Sarah , Zalzale Hussein , Soares Carolina , Saha Pampa , Madeiros Marina Scop , Bloomquist Madeleine , Hong Chang‐Hyung , Roh Hyun Woong , Karim Helmet T. , de Oliveira Jade , Karikari Thomas K , Tudorascu Dana , Zimmer Eduardo R. , Bellaver Bruna , Son Sang Joon , Pascoal Tharick A.
Published: January 2025

Background

Dysregulation of cholesterol metabolism contributes to the increase of cerebral vascular diseases, favoring the development of dementia. In this sense, high levels of high‐density lipoprotein (HDL) are considered protective against the outcomes associated with cardiovascular diseases. However, little is known about the effect of plasma HDL levels to alterations of cerebral volume in non‐vascular AD and vascular AD individuals. Here we evaluated the association of plasma HDL levels with alterations in brain volume and with plasma neurofilament light chain (NfL) levels.

Method

We analyzed 135 AD individuals from the Biobank Innovations for Chronic Cerebrovascular Disease with Alzheimer’s Disease Study [BICWALZS] cohort. Based on Fazekas scale for brain white matter lesions, we stratified AD individuals into two groups: non‐vascular AD [Fazekas score = 1 and amyloid‐β (Aβ) positive/n = 76], and vascular AD [Fazekas score = 2, 3 and Aβ positive/n = 59] (Figure 1A). Linear regression models accounting for vascular co‐pathology APOEε4 carriership, age and sex were used to test associations of plasma HDL with the variables of interest.

Result

We observed a significant interaction between plasma HDL levels and presence of vascular pathology on total brain white matter (b = 0.375, p = 0.019, Fig. 1B; Table 2). Analyzing the hippocampal atrophy through the global Schelten`s scale, we observed that high plasma HDL levels was negatively associated with hippocampal atrophy only in non‐vascular AD individuals (b = ‐0.405, p < 0.001, Fig. 1C). However, no effect of plasma HDL levels on total gray matter and hippocampal volume was observed (Table 1). Non‐vascular AD individuals with high hippocampal atrophy scores showed reduced plasma HDL levels compared to non‐vascular AD individuals with low hippocampal atrophy scores (p < 0.01, Fig. 1D). Furthermore, no associations of plasma HDL with NfL levels were detected, regardless of the brain vascular status (Fig. 1E).

Conclusion

We showed that high plasma HDL levels is associated with less white matter pathology and reduced hippocampal atrophy scores, without changing plasma NfL levels. Together our findings indicate that high HDL levels seem to be associated with preserved brain volume only in AD individuals with no vascular co‐pathology.
Aquaporin‐4: Unraveling the Link Between Reactive Astrogliosis and Neuroinflammation in Down syndrome with Alzheimer’s Disease Pathogenesis
Authors: Stringer Cherie A , Miyasato Haley , Camey Kevin , Ngo Phong , Andrews Elizabeth J. , Lai Florence , Ikonomovic Milos D , Kofler Julia , Wright Sierra , Phelan Michael J. , Head Elizabeth
Published: January 2025

Background

Down syndrome (DS) is characterized by the overexpression of the amyloid precursor protein gene (APP) and pro‐inflammatory genes, leading to progressive beta‐amyloid (Aβ) accumulation. This accumulation in DS may exacerbate neuroinflammation, contributing to the pathogenesis of Alzheimer’s Disease (AD). Experimental models suggest that aquaporin 4 (AQP4), an astrocytic water channel implicated in Aβ clearance, is mislocalized with increased Aβ burden. It is unclear whether the mislocalization of AQP4 is observed and connected with reactive astrogliosis in response to Aβ and the progression of AD in DS. We hypothesize AQP4 expression is increased and mislocalized from astrocytic endfeet, contributing to an astrocytic neuroinflammatory response in DS with AD pathogenesis.

Methods

This study analyzed AQP4 distribution and expression via immunohistochemistry for AQP4 in 70 frontal (FR) and 64 occipital (OC) cortical human post‐mortem brain samples. Diagnostic classes included aged controls, DS, DS with AD, and sporadic AD (sAD). Semi‐quantitative analysis compared AQP4 distribution across diagnostic classes and brain regions. AQP4 expression was quantified using QuPath. Immunofluorescence (IF) assessed co‐localization and distribution of neuroinflammatory markers complement C3 (C3) and S100β with GFAP‐labeled astrocytes.

Results

AQP4 immunolabeling was observed for expression, distribution, and astrocytic morphology. In DS with AD, AQP4 was expressed away from endfeet, indicating a higher prevalence of reactive astrocytic morphologies compared with DS and control groups. Two‐Way ANOVA analysis revealed increased AQP4 expression in DS with AD compared with DS in both FR (p<0.0001) and OC (p = 0.0007) regions. IF for C3 exhibited a plaque‐like distribution and S100β co‐localized with GFAP‐labeled astrocytes in DS with AD and sAD not seen in DS and controls.

Conclusion

The observed increased expression and mislocalization of AQP4 from endfeet, coupled with heightened AQP4‐labeled reactive astrocytic morphology, supports our hypothesis that AQP4 is involved in AD pathology in DS. Altered neuroimmune marker distribution and co‐localization in DS with AD, compared to DS alone, further supports the hypothesis that AQP4 localization contributes to reactive astrogliosis. Subsequent investigations will explore correlations between AQP4 localization changes, Aβ levels, and increased expression of neuroinflammatory markers, including C3 and S100β.

Funding: NINDS (T32 NS121727‐01), ADRC (P30AG066519), ABC‐DS (U19AG068054), and Brightfocus (BFF17_0008).
Older adults at‐risk for type 2 diabetes exhibit decreased performance on spatial and working memory tasks using classic and novel cognitive testing
Authors: Ghosh‐Swaby Olivia R , Al‐Shaikh Jennifer Hanna , Palmer Daniel , Khan Ali R. , Thornton Jane , Bussey Timothy J , Saksida Lisa M , Liu‐Ambrose Teresa , Nagamatsu Lindsay
Published: January 2025

Background

Type 2 diabetes (T2D) and older age are well‐known risk factors for dementia. Indeed, there is evidence that older adults not diagnosed, but at‐risk for T2D can show early signs of cognitive decline, further exacerbated by excessive body weight or high blood glucose levels. Such a finding would have implications for early treatment strategies; however, the evidence is still sparse. We examined the correlation of risk factors for diabetes with cognitive function in older adults at‐risk for T2D using a battery of touchscreen tasks translated from their rodent versions, as well as traditional pen‐to‐paper cognitive tests.

Method

Sixty‐five older adults (69.39 ± 10.31 years old, 68% female) at‐risk for T2D (BMI ≥ 25 kg/m2, hemoglobin A1c ≥ 6.0%, CANRISK score ≥ 21) completed 3 novel touchscreen tasks: paired associative learning (PAL) (learning and object‐in‐location memory), progressive ratio (motivation), and trial unique, non‐matching to location (TUNL) (spatial pattern separation and working memory). They were also tested on pen‐to‐paper cognitive tests: trail‐making (task switching), Stroop (selective inhibition), and digit span (working memory). A correlation analysis was performed between BMI or HbA1c and cognitive performance. Performance on touchscreen tasks was analyzed using a repeated measures one‐way ANOVA.

Result

Higher HbA1c levels were correlated with lower digit span scores (r2 = 0.12, p = 0.011). There was no correlation between breakpoint (motivation level) and BMI or HbA1c during the progressive ratio task (r2 = 0.0, p = 0.38). Interestingly, this population performed at chance level (59.7 ± 5.3% accuracy) on the PAL task, indicating they were unable to learn object‐location paired associates. When manipulating the spatial similarity in distance between stimuli during the TUNL task, older adults at risk for diabetes were 10% lower in accuracy when stimuli were close together compared to further apart (p<0001). Participants also responded more slowly to stimuli at choice during the TUNL task during the heaviest working memory load condition (p = 0.003).

Conclusion

Older adults at‐risk for T2D exhibit decreased performance on tasks with higher demands on spatial and working memory. Future research will compare performance on all tasks to healthy age‐matched controls and reassess performance after a six‐month exercise intervention.
APOEε4 Allele Modulates Region‐Specific Transcriptomic Changes in Epigenetic Control Pathways: Implications for Late‐Onset Alzheimer’s Disease Risk
Authors: Delatorre Nicole , Van Rossum Hannah , Parker Anna , Brinton Roberta Diaz
Published: January 2025

Background

Age, sex, and APOE genotype are well‐established risk factors for late‐onset Alzheimer’s Disease (LOAD). Previous findings demonstrate that neuroinflammatory profiles of the human midlife female brain closely resemble the human AD brain. Given APOE’s role in LOAD pathogenesis, here we investigate the contribution of this risk factor on targeted AD relevant transcriptional pathways.

Methods

Human corpus callosum, hippocampus, and hypothalamus tissue samples from 31 healthy control brain donors (n = 16 females; age = 48.4yrs ±3.7) without neurodegenerative disease and 20 LOAD (n = 10 females; age = 70.2 yrs±3.6) brain donors were obtained from the NIH NeuroBioBank (University of Maryland, University of Miami, and Mt. Sinai). APOE genotype was determined by electrophoresis and classified by the presence of APOEε4 alleles (carriers n = 26). Transcriptomic analyses were conducted via NanoString nCounter neuroinflammation panel, resulting in 23 pathways. The log2 fold change of gene expression was calculated utilizing the Rosalind platform. Wherein ε4 carriers (condition) were compared to ε4 non‐carriers (control). Primary analyses compared APOEε4 carriers to noncarriers. Whole pathway significance was determined using Fisher’s exact test.

Results

APOEε4 carriers exhibited significantly downregulated astrocyte function in the corpus callosum (p = 0.001), upregulated adaptive immune response in the hippocampus (p = 0.321), and upregulated epigenetic regulation in the hypothalamus (p = 0.007). Sub‐analyses based on sex, disease status (healthy vs. LOAD), and APOEε4 status revealed consistent within‐sex differences only for epigenetic regulation. Specifically, male (p = 0.015) and female (p = 0.001) midlife APOEε4 carriers differed significantly from non‐carrier counterparts in the hypothalamus. Significance of epigenetic regulation was also observed in AD between male and female APOEε4 carriers and their non‐carrier counterparts both in the hypothalamus (p = 0.023; 0.016) and hippocampus (p = 0.032;0.001). No between‐sex differences were identified in any sub‐analyses.

Conclusion

These results provide evidence of region‐specific differences in adaptive immune and epigenetic pathways driven by and specific for the APOEε4 allele. These targeted transcriptional analyses in post‐mortem brain indicate that at late‐stage AD, APOEε4 is the principle differentiating factor in the transcriptional profile of targeted genetic pathways. Further, the data indicate activation of epigenetic control pathways within both the hypothalamus and hippocampus. The outcomes of these analyses support future studies to characterize epigenetic regulation in late‐onset Alzheimer’s disease.
Downregulation of α‐synuclein in a mouse model of Alzheimer’s Disease: neuropathological, behavioral and transcriptomic changes
Authors: Leitao Andre Direito Goulart , Ahammad Rijwan Uddin , Spencer Brian , Wu Chengbiao , Rissman Robert A.
Published: January 2025

Background

Neurodegenerative disorders of aging are characterized by the progressive accumulation of proteins such as α‐synuclein (α‐syn) and amyloid beta (Aβ). Misfolded and aggregated α‐syn has been implicated in neurological disorders such as Parkinson’s disease (PD), and Dementia with Lewy Bodies (DLB), but less so in Alzheimer’s Disease (AD) despite the fact that synuclein pathology is present in over 50% of postmortem brains of AD patients. We are now expanding on our previous studies which showed positive therapeutic effects of downregulating α‐syn in AD mice to understand the overall brain transcriptomic and mechanistic changes induced by treatment.

Method

We first treated AD mice systemically with a α‐syn antisense oligonucleotide (ASO‐syn) conjugated with a LDLR‐specific peptide (ApoB11) that allows for transport across the blood‐brain barrier and measured the presence of the ASO in the brain by immunohistochemistry. We then treated both neurons in culture and 6 months‐old AD mice with the ApoB:ASO conjugates and measured α‐syn levels in both cells and brains by immunohistochemistry and Western blot to test the feasibility of this treatment to downregulate α‐syn. Finally, we performed single‐cell RNAseq to ask the question of how α‐syn interferes with neuropathology in AD, i.e. which genomic pathways are changed when mice are treated with ApoB:ASO‐syn conjugates.

Result

We found that treatment of APP transgenic (AD) mice with ApoB11:ASO‐syn leads to a significant reduction of Aβ plaques burden, rescued neuronal loss and prevented astrogliosis, as compared to untreated AD mice. Importantly, we found that AD mice treated with the ASO‐syn had significantly improved spatial memory function. We found specific single‐cell transcriptomic changes associated with this downregulation of α‐syn, highlighting possible pathways for α‐syn‐mediated vulnerability.

Conclusion

Collectively, our data supports the use of ApoB11:ASO α‐syn conjugates delivered systemically to downregulate α‐syn as a promising future therapeutic strategy in AD. Our work suggests that knocking down α‐syn could be necessary to prevent neuropathology in AD.
Lewy body disease stages through aging and correlations with clinical and neuropathological profile on a population‐based brain bank
Authors: Paes Vitor Ribeiro , Justo Alberto Fernando Oliveira , Rodriguez Roberta Diehl , Naslavsky Michel Satya , Leite Renata Elaine Paraizo , Pasqualucci Carlos Augusto , Zatz Mayana , Jacob‐Filho Wilson , Suemoto Claudia Kimie , Grinberg Lea T.
Published: January 2025

Background

Lewy body disease (LBD) is a neurodegenerative condition marked by the accumulation of neuronal alpha‐synuclein, leading to both Parkinson’s disease and Lewy body dementia. It is regarded as the second most common neurodegenerative disease associated with aging. However, there is limited knowledge of LBD prevalence in the general population, particularly among non‐whites. Our study aimed to investigate the prevalence of LBD in a large, diverse population‐based clinicopathological cohort. Additionally, we sought to explore the associations of LBD with comorbid neuropathology, clinical outcomes, and APOE genotyping.

Method

We investigated cases from the Biobank for Aging Studies from the University of São Paulo, collected between 2004 and 2023. Clinical and sociodemographic information were gathered from the next of kin using structured and validated protocols, including parkinsonism score (PS) assessment through Tanner’s questionnaire. Neuropathological evaluations adhered to USA/NACC guidelines, using immunohistochemistry to detect beta‐amyloid, tau, alpha‐synuclein, and TDP43.

Results

1,669 participants with complete sociodemographic, clinical, and neuropathological data were enrolled. LBD was detected in 0,84% of 50‐59 age group and the frequency increased with age reaching 15% in 90+ group. There was a trend of lower LBD presence in Black/Brown, but higher in Asians. LBD was associated with age, and higher CDR‐SOB and PS scores (Table 1). LBD prevalence increased with worse Braak‐NFT, CERAD, and LATE. The presence of LBD was associated with CDR‐SOB score in Braak PD stages ≥ III. However, Braak PD scores were not related to PS scores in adjusted analyses (Table 2). LBD interacted with LATE, CERAD, and Braak‐NFT on cognitive scores (Figure 1); no difference was observed in interaction with sex and race. Upon conducting a stratified analysis, LATE had a significant impact on cognitive abilities and LBD presence in limbic‐neocortical reas (ß = 2.30, 95%IC = 0.61; 8.59, p = 0.024).

Conclusion

In an admixed population, LBD is present since middle age. The trend of less frequent LBD in Black/Brown warrants further investigations. LBD was associated with higher CDR‐SOB scores in neocortical phases (V‐VI) and more pronounced in participants with LATE.
PS1 regulates processing and angiogenic signalling of VEGFR2; effects of FAD mutants
Authors: Dey Poulomi , Pandey Rukmani , Zarrouk Amira , Tzikas Glikeria , Georgakopoulos Anastasios , Robakis Nikolaos K. R K
Published: January 2025

Background

Presenilin1 (PS1)/γ‐secretase cleaves within the transmembrane domain of numerous receptor substrates. Mutations in PS1 have implications on the catalytic subunit of γ‐secretase decreasing its activity and becoming a potential causative factor for Familial Alzheimer’s Disease (FAD). This work studies the role of PS1/γ‐secretase on the processing, angiogenic signaling, and functions of VEGFR2 and the effects of PS1 FAD mutants on the γ‐secretase‐mediated epsilon cleavage of VEGFR2.

Method

HEK293T cells expressing WT‐PS1 or PS1‐FAD mutants (M146V, I213T, E280A, G384A, L166P, E120K, A246E) were prepared using a lentivirus‐based transduction system and used in luminescence‐based experiments. PS1‐VEGFR2 co‐immunoprecipitation (Co‐IP) experiments were analyzed on WBs. Bimolecular fluorescence complementation (BiFc) assays were carried out in HEK293T cells overexpressing PS1 or VEGFR2 tagged with half complementary portions of the mVenus and visualized by fluorescence microscopy. The ClusPro web server was used for protein‐protein docking analyses. Anti‐PS1 siRNA technology was applied to downregulate PS1 in endothelial bEnd.3 cells.

Result

Luciferase Assay shows that PS1 FAD mutants significantly decrease the γ‐secretase‐mediated epsilon cleavage of VEGFR2 when compared to WT‐PS1, leading to the production of significantly lower amount of the VEGFR2/CTF2 peptide indicating a loss of γ‐secretase proteolytic function. This loss of function is comparable to the effect of γ‐secretase inhibitor RO4929097. Co‐IP experiments show that PS1 forms complexes with VEGFR2 and BiFc experiments show that PS1 binds to VEGFR2. Docking analysis indicates that the binding is electrostatically favored. Co‐IP between the PS1‐FAD mutants and VEGFR2 show that FAD mutants do not have differential binding to the VEGFR2 compared to WT‐PS1, showing that the effect of these mutants on VEGFR2 cleavage is not due to altered binding. PS1 downregulation of endothelial cells indicates that PS1 plays a role in the regulation of the VEGFA‐induced phosphorylation of VEGFR2 at Y1175 and Y1054‐59 as well as p‐44/42 MAPK (Erk1/2) and in VEGFA‐induced tube formation in vitro.

Conclusion

PS1 FAD mutants decrease production of signaling peptide VEGFR2/CTF2 probably due to reduced γ‐secretase activity of FAD mutants. Interestingly FAD mutations do not seem to affect the PS1‐VEGFR2 association. Our data support that PS1 regulates downstream signaling and angiogenic functions of VEGFR2.
Identifying Tau proteopathic species isolated from human brains with Alzheimer’s disease
Authors: Quittot Noé , Sivasankaran Dhanush , Derosla Victoria , Wiedmer Anne , Perbet Romain , Hyman Bradley T. T
Published: January 2025

Background

In Alzheimer’s disease (AD), the spread of Tau proteopathic seeds across the cerebral cortex parallels the disease progression. Previously, it was shown that isolating high‐molecular‐weight (HMW) Tau species via size exclusion chromatography (SEC) from human brain lysate of AD patients resulted in the enrichment of Tau aggregation‐prone species. However, whether the HMW Tau population contain a homogenous or heterogeneous mixture of Tau species is still unknown. Therefore, this research proposal aims at fractionating the HMW Tau population to identify Tau proteopathic seeds.

Method

Human brains tissue from 9 AD cases have been homogenized in PBS and the resulting lysates were then run through a SEC to isolate the HMW Tau. The HMW Tau population was then fractionated according to net charge of the Tau species by anion exchange chromatography (AIEX). Following each chromatographic strategy step, the bioactivity of the different fractions was assessed via a cell‐based assay to track the aggregation‐prone Tau species.

Result

First, we have demonstrated that these chromatographic strategies can be carried out under near‐physiologic pH and salt conditions, maintaining Tau proteopathic seeds bioactivity and hence their bioactive conformation. Second, we confirmed the presence of HMW Tau subspecies, and more importantly both non‐bioactive and bioactive HMW Tau species that co‐elute from the size column. Finally, the AIEX separation technique revealed that the bioactive species were eluted later than the non‐bioactive, suggesting that the bioactive species are more negatively charged and more heavily post‐translationally modified.

Conclusion

The HMW Tau population contains various subspecies with both non‐bioactive and bioactive species, that can be separated according to their charge and their retention time on an AIEX column. In sum, these results suggest that the HMW fraction purified by SEC is a mixture of subspecies, and that the overall net charge of these subspecies appears to be a crucial biochemical feature correlating with HMW Tau bioactivity.
A common microvascular endophenotype in head injuries and Alzheimer’s disease
Authors: Xia Shangzhou , Zhao Zhen
Published: January 2025

Background

Cerebrovascular injury is a common pathological feature of a spectrum of neurological disorders, including traumatic brain injury (TBI), stroke, Alzheimer’s disease (AD), and aging. Vascular manifestations among these conditions are similar indeed, including the breakdown of the blood‐brain barrier (BBB). However, whether there is a unique molecular mechanism underlying the vascular changes among these conditions remains elusive.

Method

We performed single‐cell RNA (scRNA‐seq) sequencing and obtained 29,114 high‐quality cells combined from ipsilateral hemispheres of WT C57BL/6J Sham mice and mTBI mice at day 1, 3 and 7.

Result

Joint clustering of all groups revealed 7 cell populations using their specific genetic markers, including vEC, vcapEC, capEC, acapEC, aEC. Next, we identified differential expression genes between Sham and day 1 or day 3 or day 7 post‐mTBI within each endothelial cell cluster.

Conclusion

Based on transcriptomic analysis on cerebrovascular scRNA‐seq datasets, we identified a common molecular signature between mTBI and aging vasculature, involving a novel transmembrane protein gene Tmem252. Tmem252 upregulation in brain endothelial cells may represent a shared endophenotype of microvascular injuries in different pathological conditions, and therapeutically targeted for treating BBB breakdown and vascular dysfunctions.
Platelet aggregation and ApoE genotypes in the Framingham Heart Study
Authors: Cejudo Jaime Ramos , Figueredo Luisa F , Scott Matthew R , Lu Sophia , Beiser Alexa S , Ghosh Saptaparni , Osorio Ricardo S. , Wisniewski Thomas , Berger Jeffrey S , Seshadri Sudha , Johnson Andrew D
Published: January 2025

Background

Apolipoprotein (Apo) E4, a main susceptibility gene for Alzheimer’s disease (AD) is associated with increased vascular dysfunction, amyloid pathology, and neurodegeneration. The effector pathways leading to increased vascular risk in ApoE4 carriers needs to be established. Platelet aggregation is a key marker of vascular dysfunction and studies need to examine whether a relationship of ApoE4 allele status and platelet biology exists

Method

We examined cross‐sectional associations of platelet aggregation with ApoE genotypes (E2 or E4 against E3, the most common) in middle‐aged cognitively normal participants at the Framingham Heart Study (FHS) Gen3, New Offspring Spouse (NOS), and Omni2 Cohorts. Status was determined by PCR and defined as E4 when at least one copy of the E4 allele was present, or E2 when at least one copy of the E2 was present, after excluding E4 cases. The primary outcome was the platelet aggregation response to 0.98uM ADP stimulation measured by light transmission aggregometry, and additional agonists and stimulation doses were used for sensitivity. Linear regression models adjusted for age, sex, race, CVD risk, and the use of platelet modifying treatments (PMT) were used. Interactions with the same covariates were also examined. Data from the FHS Gen2 Cohort containing platelet aggregation and ApoE status was used for validation.

Result

The final primary sample included 3,169 participants (median [Q1, Q3] age, 55 [48, 61]; 54.2% women) of which 22.1% were on PMT. (Table 1). 716 (22.6%) were ApoE4 positive and 402 were E2 (16.4% of the sample after excluding E4). Being an ApoE4 carrier was not associated with platelet aggregation (β±SE: 0.41±1.05, P>0.05). ApoE2 was also not associated (‐0.72±1.33, P>0.05) (Figure 1). No associations with the secondary outcomes or interactions with covariates were detected. No associations were observed in the external validation cohort (n = 2,469)

Conclusion

Our results in a middle‐aged cohort indicate that the ApoE genotypes (E2 and E4) are not associated with platelet aggregation. The pathways leading to increased vascular dysfunction in ApoE4 carriers may not involve platelet activity, at least in midlife
Evidence of recent evolutionary selection at eQTLs for APOE
Authors: Ciesielski Timothy H , Tosto Giuseppe , Durodoye Razaq O , Rajabli Farid , Akinyemi Rufus O. , Pericak‐Vance Margaret A , Haines Jonathan L. ,   Alzheimer’s Disease Genetics Consortium (ADGC), Williams Scott M
Published: January 2025

Background

Late‐onset Alzheimer Disease (LOAD) risk and prevalence differ by ancestral group. Furthermore, the frequency of APOE‐4 and its effect size on LOAD risk also differ by ancestry group. If these patterns are a function of evolutionary history, we may find ancestry group‐specific evidence of recent selection at the APOE locus or APOE eQTLs. This could provide us with additional insights into APOE function, specifically its pleiotropic effects and ethnic specific mechanisms of disease.

Methods

We used chromosome 19 sequence data from 2,504 unrelated individuals in 26 populations from the latest release of the 1000 Genomes Data (phased 30x coverage build 38 data), and we ran separate selection analyses in each population. We calculated two selection measures based on Extension of Haplotype Homozygosity (EHH): iHS (integrated haplotype score) and nSL (number of segregating sites by length). Scores were then normalized in bins of similar allele frequency (AF) to account for frequency effects on EHH. Loci in the top 1% of |iHS| and |nSL| scores were considered evidence of selection.

Results

Among the two SNPs defining the APOE isoforms and 27 SNPs defining APOE EQTLs (29 sites in total) we observed 9 APOE eQTLs in the top 1% of iHS and three in the top 1% of nSL. Two SNPS demonstrated evidence of selection in both scores: rs1628394 in Kinh Vietnamese (in a SIPA1L3 intron) and rs2909088 in Han Chinese (in a ZFP30 intron). Neither of the APOE SNPs showed evidence of selection in any population.

Conclusions

We identified evidence of recent natural selection in APOE eQTLs in two East Asian populations: rs1628394 in Kinh Vietnamese and rs2909088 in Han Chinese. Prior work has established that rs1628394 is nominally associated with LOAD (p = 2.45 × 10‐3) and the genome Aggregation Database indicates that it is common in Africans (AF = 0.63), less common in Europeans (AF = 0.33), and least common in East Asians (AF = 0.13). The second SNP, rs2909088, is not associated with LOAD, but it is also less common in East Asians (AFEuropean = 0.87, AFAfrican = 0.69, and AFEastAsian = 0.38). Recent selection at rs1628394 may be enhancing the impact of APOE4 on LOAD development in Kinh Vietnamese.
Elevated tau in the piriform cortex in Alzheimer’s but not Parkinson’s disease using MR‐PET
Authors: Taghavi Hossein Moein , Karimpoor Mahta , van Staalduinen Eric , Leventis Samantha , Young Christina B. , Carlson Mackenzie L. , Davidzon Guido A. , Romero America , Trelle Alexandra N. , Zaharchuk Greg , Vossler Hillary , Rosenberg Jarrett , Poston Kathleen L. , Wagner Anthony D. , Henderson Victor W. , Georgiadis Marios , Mormino Elizabeth , Zeineh Michael
Published: January 2025

Background

Olfactory deficiency can be present in preclinical Alzheimer’s (AD) and Parkinson’s disease (PD), predicting their subsequent manifestation, including mild cognitive impairment (MCI). Analyzing key regions within the olfactory circuit could reveal important insights into the neuropathological progression. Dysfunction in the olfactory circuit has been shown in the olfactory nerve in limited postmortem studies, including involvement of a key region, the piriform cortex. FDG‐positron emission tomography (PET) and fMRI have shown differential and reduced piriform cortex metabolism/activation in AD. Thus, the piriform cortex is a promising candidate in the early identification of neurodegenerative pathology underlying olfaction. We used tau MR‐PET to analyze the piriform cortex, in comparison to the adjacent medial temporal lobe.

Method

We analyzed 115 subjects: 23 were excluded (incomplete data), leaving 31 amyloid‐negative and 25 amyloid‐positive healthy controls, 8 MCI, 15 AD, and 13 PD. All subjects underwent MR‐PET using tau tracer PI‐2620 with a simultaneous coregistered sagittal T1‐weighted 3D IR‐FSPGR and a simultaneous/recently acquired coronal T2‐weighted FSE. Automatic Segmentation of Hippocampal Subfields was performed, including the entorhinal‐perirhinal cortices (Fig. 1D‐F). Referencing published piriform segmentation guidelines, we manually segmented blind to subject diagnosis the frontal/temporal portions of the piriform cortex (Fig. 1C), including multiple independent quality control checks. As tau distributions appeared non‐normal among the five ordinal patient categories (Amyloid–HC, Amyloid+HC, MCI, AD, Normal PD), we used a nonparametric Jonckheere‐Terpstra test in Stata to test for ordinal increase in tau uptake across four regions bilaterally (whole hippocampus = CA1‐4 + DG + subiculum, entorhinal‐perirhinal, amygdala, and piriform).

Result

We found an ordinal increase in piriform tau uptake with increasing disease severity (amyloid‐negative controls, amyloid‐positive controls, MCI and AD) (Figure 2A‐D). Amyloid‐positive controls showed significantly greater uptake than amyloid‐negative controls. Piriform uptake was not elevated in cognitively unimpaired PD compared to Amyloid‐HC. Piriform volume was statistically equivalent across groups, except PD had lower volumes (Figure 2E‐H). Negative correlations were present between memory performance and piriform uptake (Figure 3).

Conclusion

Cross‐sectionally, there is an early increase in tau uptake in the piriform cortex in AD but not in PD.
Development of AI‐4‐AD tools for evaluation and prognosis of AD conversion: multi‐branch network and multi‐task deep learning algorism
Authors: Han Liang , Pang Ran , Ren Qing , Pu Xiujuan , Liu Yuan , Tan Yuanfan , Yang Qing X
Published: January 2025

Background

AD prevention and early interventions require tools for evaluation of people during aging for diagnosis and prognosis of AD conversion. Since AD is a complicated continuum of neurodegenerative processes, developing of such tools have been difficult because it needs longitudinal and multimodal data which are often complicated and incomplete. To address this challenge, we are developing AI4AD framework using ADNI data.

Method

As shown in Fig. 1, we used the multimodal features of subjects in the initial four time points to predict the disease status after 1.5 years. The informative feature set with available multi‐modal data (MRI, PET and cognitive score (CSs)), is extracted as a multivariate time series. Then, a multi‐scale local temporal attention network (MCLAN) is constructed to extract corresponding deep features from three categories of multivariate time series respectively. Furthermore, a set of statistical features are extracted from multivariate the time series. Subsequently, fusion of selected deep features, statistical features and background knowledge (demographics, CSF, genetics feature) at baseline are performed using a DL feature network. Finally, AD and CSs predictions are realized utilizing multi‐task DL algorism with Adam optimization algorithm and the five‐fold cross‐validation method. 190 CN subjects, 347 MCI subjects and 20 AD subjects were selected according to the first visit diagnosis from TADPOLE database (Table 1a). The longitudinal data for training and ground truth of AD conversion are shown in Table 1(b).

Result

The accuracy (ACC), accuracy (PRE), recall (REC) and F1 score of the proposed AD prediction method in the AD classification were 93.57%, 93.55%, 93.68%, and 93.59%, respectively, which is greatly improved the predictive ability of those by the conventional methods (Table 2). In addition, the root mean square error (RMSE) on the CSs prediction of CDRSB, ADAS11, ADAS13 and MMSE are 0.5863, 0.5238, 0.4747 and 0.5417 respectively.

Conclusion

Our DL method consolidates multi‐modal medical information at different visits to predict the disease’s progression, which greatly improved AD prognosis from those using traditional DL algorithms (CNN, LeNet and ResNet). The AI4AD framework proposed here can also be tailored to other diseases with similar data characteristics.