bluuebunny/crossref_metadata_2025 huggingface dataset:
Geographic and ancestral variation in the association between APOE ε4 and cognitive function in South Asians from LASI‐DAD
Authors: Wang Yi Zhe , Zhao Wei , Kerdoncuff Elise , Li Zheng , Moorjani Priya , Gross Alden L. , Zhou Xiang , Dey Sharmistha , Dey Aparajit Ballav , Lee Jinkook , Smith Jennifer A , Kardia Sharon L R
Published: January 2025

Background

The ε4 allele of the apolipoprotein E (APOE) gene is the strongest genetic determinant for Alzheimer’s disease and cognitive function in nearly all human populations, yet inconsistent effects have been reported in South Asians. The population of India has admixed genetic ancestry with most people falling on a North/South cline and having varying proportions of Ancestral North Indian (ANI) and Ancestral South Indian (ASI) ancestries, and those in east of India fall off the cline due to ancestry from additional ancestral populations. This study examined the ε4 association with cognitive function across 18 states/union territories of India and investigated whether ancestral background modulates ε4 association with cognitive function in 2,590 participants from the Longitudinal Aging Study in India – Diagnostic Assessment of Dementia (LASI‐DAD).

Method

APOE ε4 carrier status was determined from rs429358 and rs7412 genotypes measured by TaqMan Assays. Percent ANI ancestry (%ANI) was estimated from whole genome sequencing for those in the North/South cline (range: 22‐80%, n = 2,097). We first investigated ε4 associations with seven cognitive measures, including five broad cognitive domain scores, general cognitive function, and the Hindi Mental State Examination (HMSE) score, within each state/union territory using linear regression. Subsequently, participants were categorized into ancestral groups based on %ANI tertile (low, medium, and high), along with an out‐of‐cline group. Effect modification by ancestry groups was assessed using cross‐product interaction terms and subgroup analysis. All models were adjusted for age, sex, state of residence (if applicable), education, literacy, urban/rural residence, caste, per capita household consumption, and the first 10 genetic principal components.

Result

The ε4 effect varied significantly across states/union territories for general cognitive function, executive function, and language/fluency (Cochran’s Q test p<0.05, I2: 42.0‐57.7%). While ε4 by ancestral group interaction terms were not significant for any cognitive measure, stratified analysis showed a trend of a larger ε4 effects in the middle and high %ANI tertiles, with significant associations observed for HMSE score and memory within the highest %ANI tertile (p<0.05).

Conclusion

Our results suggest that ancestral background may play a role in modulating the ε4 effects on cognitive function, contributing to the observed heterogeneity across Indian groups.
Brazilian older adults with Alzheimer’s Disease Exhibit Telomere Shortening
Authors: Graciano Guilherme Fonseca , Soares Thayana Oliveira , Cintra Marco Túlio , Malheiro Olívio Brito , Júnior Luciano Pimenta , Milagre Samuel Oliveira , Ribeiro Letícia Jabur , Kimoto Leonardo Ryuiti , de Souza Aline Siqueira , Fonseca João Henrique , Lima Nuno de Andrade Rezende , Rocha Camila Dias , Viana Bernardo M , Jansen Ann Kristine , dos Santos Rodrigo Ribeiro , Bicalho Maria Aparecida Camargos
Published: January 2025

Background

The Brazilian population has been experiencing an increase in the number of older adults, with a simultaneous rise in the incidence of Mild Cognitive Impairment (MCI) and Alzheimer’s Disease (AD). Telomeres are structures located at the ends of chromosomes that maintain the structural integrity of the chromosome. There is a shortage of studies correlating telomeres and cognition. This study aimed to assess the relationship between telomere length and different cognitive profiles.

Method

A cross‐sectional study was conducted at the Outpatient Reference Center for Older Adults at the University Hospital of the Universidade Federal de Minas Gerais (UFMG), Brazil. The sample consisted of older adults without cognitive impairment (control group), those with MCI, and those with AD`s dementia (ADD). Participants underwent geriatric and neuropsychological evaluation for clinical and cognitive assessment. DNA analysis from peripheral blood samples was performed using a saline method. Telomere relative length was analyzed using RT‐PCR. Multivariate linear regression analysis was conducted to examine the association between telomere relative length and the sample.

Result

The sample comprised 90 participants, with 30 individuals in each group (control, MCI, and AD). The majority of the sample comprised women (68.9%), with an average education of 4.56 ± 3.70 years. The percentage of women was higher in all groups. The ADD group had a higher average age compared to the others, with a mean age of 79.5 (75.0‐83.5), p = 0.0060. Education was lower in the MCI group compared to the control group (25, p = 0.001). A shorter telomere length was observed in the ADD group (225.51), followed by the control group (428.27) and the MCI group (448.05) (p <0.001). The variable dyslipidemia was significantly associated with telomere length (p = 0.034). Other variables did not differ significantly.

Conclusion

It was observed that the relative telomere length was associated with the ADD, with a smaller telomere relative length in this group compared to the others, and an association with dyslipidemia.
Alzheimer’s disease modeling and drug screening through hiPSC 3D bioprinting
Authors: Sorrentino Stefano , Wendt Stefan , Cai Wenji , Lee Christopher , Brennan Declan , Wu Xiujuan , Nygaard Haakon B.
Published: January 2025

Background

Our current understanding of the molecular mechanisms underlying amyloidogenesis in Alzheimer’s Disease (AD) is limited by the lack of comprehensive models closely resembling human pathology. Human induced pluripotent stem cell (hiPSC) 3‐dimensional (3D) models, such as brain organoids and neurospheres, are emerging as innovative approaches to model neurodegenerative diseases in vitro. However, they rely on hiPSC self‐organization and are therefore characterized by low reproducibility and homogeneity. Moreover, they lack proper extracellular matrix (ECM) and microglial cells which both play a pivotal role in amyloid beta (Aβ) plaque dynamics. 3D‐bioprinting is an innovative bioengineering technique that combines biomaterials and live cells, in so‐called ‘bioinks’, to shape, in a layer‐by‐layer fashion, highly geometrical controlled 3D structures. The surrounding ECM improves the exchange of nutrients, oxygen, and drugs making them closer to the physiological fluidic dynamic.

Method

Here, we generated a 3D‐Bioprinted brain model suitable for long‐lasting culturing of iPSCs‐derived cortical neurons and astrocytes starting from neuronal precursor cells (NPCs).

Result

NPCs can be successfully bioprinted in a multilayer wood‐pile structure to mimic the human cerebral cortex architecture with high spatial resolution, low pressure, and high speed maintaining cell viability and proliferation. NPCs can be efficiently expanded and differentiated into functional cortical neurons/astrocytes in 3D cultures. Moreover, when exogenous synthetic Aβ42 is administrated to the culturing medium, hiPSC‐derived microglia can efficiently infiltrate into 3D bioprinted constructs and phagocyte amyloid deposits.

Conclusion

We believe our model will serve to elucidate the early stages of AD by offering a novel perspective that more closely resembles the human AD brain. Furthermore, by using synthetic Aβ enriched bioink and familial AD cell lines that overexpress Aβ our system might offer the chance to study the nucleation of Aβ deposits in real time and mimic the formation of proper Aβ plaques in vitro without the involvement of animal models.
Reelin gene therapy promotes cognitive resilience in a mouse model of amyloid induced tauopathy
Authors: Finneran Dylan , Li Qingyou , Joly‐Amado Aurélie , Desjarlais Taylor , Jackman Brianna , Gordon Marcia N. , Nash Kevin , Morgan Dave
Published: January 2025

Background

A recent study of familial Alzheimer’s disease identified a mutation in the RELN gene that appeared to delay the onset of dementia. It was hypothesized that this RELN‐COLBOS variant protected against dementia by enhanced signaling at reelin receptors. We previously developed a secreted, bio‐active reelin fragment (R36) and packaged it into AAV. Recently, we found that intravenous AAV‐tau delivered in capsids (AAV.B10) that cross the blood brain barrier led to increased tauopathy in APP+PS1 (A+P) transgenic mice compared to nontransgenic (NonTg) littermates.

Method

Nine‐month old mice were intravenously injected with AAV.B10 expressing P301L 2N4R human tau to produce A+PTAU and NonTgTAU. Concurrently, these mice were injected intracerebroventricularly (ICV) with AAV9 expressing either R36 or green fluorescent protein (GFP). Learning and memory was assessed by radial arm water maze (RAWM) four months after surgery. Untreated A+P and NonTg mice were included as controls. RIPA soluble and insoluble hippocampal fractions were assayed for total tau, phospho‐tau, Aβ40, Aβ42, and oligomeric Aβ by ELISA.

Result

All NonTg mice, regardless of tau treatment, learned and correctly recalled the RAWM platform location. Recall in untreated A+P mice was slightly impaired. A+PTAU mice given ICV‐GFP performed at chance levels on all trials. In contrast, A+PTAU mice given ICV‐R36 performed significantly better than ICV‐GFP A+PTAU mice, but not as well as untreated A+P mice, indicating a partial rescue of the tau‐associated memory deficit by ICV‐R36. Tauopathy, as measured by ELISA, was unchanged by R36 over‐expression, but insoluble Aβ42 was reduced in ICV‐R36 A+PTAU mice compared to ICV‐GFP A+PTAU mice.

Conclusion

We conclude that ICV injections of AAV expressing a bio‐active fragment of reelin can partially protect against cognitive impairment in a mouse model of amyloid induced tauopathy. This is consistent with a potential protective role of reelin signaling in Alzheimer’s disease. While we did not observe an effect of R36 over‐expression on tau pathology, we do demonstrate a significant reduction of insoluble Aβ42. We continue to investigate additional chemical and histological markers in these mice to better understand the protective influence of reelin.
Impact of Surgical Mouse Model of Large Arterial Stiffening on Cognition
Authors: Baggeroer Caroline E , Pietri Peter A , Harrison Fiona E. , Jefferson Angela L.
Published: January 2025

Background

In humans, larger artery stiffening is associated with increased tau phosphorylation and neurodegeneration. However, because arterial stiffness often co‐occurs with other age‐related conditions like hypertension, atherosclerosis, and diabetes, it is nearly impossible to distill the underlying mechanisms specifically linking arterial stiffening to abnormal brain function. We leveraged a surgical mouse model of larger artery stiffening and used it concurrently with a transgenic Alzheimer’s disease (AD) mouse model of tau pathology to investigate the impact of larger artery stiffening on cognition. Large arterial stiffening typically occurs during middle age, so this model was tested in 5‐month old mice.

Method

5‐month old, male and female, P301S (n = 6) and wild‐type littermate controls (n = 11) underwent a carotid calcification surgery, where both carotid arteries was exposed to 0.3 mol/L CaCl2 (or saline as a control) for 20 minutes. Carotid compliance, shown as change in diameter within a cardiac cycle, was measured in vivo using M‐Mode Doppler Ultrasound imaging before and after surgery. Three weeks post‐surgery, mice underwent behavioral testing, including locomotor activity, elevated zero maze, Morris Water maze, Y‐maze, novel object recognition, and nest building.

Result

CaCl2 exposure led to decreased post‐operatively compliance of the carotid artery as measured by a significantly decreased change in carotid diameter compared to saline treated mice in both left and right arteries (A. n = 8‐9; p = 0.0003. B. n = 8‐9; p = 0.015) (Figure 1). Preliminary data suggest the carotid calcification surgery impairs ability to learn the position of the escape platform in the Morris water maze in the wild type control mice (Figure 2). Data are not currently sufficiently powered to establish whether the same effect will also be observed in the P301S mice (n = 5‐6 per group WT, 3 per group P301S).

Conclusion

The carotid calcification surgery significantly decreased compliance of the carotid artery in vivo and demonstrated successful stiffening of the large artery. The preliminary data suggest this reduced compliance impairs cognition, specifically spatial learning abilities, but whether the effect is greater in P301S mice is unclear. This model will further be used to investigate whether the carotid calcification surgery accelerates development of tau pathology seen in the P301S mice.
The crosstalk between insulin resistance and tau pathology
Authors: Kumar Rashi , Varshney Ritu , Gupta Sharad
Published: January 2025

Background

Diabetes is a modifiable risk factor for Alzheimer’s disease, and GLUT4, an insulin‐dependent transporter, plays a crucial role in insulin‐resistant conditions and, consequently, in diabetes development. The study aimed to investigate the relationship between tau pathology and insulin resistance by quantifying GLUT4 expression and glucose concentration.

Method

Initially, SH‐SY5Y cells underwent transfection with either a wild‐type tau plasmid or a mutant tau plasmid. Subsequently, insulin resistance was induced using high glucose or dexamethasone. The impact of these manipulations was assessed through a glucose uptake assay measuring cellular glucose concentration. Immunocytochemistry techniques were then applied to evaluate GLUT4 expression.

Result

A significant increase in glucose concentration was observed under the latter condition. Additionally, there was a marked decrease in GLUT4 expression in neuronal cells transfected with the mutant tau plasmid, simulating tau pathology.

Conclusion

The study provides evidence supporting insulin resistance as a contributing risk factor for tau pathology development, potentially leading to Alzheimer’s disease later in life. Tau aggregates may increase the likelihood of insulin resistance by impairing the insulin signaling pathway, ultimately resulting in Type 2 diabetes. The findings suggest that impaired insulin signaling in the brain could contribute to tau pathogenesis by decreasing GLUT4 expression, leading to hyperglycemia and cellular hypertrophy.
Hippocampal degeneration is associated with GFAP levels in individuals with vascular dementia independently of amyloidosis
Authors: Oliveira Markley , Bellaver Bruna , Lussier Firoza Z , Ferreira Pamela C.L. , Povala Guilherme , Leffa Douglas Teixeira , Bauer‐Negrini Guilherme , Rodrigues Matheus Scarpatto , Abbas Sarah , Zalzale Hussein , Rohden Francieli , Felix Cynthia , Soares Carolina , Saha Pampa , Ruppert Emma Patrice , Machado Vitor Hugo , da Rocha Andreia Silva , Tudorascu Dana , Benedet Andrea L. , Ashton Nicholas J. , Tissot Cécile , Therriault Joseph , Servaes Stijn , Stevenson Jenna , Rahmouni Nesrine , Hong Chang Hyung , Roh Hyun Woong , Zimmer Eduardo R. , Blennow Kaj , Zetterberg Henrik , Karikari Thomas K , Rosa‐Neto Pedro , Son Sang Joon , Pascoal Tharick A.
Published: January 2025

Background

Vascular cognitive impairment/dementia (VD) is the second most prevalent cause of dementia following Alzheimer’s disease (AD). VD is characterized by the progression of white matter hyperintensity burden (WMH) and associated neurodegeneration. GFAP, a biomarker for reactive astrogliosis, is associated with Aβ pathology and mediates tau‐pathology in preclinical AD. However, the association of GFAP levels with the markers associated with VD is poorly understood.

Method

We assessed 796 participants from a research cohort (TRIAD: 355) and a memory clinic cohort (BICWALZ: 441) that were divided into four groups according to their Aβ (Aβ+/Aβ‐) and WMH status (WMH+/WMH‐). WMH values were corrected by intracranial volume, and cutoffs were determined based on the highest WMH value within 50% of the individuals with the lowest WMH rate in the CU Aβ‐ group. Biomarker mean level differences between groups were estimated via Ancova Tukey’s test, and linear regressions accounting for age, sex, and cognitive status were used to estimate the association.

Result

For TRIAD, WMH+/Aβ+ individuals exhibit higher levels of plasma GFAP when compared to all groups except WMH‐/Aβ+, with no differences in NfL levels and hippocampal volume between groups (Fig. 1A). In BICWALZ, only hippocampal volume differs between groups with lower levels observed in both WMH‐/Aβ‐ and WMH‐/Aβ+ (Fig. 1B’’). The association of GFAP and NfL was observed in all groups (Fig. 2A, 2B’). On the other hand, hippocampal degeneration was associated with higher GFAP levels in individuals with abnormal WMH and absence of Aβ burden in both cohorts (Fig. 3A: TRIAD: β = ‐0.3036; p = 0.0195; Fig. 3B’: BICWALZ: β = ‐0.1791; p = 0.0125).

Conclusion

Our findings suggest that astrocyte reactivity, as indicated by plasma GFAP levels, plays a significant role in the hippocampal atrophy observed in patients with vascular disease. These results suggest that therapies targeting astrocyte reactivity could potentially alleviate progressive cognitive deficits commonly found in patients with chronic vasculopathy.
Early loss of vascular‐astrocyte contact in the hippocampus in Alzheimer’s disease. Data from patients, in vitro and in vivo experimental models
Authors: Saravia Flavia Eugenia
Published: January 2025

Background

Alzheimer’s disease is characterized by the accumulation of aggregated amyloid peptides in the brain parenchyma and in the walls of brain vessels. The hippocampus ‐ a complex brain structure that plays a key role in learning and memory ‐ has been implicated in the disease. However, there is limited data on vascular changes during the pathological degeneration of Alzheimer’s disease in this vulnerable structure, which has distinctive vascular features.

Method

Our aim was to evaluate vascular changes in the hippocampus of AD patients and PDAPP‐J20 mice ‐ a model of AD ‐ and to determine the impact of Aβ40 and Aβ42 on endothelial cell activation.

Result

We found a loss of physical astrocyte‐endothelium interaction in the hippocampus of individuals with AD compared to non‐AD donors, along with reduced vessel density. Astrocyte‐endothelial interactions and levels of the tight junction protein occludin were altered early in PDAPP‐J20 mice, preceding any signs of morphological changes or blood‐brain barrier dysfunction in these mice. At later stages, PDAPP‐J20 mice showed reduced hippocampal vascular density and leakage of fluorescent tracers, indicating vascular and BBB dysfunction. In vitro studies showed that exposure to soluble Aβ40 in human brain microvascular endothelial cells (HBMEC) was sufficient to induce NFκB translocation to the nucleus, which may be related to the observed reduction in occludin levels. Inhibition of the membrane receptor for advanced glycation endproducts (RAGE) prevented these changes in HBMEC. Additional results suggest that Aβ42 indirectly affects the endothelium by inducing astrocytic factors.

Conclusion

Our results from human and mouse brain samples provide evidence for the critical involvement of the hippocampal vasculature in Alzheimer’s disease.
Personality and affective predictors of compensation and implications for intervention recommendations
Authors: Namboodiri Sudev , Farias Sarah Tomaszewski , Harvey Danielle J. , Weakley Alyssa
Published: January 2025

Background

Compensation has the potential to improve everyday functioning and delay or prevent conversion to dementia; thus, improvement of compensation is a desirable intervention target. In addition to cognition, research suggests personality and mood may affect compensation use. The primary aim of this study was to evaluate whether psychological factor(s) are significant predictors of compensation after accounting for cognition in a non‐demented older adult sample. A secondary aim was to examine if there were differences in outcome depending upon whether self or informant report of compensation was included in the model.

Method

Participants included 100 cognitively healthy older adults and 26 individuals with mild cognitive impairment (N = 126; age M = 76.67, SD = 6.79; education M = 15.58, SD = 3.03) who completed the Revised NEO Personality Inventory (used to assess Agreeableness, Neuroticism, Openness, Conscientiousness, and Extraversion) and self‐report measures from the National Institutes of Health (NIH) Toolbox (used to assess Sadness, Self‐efficacy, Anger, and Positive affect). A measurement of Grit was also completed. Self‐ and informant‐report from the Everyday Compensation (EComp) Scale were used as measures of compensation. Linear regression, controlling for cognition (Spanish and English Neuropsychological Assessment Scale Composite) was used to predict compensation (self or informant).

Result

For self‐reported compensation, anger was associated with more compensation independent of cognition (B = .18, t = 2.60, p = .01). For informant‐report, Openness was associated with greater compensation (B = .20, t = 2.02, p = .05).

Conclusion

Participants with higher scores in Anger and Openness had increased compensation after accounting for cognitive status. A higher degree of Openness indicates a person is willing to try new things, which may result in an increased likelihood of trying compensatory strategies. While it is somewhat counterintuitive that greater negative emotion was associated with more compensation, anger is an activating and externalizing emotion which could facilitate compensation in response to worry about cognitive change. Results suggest that interventions should focus on ways to improve openness and activation to enhance compensation.
Unveiling Proteomic Signatures of Tau Pathogenesis through Label‐Free Mass Spectrometry Analysis
Authors: Zeng Xuemei , Chen Yijun , Sehrawat Anuradha , Abrahamson Eric E , Kofler Julia , Paljug William R , Ikonomovic Milos D , Karikari Thomas K
Published: January 2025

Background

Neurofibrillary tangles (NFT), consisting of hyperphosphorylated tau aggregates, are one of the major pathological hallmarks of Alzheimer’s disease (AD). The burden of NFTs correlates with cognitive decline, and in vivo detection of NFT may help predict the clinical progression of AD. Mass spectrometry‐based proteomic analysis of brain regions affected by NFTs holds the potential to unveil the molecular mechanisms underlying tau pathogenesis and uncover novel diagnostic/prognostic biomarkers and therapeutic targets.

Method

Post‐mortem frozen samples of inferior temporal and middle frontal cortex were collected from 9 cases with different severity of tau pathology assessed by Braak NFT stage. Proteins were fractionated into three fractions using sequential extraction with lysis buffers with different solubility strengths (TBS, Na2CO3, and Urea), trypsin‐digested, and analyzed using label‐free nano‐flow liquid chromatography‐tandem mass spectrometry (nano LC‐MS/MS). Linear mixed models were employed to assess the significance of proteins showing a differential abundance in tissues with Braak NFT stages 0‐III and IV‐VI or displaying Braak stage‐dependent solubility changes.

Result

A total of 64908 peptides originating from 5475 protein groups were identified through the analysis of 18 brain tissue samples. Differential proteomic analysis revealed several proteins with significantly varied abundance in tissues with different severity of tau pathology. The most significant proteins among these include COL25A1, SNRNP70, MDK, ASPRV1, CLMN, DOCK5, HTRA1, LNPEP, SQSTM1 and Aβ peptides. Additionally, a number of proteins exhibited Braak‐stage dependent solubility change; a significant subset of these proteins, including SNRNP70, SNRPGP15, PRPF6, SNRPE, SNRPD1, SNRPB, and SNRPD3, is involved in the spliceosome‐mediated mRNA splicing.

Conclusion

Our study reveals numerous proteins exhibiting a significant association with tau pathology. These results align well with published findings that suggest the involvement of alternative splicing in reprogramming gene expression in the pathogenesis of AD. Further validation will be needed to assess their potential as therapeutic targets and/or diagnostic/prognostic biomarkers for AD pathologies.
Investigating the effect of Area Deprivation Index on the association of APOE‐ε4 and APOE‐ε2 with Alzheimer’s disease in a Multiethnic Autopsy Cohort
Authors: Yepez‐Sisalema Geovanna , Kuchenbecker Lindsey A , Pradeep Aishwarya , Gonzalez‐Soto Rous M , Nguyen Thuy , Sotelo Katie D , Heckman Michael G. , Reddy Joseph S. , Allen Mariet , Serrano Geidy E , Beach Thomas G. , Prokop Stefan , Dickson Dennis W. , Ertekin‐Taner Nilüfer , Carrasquillo Minerva M.
Published: January 2025

Background

African Americans (AA) and Latin Americans (LA) are at a higher risk of developing AD compared to non‐Hispanic whites (NHW) but are traditionally underrepresented in AD research. The disproportionate risk is likely multifactorial including differences in co‐morbidities and structural and social determinants of health (SSDoH). AD risk is thought to result from multiple genetic and environmental factors, and their interactions (GxE). However, the molecular mechanisms underlying these interactions are largely unknown. The best‐established genetic risk factor for AD is APOE‐ε4, while APOE‐ε2 is protective. Environmental factors, such as living in neighborhoods with greater socioeconomic disadvantage, have been associated with greater AD neuropathology and worse cognitive function. Studying the potential modifying role of neighborhood disadvantage regarding associations of APOE‐ε4 and APOE‐ε2 with AD risk using a socioeconomic metric like the Area Deprivation Index (ADI) in a multiethnic post‐mortem cohort could offer valuable insights for precision medicine.

Method

We analyzed a post‐mortem cohort of 421 multi‐ethnic donors (NHW: N = 234, AD = 70, non‐AD = 164; LA: N = 145, AD = 102, non‐AD = 43; AA: N = 42, AD = 24, non‐AD = 18), from Mayo Clinic Florida, Banner Sun Health Research Institute, and the University of Florida Brain Banks as part of the AMP AD Diversity initiative. This study used the same neuropathological criteria to categorize AD vs. non‐AD as in the MayoRNAseq study (syn5550404). ADI from the Neighborhood Atlas® was obtained from de‐identified addresses. Associations of APOE‐ε4, APOE‐ε2, and ADI with AD risk were examined using logistic regression models adjusted for age‐at‐death, sex, and ethnic group; interactions of APOE genotype with ADI were also assessed.

Result

APOE‐ε4 and APOE‐ε2 showed a significant association with AD diagnosis (APOE‐ε4combined cohort OR = 3.23, P = 3.14E‐08; APOE‐ε2combined cohort OR = 0.30, P = 0.003). However, contrary to prior findings, our study found no association between ADI and AD diagnosis [OR = 1.023 (per each 10 unit increase in ADI), P = 0.629]. No significant interactions of ADI with APOE‐ε4 or APOE‐ε2 regarding association with AD diagnosis were identified (P = 0.083, P = 0.781).

Conclusion

This is the first study evaluating the potential interaction of neighborhood disadvantage with APOE on AD risk in a multi‐ethnic autopsy cohort. However, these findings require further investigation in larger, more well‐powered cohorts for validation.
Long‐read sequencing reveals common structural variants as potential drivers of genetic rick for neurodegenerative diseases
Authors: Salazar Alex N , Tesi Niccoló , Sirvent Daniel Alvarez , Knoop Lydian , Zhang Yaran , van der Lee Sven J , Wijesekera Sanduni , Krizova Jana , van der Flier Wiesje M. , Pijnenburg Yolande A.L. , Reinders Marcel JT , Hulsman Marc , Holstege Henne
Published: January 2025

Background

Genome‐Wide Association Studies (GWAS) have identified 86 SNPs associated with Alzheimer’s disease (AD). GWAS‐SNPs are markers of genetic variation in linkage disequilibrium (LD), which may drive the association with AD. One major class of genetic variation are Structural Variants (SVs), which can regulate transcription and translation of nearby genes. Here, we explored the interplay between large SVs (>50 bp) and AD‐associated SNPs.

Method

We performed long‐read whole‐genome sequencing of 214 individuals representing the extreme ends of the cognitive spectrum: N = 93 AD patients (age 67.2∓8.5), and N = 121 cognitively healthy centenarians (age 101.2∓1.8). We identified SVs using sniffles2 genome‐wide, further characterised them through (local) de novo assembly, and annotated tandem repeats (TR) and transposable elements (TE). Next, we estimated LD between SVs and 86 AD‐associated GWAS‐SNPs, Finally, we compared SNP frequencies and SV sizes between AD cases and centenarians using logistic regression models.

Result

Across all 214 individuals, we found >27,404 SVs (>50 bp), with a Minor Allele Frequency (MAF) ≥ 5%. Most SVs were TRs (63%), followed by TEs (37%). We found that 37 AD GWAS‐SNPs paired with 90 SVs in low to strong LD (R2 > 0.1), 56 of which involved SNP‐TR pairs (62%) and 34 involved SNP‐TE pairs (38%). In six AD loci, the SVs associated more strongly with AD risk than the leading GWAS‐SNP (p < 0.05). This includes ADAM10, CTSH, SLC2A4RG, CD2AP, SPI1, and IDUA, which were encompassed by complex haplotypes harbouring multiple TRs and TEs.

Conclusion

Our findings provide the first support for SVs as candidate‐drivers of the association between respective GWAS loci with AD risk. Hence, SVs may lead to increased effect sizes.
Investigating microglial modulation of endothelial inflammation through IL1RAP
Authors: Fisher Elizabeth S , Tubbesing Kate , Stevens Katherine , Lotz Steven , Bertucci Taylor , Temple Sally
Published: January 2025

Background

Up to 84% of patients with Alzheimer’s Disease (AD) have vascular damage which precedes cognitive decline. Inflammation induces changes in blood‐brain‐barrier (BBB) integrity, though the link between induction of inflammation and AD is unclear. IL1β, a cytokine upregulated in patients with AD and in mouse models of the disease, is released and interacts with IL1R1 and its obligate co‐receptor, IL1RAP, to induce downstream signaling. A genome wide association study identified a SNP, rs12053868‐G, in IL1RAP associated with increased frequency of AD and higher rates of amyloid accumulation. This SNP exerts an independent, additive effect with APOE44, suggesting that IL1RAP could play a role in modification of AD progression.

Method

APOE33 or APOE44 allele‐containing human induced pluripotent stem cells (iPSCs) were differentiated into microglia or purified endothelial cells (ECs), which were validated via RNA sequencing. Differentiated cells were challenged with inflammation, and responses measured. Microglial inflammatory genes were analyzed via qPCR, as well as cytokine release. Barrier resistance of ECs was assessed via ECIS, and they were also evaluated with immunohistochemistry and gene expression changes. To interrogate the role of IL1RAP in microglial induction of inflammation, the gene was overexpressed and knocked down in each cell type.

Result

ECs upregulated E‐selectin upon challenge with inflammatory stimuli. ECs also showed alterations in localization of barrier proteins with immunohistochemistry upon inflammatory challenge, and between APOE33 and APOE44 cells. Microglia upregulated several cytokines in response to inflammatory challenge.

Conclusion

Human iPSC‐derived microglia and ECs are altered by inflammatory challenge, and APOE44 ECs show differences in barrier protein localization at rest. Future experiments will investigate the interactions between microglia and ECs in both APOE alleles, as well as their response to overexpression or KD of IL1RAP. These experiments will establish the functional role of inflammation in microglia‐EC interactions, and the contributions of these interactions to the development of cerebral vascular damage.
Characterization of Alzheimer’s Disease‐Related Plasma Biomarkers in Gammaherpesvirus Infected Common Marmosets
Authors: Piotrowski Stacey L , Lee Amanda , Tucker Allison , Narver Heather , Stein Brianne , Oluoch Julia , Zhang Ting , Schaeffer Lauren K Hayrynen , Silva Afonso C , Carter Gregory W , Jacobson Steven , Rizzo Stacey J Sukoff
Published: January 2025

Background

The infectious hypothesis of Alzheimer’s disease (AD) suggests that microbes may play a role in pathogenesis by triggering the pathologic cascade or contributing to disease progression. Herpesviruses, such as Epstein‐Barr virus (EBV), have been of high interest in AD and related neurodegenerative diseases, in part due to their ability to establish lifelong latent infection and potentially reactivate. However, further research is needed to fully understand the role of herpesviruses in these diseases. The common marmoset (Callithrix jacchus) is not only a translationally relevant model of AD, but also herpesvirus infection. Callitrichine herpesvirus 3 (CalHV‐3) is a naturally occurring gammaherpesvirus in the marmoset that is phylogenetically and biologically similar to EBV. This study aimed to understand the contribution of persistent gammaherpesvirus infection to AD‐related pathology in the common marmoset.

Methods

Whole blood from over 200 animals was collected from the NIH NINDS colony and the MARMO‐AD colony at the University of Pittsburgh during routine health surveillance and experimental procedures. Plasma was evaluated using MesoScale Discovery (MSD) multi‐plex ELISA Aβ peptide panel 4G8 and Neurology Panel 1 (GFAP, Neurofilament L, Total Tau). Peripheral blood mononuclear cells (PBMCs) were isolated using lymphocyte separation media. DNA was extracted from PBMCs and screened for CalHV‐3 using a droplet digital PCR (ddPCR) assay that amplified the virus and a housekeeping gene to allow for the quantification of viral loads (copies of CalHV‐3/106 cells).

Results

20‐30% of the tested colonies were positive for CalHV‐3, with a range of viral loads and the highest prevalence in aged animals (≥8 years old). There was significantly higher plasma Neurofilament L (NfL) and total tau in virally infected aged animals compared to uninfected aged animals.

Conclusions

The enhancement of plasma biomarkers, such as NfL and tau, in gammaherpesvirus infected aged marmosets suggests that viral infection may contribute to AD‐related pathology and neurodegeneration. Investigation is ongoing in additional animals to further characterize the relationship of plasma biomarkers to viral infection and viral load. The common marmoset is a unique translational model that allows for the investigation of AD and the potential role that herpesviruses play in disease manifestation and progression.
Pro‐inflammatory endothelial cell activation mediated by protofibrillar tau leads to loss of barrier function and integrity
Authors: Guzman‐Hernandez Roberto A , Fossati Silvia
Published: January 2025

Background

Neurofibrillary tangles formed by hyperphosphorylated tau aggregates in the brain are one of the classical hallmarks of Alzheimer’s Disease (AD). Tau aggregates have been shown to elicit cytotoxicity, leading to overall neuronal loss and cognitive decline in AD. These aggregates can be transmitted from neurons and glial cells to other brain cells through a process known as tau spreading, and ultimately reach the endothelial cells (ECs) lining the vessel walls, thus, causing dysfunction of the neurovascular unit (NVU), a complex multicellular system surrounding brain vessels. The NVU is extremely important for blood flow regulation, amyloid and tau clearance, and proper brain function, however, the mechanisms responsible for the effects of tau on ECs remain understudied. We hypothesize that protofibrillar tau mediates pro‐inflammatory EC activation tied to bioenergetic alterations, culminating in loss of barrier function.

Method

Immortalized (D3) and primary (hCECs) human brain microvascular ECs were challenged with protofibrillar 1N4R tau. Trans‐endothelial electrical resistance (TEER) was measured by the ECIS Zθ system as an in‐vitro model of the BBB. Cytokine production was assessed using a V‐Plex Neuroinflammatory Panel 1 (MSD). IL‐4 release was determined in cell supernatant. Immunocytochemical analysis of junction protein (ZO‐1 and VE‐Cadherin) expression and western blotting for EC activation markers (VCAM‐1 and ICAM‐1) and junction proteins was performed. EC bioenergetics were measured by Seahorse Extracellular Flux Analyzer and EC death was determined, as well as caspase activation.

Result

Reduced TEER was observed with protofibrillar tau, independently of EC death. VCAM‐1 expression significantly increased, whereas junction protein expression was decreased. Aggregated tau caused an increase in glycolysis at 24h, which reverted at further timepoints, whereas mitochondrial ATP production increased. IL‐4 production was increased at 24 hours, with similar trends at earlier timepoints. Blocking IL‐4 activity partially rescued TEER and decreased VCAM‐1 expression.

Conclusion

Our results suggest that tau protofibrils mediate pro‐inflammatory EC activation, coupled with metabolic alterations. These molecular changes can contribute to loss of barrier integrity, exacerbating cerebrovascular dysfunction.
Single‐cell spatial and non‐spatial RNA sequencing on herpes simplex virus 1 (HSV‐1) infected 2D and 3D cerebral organoids reveal molecular granularity on virus‐human gene interactions in Alzheimer’s disease
Authors: Dawes Pepper , Barton Nathaniel J , Orszulak Adrian R , Chigas Samantha M , Tran Khanh , Sundstrom Jonathan , Olson Meagan N , Murray Liam F , Oh HyungSuk , Church George M , Knipe David M , Readhead Benjamin , Chan Yingleong , Lim Elaine T
Published: January 2025

Background

Herpes simplex virus (HSV‐1) has been associated with molecular and cellular signatures associated with Alzheimer’s disease (AD). We explored the use of both recent single‐cell and bulk transcriptomics technologies in dissecting the molecular and cellular virus‐human interactions with HSV‐1 infected cerebral organoids (2D and 3D). We compared the results with our previous observations from bulk RNA sequencing and discovered novel insights into HSV‐1 induced AD‐associated molecular pathology that were made possible by each transcriptomics technology.

Method

We used recent emerging technologies such as single‐cell spatial RNA sequencing (STOmics Stereo‐seq) and single‐cell non‐spatial RNA sequencing (Parse Evercode). In addition, we have data generated from our previous work using bulk RNA sequencing.

Result

Previously, we found that differentially expressed genes in HSV‐1 infected dissociated cells from cerebral organoids (2D cOrgs) using bulk RNA sequencing data were exclusively enriched for AD‐associated genes implicated through genome‐wide association studies (GWAS), but not for genes associated with other neurodegenerative or autoimmune diseases.

UMAP analyses on single‐cell non‐spatial RNA sequencing data with GFP‐tagged HSV‐1 infected 2D cOrgs clustered by viral transcripts [Fig. 1] revealed huge differences in the proportions of true late viral transcripts but not of leaky late viral transcripts between clusters, while similar clustering of 3D cOrgs [Fig. 2] showed distinct proportions of both true late and leaky late transcripts.

Pseudobulk analyses showed no enrichment for AD‐associated GWAS genes among the differentially expressed genes for HSV‐1 infected 2D cOrgs versus uninfected 2D cOrgs, but revealed significant enrichment for GWAS genes associated with autoimmune diseases such as Type 1 diabetes and multiple sclerosis. Similar analyses of HSV‐1 infected 3D cOrgs versus uninfected 3D cOrgs did not show enrichment in GWAS gene lists across the 21 common neurodegenerative, neuropsychiatric or autoimmune diseases that we had surveyed.

Conclusion

Taken together, our use of multi‐transcriptomics technologies has enabled us to gain course to fine molecular granularity into neuroinflammation‐induced AD viral‐human gene interactions and a careful dissection of the multi‐transcriptomics data enables us to gain insights into biomarkers and gene targets for AD therapeutics development in the near future.
Deciphering Microglial Contributions to Amyloid and Tau Pathology in Diverse Genetic Contexts
Authors: Onos Kristen D , Keezer Kelly J , Perkins Bridget M , Perkins Anne , Oblak Adrian L , Howell Gareth R
Published: January 2025

Background

There is strong evidence that underlying genetics of an individual can significantly modify response to development of amyloid and tau pathology with age. Genome‐wide association studies indicate that variation in more than 25 genetic loci relevant to microglial biology are predicted to increase susceptibility to Alzheimer’s disease (AD). This work aims to understand how genetic context can impact microglia function, how these differences relate to AD pathology, and ultimately, cognitive decline.

Method

To achieve this, we have introduced humanized amyloid‐β (with and without driver mutations) and MAPT sequences in two mouse strains, C57BL/6J (B6) and WSB/EiJ (WSB). In animals that carried amyloid driving mutations, we also performed injections of human‐derived tau at 6‐months and aged mice to 10‐months. Human brain tissue was obtained from the National Centralized Repository for Alzheimer’s Disease and Related Dementias (NCRAD) (ncrad.iu.edu). Immunohistochemistry was performed on mouse brain tissue to assess presence and degree of amyloid and tau pathology, differences in microglia and astrocyte activation and states, as well as neuronal and synaptic integrity. Measurements were also performed to assess degree of tau propagation. Plasma from animals was analyzed for a variety of biomarkers such as amyloid‐β, tau, neurofilament light, VEGFA and proinflammatory cytokines.

Result

Data analysis is ongoing, however, the impact of the individual humanized alleles has been assessed. B6 and WSB mice that carry humanized amyloid‐β without mutations did not exhibit significant amyloid pathology at 10 months. However, B6 and WSB mice that carry the Swedish‐Arctic‐Austrian mutations do show significant parenchymal deposition starting at 6 months of age, and WSB exhibit mature cerebral amyloid angiopathy.

Conclusion

We expect our strategy of incorporating humanized amyloid and tau into genetically diverse mouse strains will significantly improve the alignment of neuroimmune responses in mouse to human AD. This will give the AD field a new way to determine mechanisms, identifying critical genes and pathways in early in disease onset or progression. Furthermore, this may pave the way for the development of microglia‐based therapies to reduce or prevent tau propagation and spreading in AD and related dementias.
Fecal microbiome transplantation from stroke donors promotes Alzheimer’s disease brain pathology and hypoperfusion in the 3xTg‐AD mice
Authors: Aware Chetan , Flemister Abeoseh , Chang Ya‐Hsuan , Ericsson Aaron , Gu Zezong , Cui Jiankun , Zuckerman Amitai , Ma Lixin , Lin Ai‐Ling
Published: January 2025

Background

The link between stroke and Alzheimer’s disease (AD) is recognized. However, the underlying mechanisms are not yet clear. This study seeks to determine if increased AD risk is linked to gut dysbiosis caused by acute ischemic stroke. Specifically, we examined whether fecal microbiome transplantation (FMT) from stroke patients to an AD mouse model would increase dysbiosis, reduce cerebral blood flow (CBF), and lead to increased levels of Aβ and tau of the mice.

Method

Stool samples were collected from acute stroke patients (n = 8) and age‐matched healthy controls (HC) (n = 8) (age 55‐80 yrs.). Samples were transplanted orally to male (FMT‐Stroke, n = 14 and FMT‐HC, n = 12) and female (FMT‐Stroke, n = 17 and FMT‐HC, n = 15) 3xTg‐AD mice (3 months of age) for 4 weeks after receiving antibiotics treatment. Another group of naive mice (CTL) without FMT (M:F = 5:8) were included. Both fecal DNA of the donors and mice were sequenced by 16S rRNA. A subset of mice (n = 4/group) was sent for CBF measurements by 7T MRI, and Aβ and tau determination using immunohistochemistry (IHC).

Result

Bray‐Curtis analysis on beta diversity revealed that stroke and HC donors, as well as recipient mice and CTL mice differ significantly from each other with strong sex differences (Fig. 1A). FMT‐Stroke‐treated mice showed decreased SCFA‐producing bacteria (Lactobacillus and Akkermansia muciniphila) and increased pathogenic bacteria (E. coli) compared to FMT‐HC mice (Fig. 1B). Further, the FMT‐Stroke group exhibited elevated levels of tau and Aβ in the cortex compared to the CTL and FMT‐HC groups (Fig. 2). MRI study demonstrated that FMT‐Stroke manifested in lower CBF in the cortex and hippocampus compared with the other two groups (Fig. 3).

Conclusion

Our study provides evidence that gut dysbiosis following a stroke may actively contribute to the development of AD pathology and decrease CBF, thereby increasing the risk of AD. Addressing gut dysbiosis through dietary changes or medication could be crucial in helping stroke survivors reduce their risk of developing AD. These findings could pave the way for novel treatments aimed at lowering the risk of stroke‐associated AD.
Analysis of ADNI phenotypic and mulit‐omic data identifies the role of microglial debris and lipid processing in Alzheimer’s Disease transition
Authors: Funk Cory C , Paterson Tom , Rohrs Jennifer , Hohman Timothy J.
Published: January 2025

Background

Microglial processing and recycling of debris is implicated in AD. AD GWAS loci are enriched for genes in efferocytosis, phagocytosis, endosomal trafficking and cholesterol efflux. Acting as a buffer, lipid droplets increase as a consequence of an imbalance between lipid debris influx and efflux rates. We hypothesize that a pivotal point in disease progression occurs when this buffering saturates, resulting in expanded lipid‐droplet accumulating microglia (LDAM). We anticipate a positive‐feedback effect where saturation accelerates neurodegeneration via inflammation and lipid processing via astrocytes. Susceptibility to this saturation may be connected to microglial AD GWAS loci—and would be reflected in progression rates. To explore this hypothesis, we analyzed lipidomic, proteomic, cognitive and genetic ADNI data to identify a signature indicative of this inflection point.

Method

We identified ADNI individuals in comparable states of disease progression, grouping them into ADAS13 (cognitive score) quartiles, then examined blood lipidomic and CSF proteomic data. This resulted in a cross‐sectional dataset of 608 subjects spanning from cognitively normal to demented. We examined protein/lipid correlations across each quartile, identifying and characterizing inflection points.

Result

We observed a stark and unique pattern of correlations in individuals with an ADAS13 score range from 13 to 19. We observed two subpopulations that differed in their rate of disease progression. CSF proteins in the rapid progressors point to microglial lipid droplet signaling and the lactate shuttle. We observed key changes in plasmalogens and cholesterol esters with DHA fatty acid tails, both indicative of neuronal debris processing and reverse cholesterol transport, as well as changes in acylcarnitines—indicative of reduced lipid hydrolysis. We also found differential enrichment of specific AD GWAS loci between the fast and slow progressors.

Conclusion

Our analysis provides evidence for the importance of lipid droplet saturation coinciding with correlational changes in CSF proteins and plasma lipids, occurring in individuals transitioning from cognitively normal to MCI. We connected microglial AD GWAS loci to differences in the progression rates at this transition. These results have potential clinical relevance for predicting progression rate at MCI diagnosis, and inform our understanding of the role of GWAS loci in key transitions.