bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genetic factors modify the effect of chronic viral infections on Alzheimer disease risk
Authors: Tejeda Marlene , Farrell John J. , Zhu Congcong , Wetzler Lee , Lunetta Kathryn L. , Bush William S. , Martin Eden R. , Wang Li‐San , Schellenberg Gerard D. , Pericak‐Vance Margaret A , Haines Jonathan L. , Farrer Lindsay A. , Sherva Richard 
Published: January 2025

AbstractBackgroundSeveral viruses have been linked to Alzheimer disease (AD) by independent lines of evidence.MethodWhole genome and whole exome sequences (WGS/WES) derived from brain (3,404 AD cases, 894 controls) and blood (15,612 AD cases, 24,544 controls) obtained from European ancestry (EU), African American (AA), Mexican (HMX), South Asian Indian (IND), and Caribbean Hispanic (CH) participants of the Alzheimer’s Disease Sequencing Project (ADSP) and 276 AD cases 3,584 controls (all EU) from the Framingham Heart Study (FHS) that did not align to the human reference genome were aligned to viral reference genomes. A genome‐wide association study (GWAS) for viral DNA load was conducted using PLINK software and regression models with covariates for sex, age, ancestry principal components, and tissue source. A second GWAS tested association of the interaction of SNPs with total viral read count and specific viruses previously linked to AD (HSV‐1, HPV‐71, TTV‐10, and herpes and TTV clusters) with AD risk in five population ancestry groups. Results across subgroups (cohort, WES vs. WGS, tissue source, and ancestry) were combined by meta‐analysis using METAL software. P‐values for previously established AD risk SNPs were corrected for 83 tests and a standard genome‐wide significant (GWS) threshold of 5 × 10‐8 was used for GWAS analyses.ResultHSV‐1 was associated with an increased risk of AD in EUs (OR = 1.20, P = 3.23 × 10‐6) and AAs (OR = 1.18, P = 9.46 × 10‐6), but was protective in CHs (OR = 0.43, P = 5.06 × 10‐62). HPV‐71 was associated with a reduced risk of AD in EAs (OR = 0.94, P = 0.035). No significant virus‐AD associations were observed in individuals of HMX or IND ancestry. The interaction of a known AD risk SNP (rs6489896) in TPCN1 with HSV‐1 was significantly associated with AD risk (OR_interaction = 1.11, P = 5.67 × 10‐4) in the trans‐ethnic meta‐analysis of all WGS samples. We identified GWS associations of 16 variants with viral reads in AAs. Several of these genes are involved in memory formation (KMT2A), synaptic transmission (SLC28A2), and immune response (FCN2 and CLEC12A).ConclusionThese findings provide further evidence for the role of viral infections, particularly herpes viruses, in AD pathogenesis and highlight the importance of genetic factors in modulating these associations.
Subjective Cognitive Concerns and High Frequency Mobile App Based Cognitive Assessment in Older Adults: Relationship to Adherence, Satisfaction, and Cognitive Performance
Authors: Nester Caroline O , De Vito Alyssa N. , Kunicki Zachary J. , Strenger Jennifer , Harrington Karra D , Roque Nelson A. , Sliwinski Martin J. , Thompson Louisa I. 
Published: January 2025

AbstractBackgroundSubjective cognitive concerns (SCC) are possibly one of the earliest clinical symptoms of dementia. There is growing interest in applying mobile app‐based assessment to remotely screen for cognitive status in preclinical dementia, but the relationship between SCC and relevant mobile assessment metrics remains unclear. To address this gap, we characterize the relationship between SCC and adherence, satisfaction, and performance on digital cognitive assessment in cognitively unimpaired older adults.MethodParticipants (N = 122, Table 1) completed 8 assessment days using Mobile Monitoring of Cognitive Change (M2C2), an app‐based testing platform, with brief daily sessions within morning, afternoon, and evening time windows (24 total testing sessions). M2C2 includes working memory, processing speed, and episodic memory tasks. Participants provided feedback about their satisfaction and motivation related to M2C2. SCC was assessed via the Cognitive Function Instrument (CFI). Regression analyses evaluated the association between SCC and adherence, satisfaction, and performance on M2C2, controlling for age, sex, and loneliness (UCLA Loneliness Scale). Linear‐mixed effects models evaluated whether SCC predicted M2C2 subtest performance longitudinally over the 8‐day testing period, controlling for covariates.ResultSCC was not associated with adherence to M2C2, app satisfaction, or protocol motivation. SCC endorsement significantly predicted worse overall episodic memory performance (ß = ‐0.011, p = .021, 95% CI ‐0.02, ‐0.00), but was not associated with overall working memory or processing speed (Table 2). A trend was revealed between SCC and slow processing speed at day 1. There was a significant interaction between SCC and processing speed over the 8‐day period, such that SCC was associated with initially slow, then progressively faster processing speed.ConclusionSCCs are associated with objective cognitive performance on mobile app‐based assessments, but do not impact metrics related to protocol engagement (e.g., adherence, satisfaction, and motivation), suggesting that mobile app assessments may be sensitive to early neurodegenerative changes. Results provide reassurance that SCCs do not impact the feasibility of mobile app‐based assessments in older adult samples. Future research in larger, more diverse samples which follow cognitive functioning longitudinally will be essential next steps to understand the utility of SCC to predict cognitive decline via mobile app.
SPARC‐related modular calcium‐binding proteins (SMOC1 and 2) as a modulator of amyloid pathology in Alzheimer’s Disease
Authors: Afroz Kazi Farhana , Levites Yona , Ryu Danny , Ran Yong , Gadhavi Joshna Dharmendrabhai , Liu Xuefei , Seyfried Nicholas T , Golde Todd 
Published: January 2025

AbstractBackgroundRecently, a highly significant brain proteome divergent modules change between Alzheimer’s disease (AD) and CRND8 APP695NL/F transgenic mice has been found. The M42 module is the module in human AD most highly correlated with amyloid and tau pathologies and cognitive decline. Among all proteins in this module, the (SPARC‐related modular calcium‐binding protein 1) SMOC1 is emerging as a robust biomarker of amyloid deposition in CSF. It increases in CSF in parallel with the Ab42:40 ratios’ decrease. SMOC1 is also markedly increased in the late‐onset AD CSF, suggesting its role as a robust biomarker. Our preliminary data have shown that i) recombinant SMOC1 inhibits Aβ aggregation in vitro and ii) both SMOC1 and its homolog SMOC2 bind amyloid structures. Furthermore, SMOC1 and 2 appear to be components of a subset of senile plaques and CAA.MethodWe hypothesized that Smoc1 and Smoc2 overexpression will inhibit amyloid deposition and even promote clearance of aggregated Aβ. To test the hypothesis, we cloned both genes into AAV and injected newborn CRND8 amice with rAAV2/8‐Smoc1‐Flag and rAAV2/8‐Smoc2‐Flag, aged them and assessed amyloid deposition in the brain by immunohistochemical and biochemical methods.ResultImmunohistochemical analysis showed that Smoc1 overexpression resulted in significantly lower amyloid plaque count and SDS‐soluble Aβ1‐42 and Aβ1‐40 levels in the brain, as compared to non‐injected controls. Soluble Aβ1‐42 and Aβ1‐40 levels were not changed as a result of Smoc1 overexpression. Staining with astrocyte‐specific glial fibrillary acid protein (GFAP) and microglia‐specific ionized calcium‐binding molecule‐1 (IBA‐1) antibodies showed that Smoc1 overexpression did not affect astrocytosis, but significantly increased the activated microglia cell counts. Additionally, we are currently examining the effects of Smoc1 and Smoc2 overexpression on pre‐existing plaques in aged CRND8 mice.ConclusionOur data suggest that Smoc1, in addition to being an early and sensitive fluid biomarker, is acting as an inhibitor of amyloid formation and can potentially lead to a novel therapeutic approach. Although Smoc1 and Smoc2 prevent Aβ aggregation, the specific mechanism of this action is yet to be identified. Our findings will pave the road to establishing SMOC proteins as a potential therapy for AD.
Single‐nuclei transcriptomic identifies type‐specific neuronal cell vulnerability in Amnestic and Logopenic Variant Primary Progressive Aphasia Alzheimer’s disease
Authors: Pereira Felipe Luiz , Lew Caroline , Li Song Hua , Rizzi Liara , Araujo Igor Prufer Q C , Soloviev Alexander V. , Spina Salvatore , Rexach Jessica E , Seeley William W. , Suemoto Claudia Kimie , Leite Renata Elaine Paraizo , Newell Kathy L , Ghetti Bernardino , Murray Melissa E. , Grinberg Lea T. 
Published: January 2025

AbstractBackgroundIndividuals meeting neuropathological criteria for Alzheimer’s disease (AD) may manifest with atypical clinical syndromes. Past work showed that the neurobiological basis for these differences is related to specific neuronal vulnerabilities for tau pathology. For instance, amnestic cases have a higher burden of neurofibrillary changes in CA1. In contrast, logopenic variant primary progressive aphasia (lvPPA) cases have a higher tau burden in the superior temporal gyrus (STG). Single‐cell technology enables investigations on the molecular basis of differential neuronal vulnerability in AD. Consequently, we delved into the factors that underlie this selective vulnerability by analyzing brain samples from individuals exclusively afflicted with AD but exhibiting diverse clinical manifestations.MethodsnRNA Sequencing using the Chromium Single Cell 3′ (10X Genomics, USA) on nuclei cells extracted from the CA1 sector and posterior STG of postmortem brain tissue of 48 individuals either meeting pathological criteria for AD (A3B3C3; 24 amnestic and eleven lvPPA) and healthy controls (A≤1B≤1C≤1; n = 13) (Table 1, Fig. 1A/B). Bioinformatics analyses were conducted using Cell Ranger and R software. Comparisons between cell subpopulations were conducted with the Wald statistical test, and p‐values < .05 were considered significant.ResultAfter quality control, we recovered more than 250k nuclei with a mean of 2,130 genes per nuclei. Upon cross‐sample alignment and t‐stochastic neighborhood embedding clustering (Fig. 1C), we found 21 excitatory neuronal subpopulations (Exc‐sub) in CA1 and 26 in STG, and 22 and 25 inhibitory neuronal subpopulations (Inh‐sub) in CA1 and STG, respectively; 16 astrocytes subpopulations in both areas and 20 microglia subpopulations in CA1 and 17 in STG (Fig. 2). One STG Exc‐sub, expressing CUX2 and LAMP5 genes showed vulnerability in lvPPA patients. Also, one STG Inh‐sub, expressing the ADARB2 gene, showed vulnerability for all AD patients.ConclusionOur preliminary study identified a vulnerable population of excitatory neurons related to lvPPA. We are conducting validation studies using quantitative pathology to confirm these results. Furthermore, analysis of a higher number of cases is ongoing and will continue to inform on factors associated with neuronal vulnerability.
Reducing tau acetylation rescues cognitive deficits in a mouse model of traumatic brain injury‐induced acceleration of Alzheimer’s disease
Authors: Barker Sarah , Vázquez‐Rosa Edwin , Caradonna Salvatore , Kornblit Ryan , Apostolakis Aristotle , Dou Lijun , Shin Min‐Kyoo , Corella Sofia , Tripathi Sunil Jamuna , Chakraborty Suwarna , Chaubey Kalyani , Franke Kathryn , Cintrón‐Pérez Coral , Sridharan Preethy , Woo Jung A , Kang David E. , Gan Li , Wilson Brigid M. , Cheng Feixiong , Paul Bindu D , Pieper Andrew A. 
Published: January 2025

AbstractBackgroundTBI is the 3rd greatest risk factor for developing AD, behind genetics and aging. TBI is associated with a 3‐4 year earlier onset of cognitive impairment, and increased cortical thinning and amyloid plaques in people with AD. The underlying mechanisms of this relationship are not understood, and as a result there are no treatments that protect patients from accelerated AD after TBI. We reported that tau is pathologically acetylated after TBI. Acetylated tau is significantly more elevated in the brains of human AD subjects with a history of TBI, compared to AD alone and healthy controls. Therefore, we hypothesized that early tau acetylation after TBI is mechanistically involved in the acceleration of AD.MethodWe developed a mouse model of TBI‐mediated acceleration of AD‐like pathology and cognitive impairment in 5xFAD mice. Our unique blast mediated multimodal TBI model is reproducible and clinically relevant. 8‐week‐old male and female 5xFAD and WT littermates underwent sham/TBI and were assessed after two weeks via Morris water maze, immunohistochemistry, western blot, and single nuclear RNA sequencing. For treatment studies, the FDA‐approved non‐steroidal inflammatory drug diflunisal, which inhibits the p300‐CBP acetyltransferase enzyme that acetylates tau, or vehicle was initiated 24 hours after TBI and continued daily. To investigate potential mechanisms, we developed an in vitro TBI model with Hela cells that stably express amyloid precursor protein or tau.ResultTBI causes learning deficits in young 5xFAD mice that do not occur in sham 5xFAD mice or in TBI‐injured WT littermates. TBI accelerates amyloid plaques in 5xFAD mice. 5xFAD mice show greater elevation of acetylated tau after TBI, compared to WT mice. Hippocampal snRNA sequencing showed that TBI or 5xFAD mutations alone primarily perturb neurons. By contrast, TBI in 5xFAD mice drastically alters transcription in multiple cell types. Diflunisal treatment reduces acetylated‐tau and rescues behavior deficits after TBI in 5xFAD mice. Amyloid precursor protein and tau expressing cells are more susceptible to in vitro TBI, compared to wild type cells.ConclusionTBI accelerates onset of AD‐like pathologies in 5xFAD mice. Preliminary evidence shows that pharmacologically reducing acetylated tau rescues TBI‐induced cognitive deficits in 5xFAD mice.
CNS‐active drugs for neuropsychiatric disorders differentially modulate the risk of AD development
Authors: Cortes‐Flores Helena , Torrandell‐Haro Georgina , Brinton Roberta Diaz 
Published: January 2025

AbstractBackgroundNeuropsychiatric disorders including depression, insomnia, epilepsy, schizophrenia, and attention‐deficit and hyperactivity disorder (ADHD) have been associated with a neurodegenerative process and linked to increased risk for Alzheimer’s Disease (AD). Because of the shared biological mechanisms of AD and neuropsychiatric disorders, we hypothesized that pharmacologic treatment for neuropsychiatric disorders could impact the risk for AD. CNS drugs that are first‐line therapies for neuropsychiatric disorders (including antidepressants, sedatives, anticonvulsants, antipsychotics, and stimulants) were investigated for impact on AD incidence.MethodTo address this hypothesis, we conducted a retrospective medical informatics analysis of insurance claims of patients aged 60 years and older, with and without exposure to CNS drugs. To reduce health status and demographic bias, we utilized propensity score matching to adjust for age, gender, Charlson comorbidity index (CCI), and comorbidities. The propensity score matched population was surveyed for AD diagnosis following at least 1 year of exposure to CNS drugs.ResultExposure to CNS drugs was associated with a decreased risk for AD (RR [95%CI]: 0.50 [0.47–0.53]; P<.0001), and women (RR [95%CI]: 0.46 [0.42–0.50]; P<.0001) exhibited a slightly greater risk reduction compared to men (RR [95%CI]: 0.55 [0.50–0.61]; P<.0001). Drug stratification indicated that antidepressant, sedative, anticonvulsant, and stimulant treatment were associated with reduced AD risk, while antipsychotics were associated with increased risk for AD. Additional analysis indicated that the combination of two CNS drugs was associated with a greater reduction of AD risk compared to monotherapy for most drugs assessed. Age and sex emerged as modulators of rate of disease conversion, with females older than 70 years receiving the greatest benefit.ConclusionCollectively, these results indicate that antidepressants, sedatives, anticonvulsants, and stimulants are beneficial as risk modifiers for AD, while antipsychotics appear to increase the vulnerability of the brain to AD development. The potential use of combination therapy with antipsychotics could mitigate the risk conferred by these drugs. These findings have the potential to contribute to advancing neuropsychiatric treatment that could impact the risk of Alzheimer’s disease.
Enhancing Alzheimer Disease risk prediction using machine learning for Pathway Polygenic Risk Scores (p‐PRS)
Authors: Rajabli Farid , Aguiar‐Pulido Vanessa , Scott Kyle , Feliciano‐Astacio Briseida E. , Hamilton‐Nelson Kara L. , Adams Larry D. , Mena Pedro R. , Celis Katrina , Sanchez Jose Javier , Whitehead Patrice L. , Prough Michael B. , Acosta Heriberto , McInerney Katalina F , Vance Jeffery M. , Cuccaro Michael L. , Beecham Gary W , Pericak‐Vance Margaret A 
Published: January 2025

AbstractBackgroundPolygenic Risk Scores (PRS) are important in predicting disease risk and are usually rely on markers selected by thresholding p‐values from genome‐wide association studies (GWAS). In traditional approaches, one single model is built to calculate risk scores, employing effect size to determine additive risk. However, this traditional method overlooks potential interactions between genetic loci resulting in reduced prediction power. To overcome these limitations, we propose an interpretable machine learning approach based on pathway‐level PRS (p‐PRS). Our approach improves prediction accuracy of PRS and generates both pathway specific and overall PRS considering possible nonlinear interactions. This advancement opens new avenues in personalized medicine, enabling more accurate disease prediction and prevention strategies.MethodWe used whole genome sequencing data from 652 individuals from the Puerto Rican Alzheimer’s Disease Initiative (PRADI). First, we selected Alzheimer disease (AD)‐related pathways and genes based on those reported in the largest non‐Hispanic White AD GWAS to date (Bellinguez et al. 2021). Then, we applied the Clumping and Thresholding (C+T) PRS approach using Bellinguez et al. summary statistics within each pathway (±20Kb for each gene). Finally, we used random forest with pathway‐level PRS values as input to classify AD vs. control. We assessed the performance of the p‐PRS model based on area under the receiver operating characteristic curve (AUC) using a 70%/30% split for training/testing. The outcomes were compared to a traditional C+T PRS model (AD∼PRS+APOE).Resultp‐PRS improves the performance of the traditional PRS model by 4.2% (p = 5.54E‐32). Performance is centered around AUC = 0.689(SE = 0.0022) for p‐PRS and 0.647(SE = 0.0024) for traditional PRS. PRS by pathway enables determining individual‐level important pathways for accurate classification. Top pathways obtained are related to processes implicated in cognitive deficit, neuroinflammation, neurodegeneration and vesicle mediation.ConclusionUtilizing the innovative p‐PRS approach has improved the estimation of AD risk in the PR cohort. The application of interpretable machine learning approaches allows identifying the most relevant pathways for effective risk prediction and classification. Importantly, improved precision will provide more effective actionable risk mitigation strategies, optimize the selection process for clinical trials, and contribute to the development of more personalized treatment interventions.
Sex differences in the response to high pulse pressure in APOE4 mice
Authors: Ferguson Skylyn J , Isakharov Lazar N , Walker Ashley E 
Published: January 2025

AbstractBackgroundElevated arterial pulse pressure (PP) is associated with cognitive decline and Alzheimer’s disease (AD). High PP damages the brain vasculature by causing endothelial cell dysfunction. Stiffer cerebral arteries have an impaired ability to dampen PP, which transmits the pulsatility further into the microvasculature, where it can damage brain tissue. At the same time, the APOE4 genotype is associated with cerebrovascular dysfunction; however, it is unknown if elevated PP amplifies this risk. Furthermore, female APOE4 carriers are at a higher risk for developing AD than males. Thus, we hypothesized that female APOE4 mice would be more vulnerable to high PP and have greater cerebral artery stiffness and cognitive impairments compared with male mice.MethodIn male and female mice homozygous for APOE4 and humanized Aβ1‐42 (APOE4/hAβ, n = 26, 6 months), we assessed ex vivo endothelium‐dependent vasodilation by the dose‐responses to acetylcholine in isolated posterior cerebral arteries (PCAs) following exposure to static pressure (50 mmHg), low PP (50‐75 mmHg), or high PP (37.5‐87.5 mmHg). PCA endothelium‐independent vasodilation was measured by the response to sodium nitroprusside, and stiffness was measured during the high PP condition. We assessed cognition by the Morris Water Maze.ResultUnder static pressure, PCA endothelium‐dependent vasodilation was similar between male and female mice (p = 0.13). In females, PCA endothelium‐dependent vasodilation was similar between static and low PP (p = 0.37), while exposure to high PP resulted in a 38% decline in endothelium‐dependent vasodilation (p = 0.004 vs. static). In contrast, PCA endothelium‐dependent vasodilation in male mice was similar between static and PP conditions (p>0.05). Endothelium‐independent vasodilation did not differ between sexes (p>0.05). Female mice also exhibited a higher PCA β‐stiffness index than male mice (p = 0.03). Additionally, during the Morris Water Maze probe trial, females crossed the platform area significantly fewer times than males (p = 0.048).ConclusionOur data indicate that high PP is detrimental to cerebral artery endothelial function in female, but not male, APOE4/hAβ mice. Additionally, female APOE4/hAβ mice have stiffer cerebral arteries and poorer spatial memory than male APOE4/hAβ mice. Our findings suggest that sex may influence the interactive effect of APOE4 and PP on cerebrovascular and AD‐related outcomes.