bluuebunny/crossref_metadata_2025_split huggingface dataset:
Comparing the diagnostic performance of the INECO Frontal Screening in illiterate vs. literate older adults with cognitive impairment in Lima, Peru
Authors: Custodio Nilton , Malaga Marco , Montesinos Rosa , Ruiz‐Yaringaño Arturo Jhonny , Baca Fiorella , Chambergo‐Michilot Diego , Verástegui Graciet , Agüero‐Flores Katherine , Cruzdel Castillo Rossana , Cuenca José , Huilca José Carlos , Lanata Serggio , Bustamante‐Paytan Diego 
Published: January 2025

AbstractBackgroundRising dementia prevalence in Low and Middle‐Income Countries (LMICs), fueled by socio‐economic disparities, necessitates accessible brief cognitive tests. The INECO Frontal Screening (IFS) proves effective for detection of Mild Cognitive Impairment (MCI) and early dementia. It prioritizes executive functions, is suitable for low‐educated or illiterate individuals, and robust diagnostic capacity.MethodWe conducted a secondary analysis of a prior patient cohort. Illiterate participants met the following criteria: proficiency in Spanish for over 10 years, age ≥ 60, less than 1 year of formal education, and inability to read and write. Literate patients were aged 60 or older, Spanish speakers, and had a minimum of 6 years of formal education. A clinical evaluation with three consecutive phases was used as gold standard diagnosis, resulting in a final classification based on international criteria. The IFS was applied to all participants. To compare the diagnostic performance of the IFS, a Receiver‐Operator Curve (ROC) analysis was conducted. The average scores for each IFS domain were compared among all groups in each cohort using a Wilcoxon test.ResultWe included 114 controls, 101 MCI patients, and 105 all type dementia patients. Median age was 68 (67‐71), 69 (66‐71) and 72 (71‐75), respectively, and female participants accounted for 45.6%, 47.5% and 45.7% for each group, respectively. An excellent diagnostic performance was found when we evaluated the IFS Total score for discrimination between controls, MCI, and dementia patients across both groups (Fig. 1). The analysis based on the Youden index showed that, the optimal cut‐off points for MCI (22 vs 23.7), and dementia patients (17.6 vs 18.3), was lower in illiteracy participants (Table 1). Finally, when evaluating each IFS domain among control patients in both groups, statistically significant differences were found in Digits backward and the Hayling test (p‐value <0.001) (Table 2).ConclusionThe IFS seems to be useful in assessing both illiterate and literate older adult patients for the presence of MCI and dementia in LMIC settings.
Multi‐tissue multi‐omic trans QTL mapping identified novel causal and druggable targets and gene‐gene interactions
Authors: Cruchaga Carlos 
Published: January 2025

AbstractBackgroundThe integration of quantitative trait loci (QTLs) with disease genome‐wide association studies (GWAS) has proven successful at prioritizing candidate genes at disease‐associated loci. Most of QTL studies are focusing on expression QTLs in plasma and brain and cis‐signals.MethodHere we analyzed a large proteomic (Somalogic 7K) and metabolomic (Metabolon HD4) CSF (n = 3, 000) and plasma (African (AFR, N = 400) and European (EUR, N = 2,300) ancestry, respectively) to identify novel QTLs. We integrated with FUSION, colocalization and Mendelian Randomization approaches to identify novel causal and druggable targets.ResultIn CSF we identified 2,316 significant pQTLs (1,247 in cis and 1,069 in trans) for 1,960 proteins, of which 1,228 were not observed in plasma. For metabolomics we identified 219 independent associations (59.8% novel) for 144 CSF metabolites. In plasma, we identified 2,400 pQTL in EUR and 881 pQTL in AFR. In EUR and AFR metabolomics, we reported 403 and 60 metabolites with at least one significant QTL, respectively. Approximately 40% of these findings were novel associations compared to previous studies Through PWAS, we identified 473 CSF proteins associated with AD risk. MR prioritized 40 proteins as causal and colocalization identified 158 proteins that share genetic etiology. 42 of these overlap between at least two of these methods and are enriched in immune and lysosomal pathways. Multiple (including PILRA, PRSS8, and SIRPA) represent novel candidate proteins. We also identified novel regulators for TREM2 including TGBR2 and NECTIN2, which represent novel therapeutic targets for AD.ConclusionWe have developed the largest CSF proteomics and metabolomics data. Through a rigorous approach combining three methods, we have identified high‐confidence proteins involved in AD that confirm previously reported candidate genes and prioritize new ones at GWAS loci. Our findings offer insights into Alzheimer’s disease biology that were missing when using plasma analyses, supporting the development of tissue‐specific proteomics databases in neurologically‐relevant tissues.
ABCA1 rare variants interact with APOE isoforms to confer Alzheimer’s Disease risk
Authors: Peña‐Tauber Andrés , Arriaza Ricardo Hernandez , Guen Yann Le , Khosla Chaitan , Greicius Michael D 
Published: January 2025

AbstractBackgroundSeveral lines of evidence now suggest that ABCA1 plays a role in Alzheimer’s disease (AD). Rare variants on ABCA1 increased AD risk in a large genetic study, and mouse models suggest that increasing ABCA1 activity can reverse signs of AD pathology. While there is growing consensus that ABCA1 and ApoE directly interact, it is unclear how APOE genotype affects this interaction in the context of neurodegeneration.MethodWe conducted burden tests of rare variants (MAF < 1%) on ABCA1 either causing loss of function or having a REVEL score above 0.75 in European‐ancestry participants from ADSP whole‐genome (WGS), whole‐exome (WES) sequencing, and UK Biobank WES datasets. All analyses were adjusted for sex, PCs 1‐4, and sequencing platform. Stratifying by APOE genotype, we tested the association between ABCA1 variant carrier status and AD using logistic regression, then meta‐analyzed the results with fixed‐effect inverse‐weighted variance. To test directly for an APOE interaction with ABCA1, we analyzed all APOE genotypes together adding interaction terms ε2*ABCA1 and ε4*ABCA1, and additionally adjusted for APOE ε2/ε4 dosages.ResultCarrying an ABCA1 variant was associated with increased AD risk in APOE ε2/ε3 and ε3/ε3 cohorts. In contrast, the association was not significant in ε3/ε4 or ε4/ε4 (Fig. 1). Models including cross‐terms in the whole‐APOE cohort supported an interaction between ABCA1 variants and APOE ε4 dosage diminishing risk compared to having an ABCA1 variant by itself (Table 1). Analysis of missense variants by themselves showed a significant protective effect for extracellular domain mutations in ε3/ε4, whereas they increased risk in ε3/ε3 and showed no effect in ε2/ε3 (Fig. 2). Conversely, ε2/ε3 saw a risk‐increasing association only with nucleotide‐binding domain mutations.ConclusionABCA1 rare variants are associated with AD risk and the effect size appears to be modulated by APOE genotype, showing significant interaction with ε4 dosage. This suggests an interplay between ABCA1 and different ApoE isoforms in contributing to AD, highlighting a potential pathogenic mechanism. Further, as extracellular domain mutations show diverging impacts on AD risk depending on APOE genotype, this domain may play a critical role in the pathogenic interaction between ABCA1 and ApoE.
Unveiling the Role of A2AR Dysregulation in Olfactory Dysfunction and Amyloidogenesis in Alzheimer’s Disease
Authors: AILIYA AILIYA , BAO Ligao , XIJIRI XIJIRI , KAKUTA Shigeru , Eerdunfu Eerdunfu 
Published: January 2025

AbstractBackgroundAlzheimer’s Disease (AD) manifests early in the olfactory system, yet its precise role in the pathophysiology of AD remains elusive. This study aims to elucidate the progression of olfactory dysfunction in AD by investigating the dysregulation of the adenosine 2A receptor (A2AR) and its potential involvement in the formation of abnormal plaques and tangles. A2AR plays a pivotal role in modulating synaptic transmission and neuroinflammation by regulating both neurons and glial cells. Its regulatory impact on olfactory function prompted the hypothesis that A2AR tightly binds to the Amyloid Precursor Protein (APP), influencing the formation of Amyloid β‐Protein (Aβ).MethodTo explore the impact of A2AR dysregulation in the olfactory system of AD, we examined A2AR expression patterns in the olfactory bulb, striatum, and hippocampus of single amyloid precursor protein knock‐in (APPNL‐G‐F) mice. Additionally, in vitro experiments like RNAi knockdown using SH‐SY5Y cell line were conducted to mimic the regulatory effects of A2AR on APP and Aβ, providing insights into the pathological mechanisms.ResultOur findings revealed an age‐dependent increase in A2AR expression in the olfactory bulb, hippocampus, and striatum in APPNL‐G‐F mice. Notably, A2AR expression precedes APP expression in the olfactory bulb, suggesting A2AR has a regulatory role in amyloidogenesis. Furthermore, co‐expression analysis revealed a significant association between A2AR and APP, underscoring their potential interaction in AD pathology. The APP expression pattern will be led by A2AR expression from glomerular layer to the granule cell layer of the APPNL‐G‐F mice olfactory bulb. Additionally, modulating A2AR expression alters cellular responses to caffeine and adenosine on SH‐SY5Y cell line and regulating APP expression, implicating its involvement in synaptic transmission and amyloid pathology.ConclusionThis study underscores the pivotal role of A2AR dysregulation in olfactory dysfunction associated with AD. The observed tight binding of A2AR with APP implies its direct involvement in Aβ formation. These findings highlight the significance of A2AR dysregulation in olfactory dysfunction and amyloidogenesis, suggesting novel therapeutic targets and early diagnosis for AD intervention.
Fukushimura Brain Bank ‐Nursing home based brainbank project in Japan‐
Authors: Kaneda Daita , Ogawa Norihiro , Kanesaka Takeshi , Hishida Chie , Sakurai Keita , Akatsu Hiroyasu , Yamamoto Sakon , Yamamoto Takayuki , Yoshio Hashizume 
Published: January 2025

AbstractBackgroundThe Fukushimura (welfare village), located in Toyohashi city, Japan, is a unique complex of various nursing home facilities including dementia homes, Day‐care houses, homes for disabled and mentally retarded, and the Fukushimura Hospital. This village is totally managed by private sector, the Sawarabi Medical Cooperative. About 800 elderly people reside in this area. The hospital plays a pivotal role within the village and acts as the central facility for each nursing homes.Fukushimura BrainBank (FBB) was established in 1990. The neuropathological investigation of FBB was initially conducted by Kenji Kosaka, who initially reported cortical Lewy bodies. Our research institute was approved in 2004 by the Ministry of Education, Culture, Sports, Science and Technology, as one of the non‐governmental institutes which is permitted to apply for governmental grants.MethodDetailed serial imaging tests including MPRAGE T1 volume datas and diffusion tensor imaging (DTI) using 1.5T MRI (Siemens) are perfomed in the clinical setting. Clinical datas including behavioral and psychological symptoms are collected from medical records and each nursing homes at the autopsy. Donation of retina is an optional offer at the autopsy.For collecting CNS specimens, the brains are separated into two hemispheres, one for neuropathological analyses with using several antibodies for beta‐amyloid, phosphorylated tau, alpha‐ synuclein, and TDP‐43. Modified gallyas‐silver staining is applied for evaluating argyrophilic grain disease. The other hemispheres are stored for frozen sections.ResultAt the end of 2023, 841 of frozen brains with detailed medical record are stored in FBB and readily available for research. 56 brains with DTI scans are collected. The number of consents for retinal donation became 146, which is expected as one of the largest Asian retinal tissue bank of post‐mortem. We already have over 20 collaborators and supply our samples for more than 30 research institutes in Japan.ConclusionThe challenge of FBB will play a unique and important role to clarify cliniconeuropathological correlation of the nursing home residential with various geriatric conditions.
Unravelling neurodegenerative effects of SARS‐CoV‐2 infection in Alzheimer’s disease‐ brain organoids
Authors: Gonzalez Laura Garcia , Sarrias Andrea Martí , Puertas Maria Carmen , Turpin Isabel , Gil Ángel Bayón , Infante Patricia Resa , Picado Javier Martinez , Navarro Arcadi , Acosta Sandra 
Published: January 2025

AbstractBackgroundThe increased vulnerability of Alzheimer’s disease patients to severe SARS‐CoV‐2 infection raises crucial concerns, especially with the potential transition of the COVID‐19 pandemic to an endemic state. Given the rising prevalence of Alzheimer’s in an aging world‐wide population, elucidating whether SARS‐CoV‐2 infection may induce or accelerate neurodegeneration becomes imperative.MethodTo investigate the neurodegenerative effects of SARS‐CoV‐2 infection, we generated brain organoids using human induced pluripotent stem lines from one non‐demented control, one with sporadic Alzheimer’s, and one with familial Alzheimer’s. After 6 months of differentiation, aged organoids were infected with SARS‐CoV‐2 in duplicates (n = 4 organoids/each). Post‐infected organoids were analyzed systematically 6 weeks post‐infection in order to simulate long‐lasting viral effects. We collected cell media, and fixed the brain organoids to monitor cellular infection, the status of neurons, the reactivity of astrocytic glia, and the presence of neurodegeneration markers.ResultSustained low‐level virus replication was detected in the organoids medium for 6 weeks. We observed a higher proportion of infected cells in Alzheimer’s‐derived organoids compared to the control organoids (Fig. 1A and Fig. 1B). In addition, neuronal infection rates surpassed astrocytes across all genotypes (Fig. 1C). RNA expression analysis of SARS‐CoV‐2 receptors expression showed no significant differences between different genotypes, suggesting that the differences in infection rates is not solely attributable to receptor expression. We found no significant differences in the total number of neurons or astrocytes, nor the proportion of caspase‐3 positive cells. However, an increase in β‐amyloid peptide counts and particle area along with an elevated Aβ42/ Aβ40 ratio was observed after infection (Fig. 2). Regarding Tau phosphorylation levels, there were no clear differences between genotypes or conditions.ConclusionOur research reveals a heightened susceptibility of Alzheimer’s disease‐derived brain organoids to SARS‐CoV‐2 infection together with a notable accumulation of Aβ peptides. These findings suggest a potential link between viral exposure and exacerbation of neurodegenerative markers in Alzheimer’s disease, underscoring the urgent need for further exploration of this relationship amid the evolving landscape of the COVID‐19 pandemic.
Synaptic density in the hippocampal and parahippocampal subregions and its association with the severity of axonal damage and cognitive decline in Alzheimer’s disease
Authors: Bouwman Maud M.A. , Frigerio Irene , Reijner Niels , van de Berg Wilma D.J. , Jonkman Laura E. 
Published: January 2025

AbstractBackgroundThe hippocampus is highly vulnerable to amyloid‐b (Aβ) and phosphorylated tau (p‐tau), and shows synaptic loss in Alzheimer’s disease (AD). Moreover, the loss of synapses correlates strongly with cognitive decline and leads to neuronal network dysfunction. Here, we aim to map the selective synaptic loss in hippocampal and parahippocampal subregions in AD and its association to the severity of neuropathology, axonal damage and cognitive decline.MethodWe included (para)hippocampal tissue of 26 AD and 17 age‐matched control donors. Synaptophysin puncta was measured using multiple measurements per subregion, distinguishing superficial and deep cortical layers in the parahippocampus. Aβ and p‐tau load, and NfL immunoreactivity were quantified in manually segmented hippocampal and parahippocampal subregions. Clinical Dementia Rating (CDR) scores were retrieved from the clinical reports. Group differences were analysed using linear mixed models and correlations between synaptic and pathological measures and cognitive scores were studied using linear regression, correcting for age, sex and post‐mortem delay.ResultThe AD (para)hippocampus tended to have a lower synaptic density compared to controls (‐5.6%, p = 0.270). Within hippocampal and parahippocampal subregions, we observed synaptic loss in the entorhinal cortex in AD vs controls (‐8.9%, p = 0.028) and a trend for the subiculum (‐8.8%, p = 0.069) (Fig. 1). Synaptic degeneration was most pronounced in the deeper layers of the enthorinal cortex (layer V‐VI) (Fig. 2). Synaptic loss was not correlated with Aβ and p‐tau load, however higher NfL immunoreactivity associated with synapse loss in the fusiform gyrus (r = ‐0.467, p = 0.008). Synaptic degeneration in the CA1 (r = ‐0.769, p = 0.023), entorhinal cortex (r = ‐0.700, p = 0.035) and fusiform gyrus (r = ‐0.762, p = 0.014) was strongly correlated with higher CDR scores (Fig. 3).ConclusionThe entorhinal cortex is vulnerable to synapse degeneration in AD. Moreover, our results confirm the strong relation between (para)hippocampal synaptic loss, axonal damage and cognitive decline in AD, while neuropathological load (Aβ and p‐tau) could not explain differences in vulnerability across donors. These results suggest that the synaptic integrity in these regions seem to be important for cognitive function. A better understanding of the selective vulnerability of hippocampal subregions would provide insight into their intricate connections and functions, underpunning their involvement in cognitive decline.
Genetic proxies for predicting plasma protein levels reveal TIMP2 role in human cognitive performance
Authors: Anastasi Federica , Genius Patricia , Rodríguez‐Fernández Blanca , Escalante Armand González , Hernández‐Villamizar Luis Felipe , Lorenzini Luigi , del Campo Marta , Sánchez‐Benavides Gonzalo , Yang Chengran , Timsina Jigyasha , Minguillón Carolina , Esteller Manel , Navarro Arcadi , Cruchaga Carlos , Suarez‐Calvet Marc , Vilor‐Tejedor Natalia 
Published: January 2025

AbstractBackgroundMurine studies have identified blood proteins that influence brain aging, but translating these findings to humans remains challenging. We used an innovative approach to investigate whether genetically predicted blood levels of proteins linked to brain aging in animal models are associated with cognitive performance in individuals at risk of Alzheimer’s disease (AD) [Figure 1].MethodThrough systematic review, we identified 13 circulating proteins with an aging/rejuvenating effect on the mouse brain. We retrieved summary statistics of protein quantitative trait loci (pQTLs) associated with these proteins in human plasma from the Fenland study (Pietzner et al., 2021). We validated their predictive capacity by computing protein‐based genetic scores (protPRS) in 1,380 cognitively unimpaired (CU) individuals from the Knight‐ADRC cohort and analyzing their association with plasma protein levels (measured by Somalogic). We also computed the protPRS for 410 CU individuals at risk for AD from the ALFA+ study (60% women, 55% APOE‐ε4 carriers; Table 1) and assessed their associations with cognitive performance through linear models adjusted by age, sex, and years of education. Stratified models by sex, APOE‐ε4 carriership, and Aβ status were also assessed. pQTLs included in the significant scores were annotated to explore their biological significance.ResultMost computed protPRS (10/13) significantly predicted plasma protein levels in the Knight‐ADRC cohort. In ALFA+, we found a significant association between genetic predisposition to elevated plasma TIMP2 (TIMP2‐protPRS) and better cognitive performance (PACC and episodic memory composites). Associations of TIMP2‐protPRS with PACC remained significant in stratified models [Figure 2]. TIMP2‐protPRS was associated with the actual plasma TIMP2 levels in ALFA+. The annotated pQTLs included in the TIMP2‐protPRS were associated with traits related with cognition and neuropsychiatric disorders. We also found an age‐dependent expression of genes regulating blood TIMP2 levels in the human brain.ConclusionProtein‐based PRS computation may overcome translational challenges encountered in animal studies. Through this method, we showed that genetically predicted levels of plasma TIMP2, known for its rejuvenating effect on mice’s brain, are linked to cognitive performance in CU at risk of AD. This highlights TIMP2 as a potential therapeutic target for age‐related brain diseases.
Evaluating the link between hearing loss and Alzheimer’s disease neuropathology: A systematic review and meta‐analysis
Authors: Chandra Avinash , Levett Benjamin Aaron , Waters Sheena , Hardy Chris JD , Warren Jason D , Marshall Charles R 
Published: January 2025

AbstractBackgroundVarious explanations have been proposed for how hearing impairment might be associated with increased risk of dementia. Several theories have proposed direct links with Alzheimer’s disease (AD) neuropathology, either due to shared aetiology (i.e. AD proteinopathies cause impaired hearing), or due to an interaction (i.e. functional brain changes due to impaired hearing drive pathogenic protein accumulation). We performed a systematic literature review and meta‐analysis to evaluate evidence associating AD neuropathology (amyloid‐β and tau) with hearing loss.MethodSearches were conducted using electronic biomedical databases for articles published in the past 20 years. Studies evaluating hearing loss as an exposure and AD neuropathology using molecular biomarkers or histopathology as an outcome were included. Initial search identified 7,313 studies, which were screened, independently reviewed, and assessed for quality before being synthesised and meta‐analysed.ResultsStudies were highly heterogeneous, with mixed and inconsistent results. There was overall no strong evidence linking hearing loss with amyloid‐ β pathology, with some studies reporting weak effect sizes and others null results. Associations between hearing and tau pathology were more robust. Associations between hearing and neuropathology were stronger when hearing impairment was measured using more “central” tests of hearing than standard “peripheral” measures such as pure tone audiometry, suggesting that changes in the auditory brain may be a consequence of AD neuropathology.ConclusionThere is no strong evidence to suggest that changes in peripheral hearing are associated with AD neuropathology. Tests of central auditory function may signal AD neuropathological changes in auditory cortical areas. These results suggest the need for caution in developing hearing‐targeted interventions, such as hearing aid use, for prevention of neuropathological change due to Alzheimer’s disease.