bluuebunny/crossref_metadata_2025_split huggingface dataset:
The association of APOE with Alzheimer’s Disease in four Hispanic cohorts
Authors: Tosto Giuseppe , Barber Robert , Phillips Nicole , O'Bryant Sid E. 
Published: January 2025

AbstractBackgroundThe long‐term goal of Health & Aging Brain Study – Health Disparities (HABS‐HD) is to establish population‐specific informed precision medicine for novel treatment and prevention strategies as has been done in other fields. Genomic studies are integral to these efforts and contribute vital data regarding genetic ancestry of the HABS‐HD participants, as well as whole genome sequence data, genome‐wide genotype (Illumina Global Screening array version 3.0) and epigenetic data (Illumina EPIC DNA methylation array).MethodWe evaluated the association of APOE with Alzheimer’s Disease and Related Dementia (ADRD) in four different Hispanic populations: Mexicans in the Mexican Health and Aging Study (MHAS), Caribbean Hispanics in the Washington Heights Inwood Aging project (WHICAP) and Estudio Familiar de Influencia Genetica en Alzheimer (EFIGA), Peruvians in the Genetics of Alzheimer’s disease In Peruvian Populations (GAPP) and Mexican Americans from The Health & Aging Brain among Latino Elders (HABLE) and the Texas Alzheimer’s Research and Care Consortium (TARCC). Analyses were adjusted for age (≥60 years old), sex, and education. Global ancestry proportions, Native Americans (NAA), European (EUR), African (AFR) were estimated with ADMIXTURE software using the Human Genome Diversity Project as the reference panel. Specific secondary analyses of genetic ancestry were conducted using the same models.ResultThe genetic ancestral composition was significantly different across cohorts. Peruvians and Mexicans showed a predominant NAA ancestry, Caribbean‐Hispanics appeared to have a major contribution of European and African ancestry, and Mexican‐Americans exhibited similar proportions of both European and Native ancestries. We observed a significant association with the ε4 allele dosage in all the cohorts. The strongest association between APOE‐ε4 and risk for ADRD was observed in the Peruvian population (OR = 6.05, 95%CI = 3.01‐12.40). The genetic effect of at least one copy of the ε4 allele on ADRD risk was very similar in WHICAP+EFIGA, HABLE/TARCC and MHAS (OR = 2.52, 95%CI = 2.22‐2.85, OR = 2.86, 95%CI = 1.94‐4.22, OR = 2.76, 95%CI = 1.52‐5.02, respectively). Overall, random‐effect metanalysis estimated the ε4 OR for ADRD at 2.56 (95%CI = 2.26‐2.87).ConclusionTo our knowledge, this is the largest collection of Hispanic participants phenotyped for ADRD. Our results showed a differential risk for ADRD from the APOE‐ε4 allele across populations with admixed genetic ancestry.
Nuclear HMGB1 Loss in the Aging Brain Triggers cGAS‐STING Pathway and Neuroinflammation that Contributes to Senescence and Cognitive Decline in Tauopathies
Authors: Gaikwad Sagar , Haque Md Anzarul , Samples Madison , Xavier Rhea , Jerez Cynthia , Al‐Shaebi Fadhl , Kayed Rakez 
Published: January 2025

AbstractBackgroundAging, tau pathology, and chronic inflammation in the brain play crucial roles in neuroinflammation, synaptic loss, neurodegeneration, and cognitive decline in tauopathies, such as Alzheimer’s disease. However, the molecular mechanisms that trigger aberrant chronic inflammatory signaling in tauopathies are poorly understood.MethodWe utilized brain tissues from tauopathy patients and the tauopathy mouse models. Our study involved immunofluorescence microscopy and biochemical assays to investigate the role of nuclear HMGB1 in DNA damage, brain inflammation, senescence, and cognitive dysfunction. We evaluated impact of HMGB1 knockdown on tau pathology (including phospho‐tau, tau oligomers, and neurofibrillary tangles), senescence, inflammation, synaptic and postsynaptic proteins, as well as cognitive functions using the Y‐maze and novel‐object recognition tests.ResultHere, we show that nuclear high mobility group box 1 (HMGB1) protein is reduced in the brains of human tauopathy patients and mouse models of tauopathies. Knockdown of nuclear HMGB1 using AAV‐based shRNA resulted in increased DNA‐damage and activation of the cyclic GMP–AMP synthase stimulator of interferon genesis (cGAS–STING) signaling pathway in the brain of hTau tauopathy mice. The activation of cGAS–STING upon HMGB1 knockdown induced inflammatory phenotypes of senescent cells and promoted neuroinflammation, tau pathology, synaptic loss, and cognitive decline in hTau mice. Further investigations in human tauopathy brains revealed that HMGB1 loss enhances DNA damage, and cytosolic DNA release, activating cGAS signaling and bystander inflammation.ConclusionOur findings demonstrate that during tauopathies, the loss of nuclear HMGB1 leads to DNA‐damage and triggers activation of the cGAS–STING pathway, contributing to aging‐related inflammation, tau pathology and synaptic loss in the brain, and ultimately leading to cognitive decline.
Evaluate the Efficacy of the Axl inhibitor Bemcentinib in the 5xFAD mouse model of Alzheimer’s Disease
Authors: Chen Guyin , Ozturk Gizem , Porta Sílvia , Lee Virginia M.‐Y. 
Published: January 2025

AbstractBackgroundAlzheimer’s disease (AD) is a neurodegenerative disease characterized by the presence of phosphorylated tau neurofibrillary tangles and extracellular deposits of amyloid beta plaques (Aβ) in the brain. Microglia cells have been proposed to be involved in amyloid plaque formation since activated microglia produce inflammatory cytokines that contribute to a hostile neuronal environment, exacerbating AD pathogenesis.MethodWe aim to evaluate if the pharmacological inhibition of the myeloid/microglial receptor tyrosine kinase AXL, with bemcentinib (BGB) could be used as a novel therapeutic approach for AD. The objective is to evaluate the efficacy of the BGB inhibiting Axl activity in the brain of the 5xFAD mouse model, which recapitulates pathological hallmarks of AD, including Aβ plaques formation and overactive microglia. We evaluated target engagement and performed an efficacy study in 5xFAD and WT mice orally dosed with BGB and Vehicle (Veh) as control. Mice were dosed twice a day for 1 week. Mice were anesthetized to collect CSF and plasma and perfused to obtain their brains.ResultIn the present work, we have used the pharmacological Axl inhibitor BGB, to evaluate the therapeutic potential of targeting Axl signaling in 5xFAD mice. We have evaluated the effect of Axl inhibition measuring changes in total Axl levels and its soluble fragment (sAxl) across the hippocampus, plasma, and CSF of 5xFAD mice and WT mice. As expected, we found a significant upregulation of Aβ plaques and microglia in 5xFAD mice, and interestingly, a concomitant upregulation of Axl levels in the hippocampus of 5xFAD mice. We observed, although not statistically significant, a trend of increasing levels of sAxl in CSF and plasma of mice receiving BGB. Unfortunately, no significant effect of BGB drug was detected in 5xFAD mice when Aβ‐plaque burden and Iba1 immunoreactivity was measured after the treatment.ConclusionOverall, the preliminary findings do not show a significant effect of Axl inhibitor BGB in the brain. The reduced BBB penetrance of the drug could be a potential explanation for lack of significant changes in Axl levels and microglia activation. Further studies of increasing dosing time and cohort size could potentially improve the outcome.
Spatial proteome profiling for distinguishing tangle‐bearing neurons and their microenvironments from healthy neurons in Alzheimer’s disease brains
Authors: Dehkordi Shiva Kazempour , Orr Timothy C. , Bodamer Ryan H , Hudson Hannah R. , Sun Victoria , Keene C Dirk , Zare Habil , Orr Miranda E. 
Published: January 2025

AbstractBackgroundAn important hallmark of Alzheimer’s Disease (AD) is the presence of neurofibrillary tangles (NFTs) composed of phosphorylated tau, which are commonly assessed using AT8 immunostains. Identifying additional markers to characterize the spectrum of NFT pathology is crucial for advancing our understanding and diagnosis of AD. This study introduces new potential markers to differentiate between tangles and healthy neurons.MethodPostmortem human AD brains were analyzed using GeoMx (NanoString, Inc) digital spatial profiling. The analysis focused on specific regions of interest (ROIs) in the hippocampal CA1 and entorhinal cortex (EC) region of the brain, chosen for their presence or absence of AT8. We measured the levels of 85 proteins associated with neuropathology, inflammation, and autophagy across these ROIs. Differentially expressed (DE) proteins in NFTs versus healthy neurons were identified. The top 10 DE candidate proteins were used to construct an eigengene, a weighted average expression of proteins, to summarize biological signatures. We also trained a classifier using a non‐linear support vector machine to distinguish NFTs from healthy neurons, which is validated on an independent unlabeled dataset.ResultTau phosphorylation at four specific epitopes, S199, S214, S396, and S404 were significantly elevated in tangle‐bearing neurons in both CA1 and EC (Fig. 1a‐b). Other top DE proteins, including P62, Neprilysin, Ubiquitin, and PSEN1, were also highlighted. Specifically, an eigengene combining these proteins exhibited distinct clusters separating AT8‐positive and negative cells (Fig. 1c). Our classification models using these markers as well as phosphorylated tau proteins showed significant concordance with AT8‐based labels, suggesting their potential as alternative diagnostic tools (Fig. 1d). Validating the association of each of these markers with tangles across the adult lifespan and with AD progression informs on the time course of their upregulation in relation to tau phosphorylation.ConclusionThis study identifies alternative markers, particularly phospho‐tau epitopes S214, S396, S404, and other proteins including P62, Neprilysin, and Ubiquitin for tangle‐bearing neurons. These markers are promising to improve AD diagnosis and fill gaps in knowledge regarding molecular pathogenesis of NFTs, paving the way for possibly earlier and more accurate detection and intervention strategies
Comparing driving behaviors and physiological features of older adult drivers with and without elevated amyloid burden
Authors: Kumar Anu M , Murphy Yi Lu , Maher Amanda Cook , Persad Carol C , Flynn Emma , Bross Jordan R , Koeppe Robert A. , Giordani Bruno 
Published: January 2025

AbstractBackgroundIdentifying markers for increased risk of cognitive change and early Alzheimer’s disease (AD) is key to enhancing the effectiveness of treatments. Changes in instrumental activities of daily living, including the complex task of driving, may serve as potential markers to identify older adults at risk of cognitive decline. This study evaluates driving behaviors and associated physiological signals in older adults with and without elevated brain amyloid burden.MethodVideo and physiological data from 21 amyloid positive and 21 amyloid negative consensus diagnosed cognitively normal participants over the age of 65 who participated in the University of Michigan’s Driving and Physiological Responses study were analyzed. Amyloid positivity was determined based on the PET centiloid scale. All drivers completed the same fixed course route. Road‐ and driver‐view videos of each participant were annotated to mark 40 key road events and driving behaviors, such as right turns and looking at the rear‐view mirror. Heart rate (HR) and electrodermal activity (EDA) data collected through an Empatica E4 watch were analyzed for each road/driving event (e.g., average HR during freeway entrance). Independent sample t‐tests with α’s = 0.05 were used to look for differences between amyloid positive and negative groups.ResultHR responses to intersections without signs and freeway entrance ramps were consistently higher among amyloid positive drivers compared to amyloid negative drivers (p’s<0.05). Furthermore, amyloid positive drivers showed a pattern of lower EDA responses to freeway exit ramps than amyloid negative drivers (p<0.05).ConclusionCognitively normal amyloid positive older drivers demonstrated consistently higher HR and lower EDA in key driving situations compared to their amyloid negative peers. Findings suggest physiological responses of older drivers under different driving conditions may represent markers for identifying those individuals at higher risk of future cognitive decline. These results can be used to build an accurate and generalizable Machine Learning‐based AD diagnostic tool to detect early‐stage AD in drivers.
Do Alzheimer Disease genetic loci influence the risk of Age‐Related Macular Degeneration?
Authors: Moore Noel C. , Song Yeunjoo E. , Lynn Audrey , Miskimen Kristy L. , Wang Weihuan , Laux Renee A. , Fuzzell Sarada L. , Hochstetler Sherri D. , Caywood Laura J. , Clouse Jason E. , Herington Sharlene D. , Nittala Muneeswar Gupta , Sadda SriniVas R , Stambolian Dwight , Lerner Alan J. , Vance Jeffery M. , Cuccaro Michael L. , Scott William K. , Pericak‐Vance Margaret A. , Haines Jonathan L. 
Published: January 2025

AbstractBackgroundAlzheimer’s Disease (AD) and Age‐Related Macular Degeneration (AMD) are two age related neurodegenerative diseases that share multiple characteristics, including deposition of amyloid beta. In AD, amyloid plaque accumulation contributes to neurological dysfunction, while in AMD amyloid is a component of the hallmark retinal drusen complexes that lead to degeneration of central vision. Both diseases have significant and opposite risk due to the APOE e4 and e2 alleles. Investigation into other potential genetic similarities between the two diseases is warranted.MethodsVariants from the recent AMD meta‐analysis (Fritsche et al., 2016) and AD meta‐analysis (Bellenguez et al., 2022) were utilized to generate genetic risk scores (GRS) in an Amish founder population. 1293 individuals (1120 controls and 173 cases) were included in the AD analysis and 654 individuals were included in the AMD analysis (334 controls and 320 cases). AMD‐only and AD‐only GRSs were applied separately to both AMD and AD. We then combined both the AMD and AD variants into a single GRS applied to each disease. We subsequently removed AD SNPs sequentially from the GRS to identify any AD variants that might improve the association with AMD.ResultsAs expected, the AD‐only GRS successfully predicted AD (p = 0.01). However, the AMD‐only GRS was less successful in predicting AMD (p = 0.145). The combined AD/AMD GRS was more successful in predicting AMD (p = 0.12) than the AMD‐only GRS, while AD prediction decreased in performance (p = 0.67) compared to the AD‐only GRS. The sequential analysis identified thirteen AD variants that improved the AMD‐only GRS when combined with the AMD variants (p = 0.06).ConclusionsWhile the AD‐only GRS was most successful in predicting AD, the AD/AMD GRS outperformed the AMD‐only GRS in predicting AMD. These results suggest that several AD loci in addition to APOE may also influence AMD.
Sex‐specific genetic regulation of proteomics in cerebrospinal fluid uncovers genetic causes for sex differences in neurodegeneration
Authors: Sung Yun Ju , Wang Lihua , Western Daniel , Timsina Jigyasha , Gorijala Priyanka , Ruiz Agustin , Pastor Pau , Chen Han , Cruchaga Carlos 
Published: January 2025

AbstractBackgroundClear sex differences exist in AD and PD. Several studies examined genetic regulations for AD phenotypes and gene expression data in a sex‐specific manner, identifying some differences between males and females. In contrasts, although proteins are final effectors of most physiological pathways and important drug targets, sex‐specific regulations for proteins remain vastly understudied. This study therefore aims to investigate sex‐specific genetic regulation of proteomics in neurologically relevant cerebrospinal fluid (CSF).MethodWe recently identified 3,885 protein quantitative loci (pQTL) for 1,883 proteins, many of which were unique to CSF, demonstrating genetic regulation specific to the CSF proteome. Here, we performed a sex‐stratified pQTL (in 1,640 males and 1,713 females, separately) with >7000 proteins (SomaScan7K) on ∼13 million TOPMED imputed autosomal variants. pQTL considered significant at P<5 × 10‐8 (in cis) and P<3.45 × 10‐11 (in trans) in either sex. We subsequently examined shared genetic regulation using colocalization with neurodegeneration and psychiatric diseases.ResultWe identified 3,179 significant pQTLs (1,210 cis and 1,969 trans) in either sex in 726 genetic loci for 1,794 proteins. While 69.4% of pQTLs had similar regulation in both sexes, 21.1% (173 female‐specific; 220 male‐specific) were significant only in one sex. For example, pQTL for IST1 at rs71709684 (MAF = 0.047) on chr16 was female‐specific, significant only in females (β = 0.43, P = 4.40 × 10‐8 in females vs β = ‐0.02, P = 7.89 × 10‐1 in males). In addition, 8.5% (47 female‐biased; 97 male‐biased) were significant in both, but with different magnitudes. The PD locus LRRK2 on chr12 regulated several proteins (GRN, GPNMB, ITGB2), enriched in microglia, in males only. As the most pleiotropic region, the APOE region on chr19, the strongest AD locus, sex‐specifically regulated multiple proteins relevant to AD (PPP3R1, YWHAZ, PPP3CA, amyloidosis‐related NRXN2, VSNL1, and dementia‐related TIMM8A), enriched in neurons. The female‐specific pQTL of PLOD3 on chr17 colocalized with alcoholism, testosterone levels, and sex hormone‐binding globulin (SHBG). The male‐specific pQTL of NRXN2 on chr19 colocalized with AD, along with SHBG and telomere length.ConclusionBy performing sex‐stratified pQTL, we uncovered distinctive sex‐specific genetic regulation of CSF proteome. Our findings complement sex‐aware eQTL from GTEx and provide insights on dissecting the underlying biological causes and mechanisms contributing to sex differences in neurodegeneration.
DCTclock metrics differentiate between amnestic and vascular mild cognitive impairment
Authors: Haas Brendan , Jannati Ali , Showalter John , Bates David , Tobyne Sean , Pascual‐Leone Alvaro 
Published: January 2025

AbstractBackgroundAmnestic and vascular dementia are two common types of dementia. Currently, diagnosing and differentiating between these two conditions requires comprehensive neuropsychological testing, neuroimaging studies, and cerebrospinal fluid analysis. Identifying these conditions at early stages, i.e., mild cognitive impairment (MCI), is crucial for maximizing the therapeutic benefits of pharmacological agents or lifestyle modifications. Here we evaluated the utility of metrics derived from the DCTclock, a brief ML‐enabled digital cognitive assessment, in differentiating between amnestic and vascular MCI.MethodWe analyzed DCTclock tests from N = 215 participants (age 48‐90, 126 females, education = 6‐20 yrs) including patients at Lahey Hospital and Medical Center and participants in the Framingham Heart Study, for whom a diagnosis of vascular (n = 46) or amnestic (n = 169) MCI was available. Mann‐Whitney U Tests were used to compare the distributions for 78 features derived from the DCTclock performance. Random forest models with recursive feature elimination and 5‐fold cross‐validation were used to differentiate between the two MCI subtypes.Result16 DCTclock features returned p‐values below the 0.05 threshold for statistical significance, and one feature reached the Bonferroni‐corrected threshold of 6.4e‐4. The features showing the largest difference between the two populations were the total time to complete the copy clock (p = 4.2e‐4), drawing process efficiency on the copy clock (p = 1.7e‐3), and average latency on the copy clock (p = 3.7e‐3). 13 of the 16 top features were derived from the copy clock test. A random forest model using only 6 features (figure below) returned an accuracy of 77.9%.ConclusionMetrics derived from the process of DCTclock performance, especially those obtained during the copy clock condition, showed utility for differentiating between vascular and amnestic MCI. Comparing cognitive phenotypes at the early stage of MCI is arguably a more difficult task than comparing those phenotypes among individuals who have progressed to dementia and thus exhibit more pronounced signs of cognitive impairment. More data from individuals with such cognitive profiles are needed for building robust ML models that can differentiate among MCI subtypes with higher accuracy.
Therapeutic approach in an Alzheimer’s Disease rat model through GDNF overexpression by an astrocyte‐selective adeno‐associated virus
Authors: Escobedo Ana Abril Vidal , Peralta Facundo , Reggiani Paula Cecilia , Pardo Joaquín 
Published: January 2025

AbstractBackgroundSporadic Alzheimer’s disease (sAD) is the most common form of dementia, characterized by a progressive decline in cognitive function and, cortical and hippocampal atrophy. Our objective is to develop neuroprotective therapies that promote the homeostatic and modulatory properties of astrocytes, and enhance their protective functions. Glial‐derived neurotrophic factor (GDNF) has emerged as a promising factor for its ability to promote neuronal survival and function. However, the therapeutic potential of GDNF in AD remains uncertain. Consequently, we explored it in the sAD model induced by intracerebroventricular (icv) streptozotocin (STZ) in rats.MethodWe produced serotype 9 bicistronic adeno‐associated viruses (AAV), expressing GDNF and GFP (control), driven by the gfaABC1D promoter, targeting astrocytes expressing glial fibrillary acidic protein (GFAP). AAVs were characterized using RT‐qPCR and immunohistochemistry (IHC). For therapeutic approach, young male rats were divided into 4 groups: SHAM, STZ, GFP, and GDNF. On Experimental Day (ED) ‐28, animals received bilateral intrahippocampal injections of artificial cerebrospinal fluid (aCSF) (SHAM and STZ groups) or AAV‐GFP/GDNF (GFP and GDNF groups). On ED 0, animals received bilateral icv injections of aCSF (SHAM group) or STZ (3mg/kg) (STZ, GFP, and GDNF groups). Between ED +17/+26, behavioral tests were conducted to evaluate species‐typical behavior, object recognition memory, and spatial memory.ResultAAV‐GDNF and AAV‐GFP were generated, and the overexpression of transgenes was confirmed by RT‐qPCR and IHC. In the therapeutic approach, animals belonging to STZ and GFP groups showed significant deterioration in all assessed behaviors. GDNF overexpression prevented cognitive impairment in treated animals, as they showed no significant differences compared to the SHAM group in the analysed parameters. Additionally, AAV‐GDNF treatment promoted an increase in branching and length of processes in the analysed astrocytesConclusionWe investigated an innovative therapeutic method specifically focused on hippocampal astrocytes. This allowed us to overexpress GDNF, generating protective actions that mitigated behavioral and cognitive alterations in our sAD animals. Furthermore, by acting on the brain’s astrocyte population, promoting an increase in their complexity, we could potentially have a positive effect on maintaining cerebral homeostasis.