bluuebunny/crossref_metadata_2025_split huggingface dataset:
Alzheimer’s disease genetic risk factors' influence on tau onset age
Authors: Deming Yuetiva , Teague Jordan P , Heston Margo B. , Hammad Yazan , De Chavez Elena Ruiz , Morse Jacob , Chappell Richard J , Langhough Rebecca E. , Zuelsdorff Megan L. , Engelman Corinne D. , Betthauser Tobey J. 
Published: January 2025

AbstractBackgroundNew methods developed to estimate when AD biomarkers became abnormal in individuals have shown considerable heterogeneity in amyloid and tau pathology onset age. This work used polygenic scores (PGS) generated from CSF Aß42 and ptau181 GWAS, individual‐level genetic data, and estimated tau onset age (ETOA) to identify genetic influences on tau onset beyond APOE.MethodParticipants from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) with genetic data, CSF biomarkers (Aß42 and ptau181), and longitudinal [18F]Flortaucipir (FTP) tau PET were analyzed (N = 462). Sampled iterative local approximation (SILA) was used to model longitudinal FTP meta‐temporal SUVR and generate ETOA for T+ and T‐ participants who could become T+, based on tau‐positivity (T+) defined using Gaussian mixture modeling (SUVR>1.41). Amyloid‐ and ptau‐PGS were generated from publicly available summary data, excluding the APOE region (±500kb). APOE neuropathology‐based scores (APOEscore) were used to test APOE. We analyzed individually a set of 14 SNPs that were previously associated with AD risk (P<1×10‐5) and both CSF biomarkers (P<0.05). Amyloid‐PGS, ptau‐PGS, APOEscore, and individual SNPs were tested as ETOA predictors using Cox regression modeling.Result73 (16%) participants were T+ by their last tau PET (Table 1). APOEscore was significantly associated with earlier ETOA (P = 1.10×10‐13; Figure 1) as was the amyloid‐PGS (P = 0.036), but ptau‐PGS was not (P = 0.166; Table 2). An intronic variant in complement receptor 1 (CR1), rs1408077 (A allele, MAFEUR = 0.19) which was previously associated with higher AD risk and AD‐associated changes of CSF biomarkers, was also significantly associated with earlier ETOA (P = 0.005; Figure 1). The association remained significant (P = 0.017) after adding the APOEscore (P = 3.93×10‐13) and both were still significantly associated with ETOA (Prs1408077 = 0.022 and PAPOEscore = 1.50×10‐6) after accounting for amyloid‐positivity (P = 3.91×10‐5; Table 2).ConclusionOur preliminary results support a key role for CR1 in the age when tau pathology becomes abnormal in AD. The tested variant, rs1408077, is in high linkage disequilibrium with a missense variant, rs2296160, and was previously associated with CR1 expression in the temporal cortex. This adds to previous studies that reported an interaction between CR1 and APOE‐e4 associated with episodic memory decline. Future work will include genome‐wide analyses of biomarker timing and multi‐trait analyses.
Exploring Sex‐Specific Accelerated Hippocampal Atrophy Across AD Stages beyond APOE‐e4 Assessment in Genetic Risk Evaluation
Authors: Evans Tavia E , Vilor‐Tejedor Natalia , Rodrigo Albert , Genius Patricia , Rodríguez‐Fernández Blanca , Anastasi Federica , Navarro Arcadi , Adams Hieab H.H. , Gispert Juan Domingo 
Published: January 2025

AbstractBackgroundCurrent evidence suggests that hippocampal subfields have partially different genetic architecture and may improve the sensitivity of the detection of Alzheimer’s disease (AD). In this study, we investigated whether genetic predisposition to AD contributes to the accelerated rate of hippocampal volume atrophy across sex and AD stages and how this contribution is specifically driven by functional variants located in the APOE gene.MethodsThe study comprised 1,051 participants from ADNI cohort (75.2 yo; 42.3% women), with complete demographic, genetic, and magnetic resonance imaging scans at baseline and every 6 months for a total of 96 months (Controls (amyloid negative), CUN = 363; mild cognitive impairment, MCIN = 474, AD patients, ADN = 214). Hippocampal subfields were extracted using the longitudinal processing method within FreeSurfer (v6.0). Genetic predisposition to AD was assessed through polygenic scoring with and without considering the APOE región. Effects of polygenicity of plasma APOE, functional APOE brain eQTLs and CSF pQTL were also considered. Linear mixed‐effect models with random‐ time slope and intercept for individuals were used to investigate the association between genetic predisposition to AD and hippocampal subfields volumetric trajectories over time. Models were adjusted by age, sex, AD disease status, years of education and total hippocampal volume. Disease and sex status‐specific trajectories dependent on genetics predisposition were assessed by including an interaction term.ResultsSignificant hippocampal subfield volume reductions were observed, with more pronounced atrophy in MCI and AD participants [Figure 1A]. High genetic predisposition to AD was associated with accelerated atrophy in various subfields [Figure 1B]. MCI individuals with high genetic predisposition showed more severe atrophy in several subfields, with sex‐related differences observed, particularly in women [Figure 2]. Notably, these effects were non‐significant when excluding APOE variants. Further functional analyses pinpointed CSF pQTLS of the APOE gene and APOE‐e4 carriership status as primary drivers [Figure 3].ConclusionsOur findings underscore the significance of genetic predisposition, especially functional APOE variants, in understanding AD progression and sex‐specific trajectories. The results reveal varying atrophy patterns across disease stages, offering crucial insights for refining AD detection and tailoring interventions for more effective management.
AI‐derived endophenotypes are causally associated with Alzheimer's disease
Authors: Wen Junhao , Toga Arthur W. , Davatzikos Christos 
Published: January 2025

AbstractBackgroundBrain morphology changes due to both natural aging and various pathological conditions. We used magnetic resonance imaging (MRI) and artificial intelligence (AI) to derive three brain age gaps (Wen et al., 2023b) [gray matter (GM), white matter (WM), and functional connectivity (FC)‐BAG] for brain aging and 9 dimensional neuroimaging endophenotypes (Wen et al., 2023a) [DNE: Alzheimer's disease (AD)1‐2, autism spectrum disorder (ASD)1‐3, schizophrenia (SCZ)1‐2, and late‐life depression (LLD)1‐2) for disease heterogeneity (a.k.a., subtypes). We applied genome‐wide association study (GWAS) summary statistics of the 3 BAGs, 9 DNEs, and two AD case‐control studies (Lambert et al., 2013; Wightman et al., 2021) to decipher the potential causality between these AI‐derived endophenotypes and AD (Fig. 1).MethodWe investigated whether the 3 BAGs and 9 DNEs (AD1‐2, ASD1‐3) were causally linked to AD using a bi‐directional two‐sample Mendelian randomization implemented in the TwoSampleMR R package (Hemani et al., 2018) with five different estimators. No individual data were used. The GWAS summary statistics of the 3 BAGs and 9 DNEs were performed using the UK Biobank data publicly available at https://labs.loni.usc.edu/medicine. The AD summary statistics are obtained at https://pgc.unc.edu/for‐researchers/download‐results/ for Wightman et al. and at https://gwas.mrcieu.ac.uk/ for Lambert et al., excluding the UK Biobank participants.ResultWe identified potential causal relationships from AD2, characterized by medial temporal lobe atrophy, to AD [P‐value=1.74x10‐4, OR (95% CI) = 1.25 (1.11, 1.40), number of SNPs=7], and AD to WM‐BAG [P‐value=7.18x10‐5, OR (95% CI) = 1.04 (1.02, 1.05), number of SNPs=13] (Fig. 1). Regarding the latter, our sensitivity check indicated the absence of apparent outlier SNPs or horizontal pleiotropy (Verbanck et al., 2018) (Egger estimator intercept: ‐2.22x10‐3±3.87810‐3, P‐value=0.57). All five estimators demonstrated consistent causal effects. The funnel plot displayed no noticeable asymmetry. Most IVs exhibited positive effects on AD, with three showing a negative association. Additionally, leave‐one‐out analyses indicated that no single IV dominated this causal relationship (Fig. 2).ConclusionThis investigation revealed a causal association between two AI‐derived endophenotypes and AD. These endophenotypes could be used to identify individuals at high risk of developing AD and select populations in future AD clinical trials.
Alzheimer’s disease APOE neuropathology‐based score, amyloid, and ptau polygenic scores' association with amyloid PET positivity
Authors: Hammad Yazan , Deming Yuetiva , Morse Jacob , Grover Ethan , Bendlin Barbara B. , Betthauser Tobey J. 
Published: January 2025

AbstractBackgroundAPOE is the greatest genetic risk factor for AD, however, other smaller genetic effects are often ignored. In this work, endophenotype‐informed polygenic scores (PGS) that exclude the APOE region were tested along with a separate, previously published, APOE neuropathology‐based score (APOEscore). The APOEscore serves as a more nuanced quantification of APOE genetic risk that considers the effects of the different haplotypes. PGS and APOEscore were compared to amyloid positivity, determined via PET imaging, which is used as a measure for AD risk and progression.MethodsAlzheimer’s Disease Neuroimaging Initiative (ADNI) participants with genetic data and Florbetapir (18F‐AV‐45) amyloid PET summary SUVR (whole cerebellum reference region) values were included in analyses. Amyloid positivity (A+) was defined as SUVR > 1.11. PGS were calculated using the weights from genome‐wide association studies (GWAS) of CSF Aß42 (amyloid‐PGS) or ptau181 (ptau‐PGS), after excluding the APOE region (±500kb). APOE effects were accounted for using the APOEscore that was calculated following Deming et al (2023).Results1094 participants (618 A+) were included in the analyses (Table 1). The APOEscore was significantly associated with A+ after accounting for sex and age at scan (OR = 2.931, P = 6.38e‐45; Table 2). The amyloid‐PGS was also significantly associated with A+ (OR = 0.492, P = 0.026), whereas the ptau‐PGS did not quite reach significance (OR = 3.218, P = 0.054). After adding the APOEscore, the effect of amyloid‐PGS on A+ remained but did not quite reach significance (OR = 0.515, P = 0.072) and ptau‐PGS was not significant (OR = 1.845, P = 0.375).ConclusionThese results validate the utility of the APOEscore with PET amyloid as well as the potential value of including non‐APOE genes in quantifying the genetic risk for amyloid accumulation and AD. The significant association between amyloid‐PGS and A+, and near significance after adding the APOEscore, demonstrates the existence of additional genetic effects outside of APOE that have an impact on amyloid accumulation. While the ptau‐PGS did not reach significance, possibly due to sample size, the OR (3.218) was greater in magnitude than the amyloid‐PGS (1/OR = 2.033). Future work will explore these relationships in other cohorts and with other PET AD biomarkers.
Image‐derived phenotypes in the AMYPAD Prognostic and Natural History Study
Authors: Pieperhoff Leonard , Lorenzini Luigi , Tranfa Mario , Padrela Beatriz E , Ritchie Craig W , Boada Mercè , Marquié Marta , Scheltens Philip , Vandenberghe Rik , Hanseeuw Bernard J , Martinez‐Lage Pablo , Payoux Pierre , Stephens Andrew W. , Buckley Christopher , Farrar Gill , Jessen Frank , Gispert Juan Domingo , García David Vállez , Mutsaerts Henk‐Jan , Collij Lyduine E. , Wink Alle Meije , Barkhof Frederik 
Published: January 2025

AbstractBackgroundThe Amyloid Imaging to Prevent Alzheimer’s Disease (AMYPAD) Prognostic & Natural History Study (PNHS) is a prospective longitudinal PET cohort of over 1,500 non‐demented individuals from 10 parent cohorts across Europe. We provide an overview of ongoing efforts to curate and integrate magnetic resonance imaging (MRI) multimodal images across sites and to extract biologically meaningful information (i.e., image‐derived phenotypes; IDPs) in this early AD population. Data will be made available on the ADDI platform (fair.addi.ad‐datainitiative.org).MethodImaging protocols included core (T1w, T2w, T2*, FLAIR) and advanced (rs‐fMRI, SWI, DWI, and ASL) MRI sequences. Figure 1 provides an overview of the different acquisitions, their corresponding pipelines, and the obtained IDPs. For T1w images, we computed regional volumes and thickness values using FreeSurfer v7.1.1 (surfer.nmr.mgh.harvard.edu/). Morphometric similarity networks were computed using MIND (github.com/isebenius/MIND). White matter hyperintensity volumes were obtained from FLAIR images using Bayesian Model Selection (BaMoS). With rs‐fMRI, mean functional connectivity of canonical networks were extracted using FSL MELODIC and dual‐regression analyses after preprocessing with fMRIPrep v23.0.1 (fmriprep.org). Diffusion MRI scans were processed with QSIprep v0.16 (qsiprep.readthedocs.io) to compute tract‐based spatial statistics and tractograms to build structural connectivity matrices. Finally, cerebral blood flow and the spatial coefficient of variation were computed from ASL images using ExploreASL (github.com/ExploreASL). Statistical harmonization was performed using RELIEF (github.com/junjypark/RELIEF).ResultBaseline and follow‐up characteristics of the 1537 subjects with available T1w are described in Table 1. Raw and statistically harmonized variants of 380 core and 298 advanced IDPs were calculated. Figure 2 shows the distribution of hippocampal volumes per site before and after statistical harmonization, and their relation with participants' age (R2raw=0.179, R2harmonized=0.422). Considering recent developments in the field, the AMYPAD PNHS aims to include additional IDPs associated with vascular health, such as perivascular spaces and other glymphatic system‐related markers.ConclusionWe present the pipeline built for MRI harmonization and feature extraction of the AMYPAD PNHS dataset. The extracted IDPs can help identify novel imaging outcomes, support the development of disease progression models for the preclinical stages of AD, and provide a reference point for future studies to promote replicability and robustness of findings.
Brain arteriolosclerosis is linked to lower gray matter volume in community‐based older adults
Authors: Tomash Ana , Tazwar Mahir , Yasar Md Tahmid , Bennett David A. , Schneider Julie A. , Arfanakis Konstantinos 
Published: January 2025

AbstractBackgroundBrain arteriolosclerosis is characterized by the thickening of vessel walls and arteriolar stenosis and is one of the primary pathologies of cerebral small vessel disease. Arteriolosclerosis is linked to lower cognitive and motor function, as well as an elevated risk of dementia. This study aimed to investigate the association of brain arteriolosclerosis with regional gray matter volumes in a large number of community‐based older adults.MethodData from ex‐vivo MRI and detailed neuropathological evaluation were collected from older adults (N=882) participating in four longitudinal, clinical‐pathologic cohort studies of aging (Rush Memory and Aging Project, Religious Orders Study, Minority Aging Research Study, and Clinical Core of the Rush Alzheimer’s Disease Research Center) (Figure 1A). Cerebral hemispheres from all participants were obtained at autopsy and imaged ex‐vivo with a multi‐echo spin‐echo sequence (ME‐SE) on 3T clinical MRI scanners approximately one month postmortem. The acquired voxel size was 0.6mm × 0.6mm × 1.5mm, and the scan time was approximately 30 minutes. The gray and white matter were segmented in the ex‐vivo MRI data. Subsequently, the gray matter underwent further division into 42 cortical and subcortical regions using multi‐atlas segmentation. The volume of each region was measured and normalized by the participant’s cerebral hemisphere volume. Following ex‐vivo MRI, a detailed neuropathologic assessment was performed on pathologies including arteriolosclerosis, atherosclerosis, cerebral amyloid angiopathy, gross and microscopic infarcts, Alzheimer's pathology, Lewy bodies, limbic‐predominant age‐related TDP‐43 encephalopathy neuropathological change (LATE‐NC), and hippocampal sclerosis (Fig. 1B). For statistical analysis, linear regression was employed to explore the association of brain arteriolosclerosis with regional gray matter volumes (normalized by cerebral hemisphere volume) controlling for all other neuropathologies (Fig. 1B), demographics (age at death, sex, years of education), postmortem intervals, and scanner (Fig. 1A).ResultMore severe brain arteriolosclerosis was associated with lower volume in several gray matter regions, including medial orbitofrontal, superior frontal, pericalcarine, cuneus, and lateral occipital areas, independently of the effects of other neuropathologies (Figs. 2, 3).ConclusionThis study demonstrated that brain arteriolosclerosis is associated with lower volume in multiple gray matter regions independently of the effects of other vascular or neurodegenerative pathologies.
[18F]SMBT‐1 PET can visualize the spatial distribution of reactive astrogliosis in patients with neurodegenerative dementias
Authors: Okamura Nobuyuki , Hiraoka Kotaro , Kobayashi Ryota , Tomita Naoki , Ishiki Aiko , Mesfin Berihu , Wu Yingying , Harada Ryuichi , Kikuchi Asuka , Takeda Kazuko , Kikuchi Akio , Furukawa Katsutoshi , Watabe Hiroshi , Mugikura Shunji , Kawakatsu Shinobu , Ishii Kenji , Nihashi Takashi , Kato Takashi , Furumoto Shozo , Tashiro Manabu 
Published: January 2025

AbstractBackgroundReactive astrogliosis refers to functional and morphological changes in astrocytes that occur with neuronal damage in numerous neurological conditions. PET tracers targeting monoamine oxidase B (MAO‐B) are used to visualize reactive astrogliosis in the living brain. [18F]SMBT‐1, a MAO‐B selective PET tracer, was developed by modifying the chemical structure of [18F]THK5351. This study investigates the changes in [18F]SMBT‐1 binding in the brains of patients with Alzheimer's disease (AD) and frontotemporal lobar degeneration (FTLD).MethodThe study involved 85 subjects, including healthy controls (HCs), subjects with mild cognitive impairment (MCI), patients with AD dementia, and FTLD including behavioral variant frontotemporal dementia (bvFTD) and semantic dementia (SD). To compare the regional standardized uptake value ratio (SUVR) values between disease groups, 30‐minute dynamic scans were conducted 60 minutes after administration of [18F]SMBT‐1. The cerebellar white matter was used as a reference region for calculating the SUVR values. PiB PET or flutemetamol PET was performed to confirm the existence of amyloid‐ß pathology in the brain.Result[18F]SMBT‐1 binding in the cerebral cortex was elevated in amyloid PET‐positive HC, MCI, and AD patients compared to amyloid PET‐negative subjects. The amount of SMBT‐1 binding in the neocortex correlated with changes in cognitive function of HC and MCI subjects. In addition, a distinct spatial pattern of [18F]SMBT‐1 retention was observed in patients with bvFTD and SD, consistent with areas of brain atrophy in the frontal and temporal lobes.ConclusionDistinctive patterns of [18F]SMBT‐1 binding were observed in the neocortex of AD and FTLD, indicating its usefulness for the differential diagnosis of dementia. The study also implies that reactive astrogliosis is present before dementia onset, associated with amyloid‐ß accumulation and cognitive decline.
Short‐term Sirolimus Treatment Increases Cerebral Blood Flow in Asymptomatic APOE4 Females Determined by 3T MRI
Authors: Neher Caitlin M. , Khegai Oleksandr , Overschmidt Jessica , Cassani Joanne , Xing Xin , Flemister Abeoseh , Green Stefan J. , Kurt Mehmet , Beversdorf David Q. , Xu Feng , Grinstead John W. , Balchandani Priti , Altes Talissa A. , Lin Ai‐Ling 
Published: January 2025

AbstractBackgroundApolipoprotein e4 allele (APOE4) is the strongest genetic risk factor for late‐onset Alzheimer’s disease (AD) with females having higher risk than males. Compared with non‐carriers, cognitively normal, middle‐aged APOE4 carriers have lower cerebral blood flow (CBF) decades before clinical symptoms appear. Early intervention to protect CBF would be critical for APOE4 carriers to mitigate AD progression. We have shown in APOE4 mice that Rapamycin (a.k.a. Sirolimus), a FDA‐approved mTOR‐inhibitor, can restore CBF. Here, in the first human study, our goal is to determine whether the findings translate to human APOE4 carriers by measuring CBF with MRI.MethodThe study was performed at the University of Missouri. Low dose Sirolimus (1 mg/day) was given for 4 weeks to two middle‐aged, cognitively normal APOE4 females (45‐65 yrs; MOCA>28). APOE status was determined by oral swabs. 3T MRI‐based pseudo‐continuous arterial spin‐labeled (PCASL, 1.7x1.7x4mm resolution) images were acquired at four time‐points: baseline (pre‐treatment), 2nd and 4th week into treatment, and washout (2 weeks post‐treatment). PCASL data was processed with FSL BASIL toolbox and regionally analyzed using FreeSurfer segmentation of T1‐weighted images.ResultAverage values of CBF (ml/100g/min) increased in all areas of investigation. When compared to baseline values, we observed an average 34.8±2.1% increase in washout CBF in the cortex across subjects (Fig. 1). Within the cortex, there was an average increase of 41.5±8.9, 28.2±6.2, 37.4±1.7, and 33.1±0.3% in the frontal, parietal, temporal and occipital lobes, respectively. White matter CBF showed a similar trend, increasing by 33.7±4.9% across subjects from baseline to washout (Fig. 2). Smaller AD‐associated regions were evaluated and also showed CBF improvement: the entorhinal cortex showed a 25.1±4.3% increase, while the hippocampus and amygdala showed a 21.4±1.1 and 23.6±9.8% increase, respectively (Fig. 3). No side effects were observed, and no changes in blood glucose and HbAc1 levels were found in the participants.ConclusionShort‐term Sirolimus treatment can effectively increase CBF for asymptomatic APOE4 females, who have the highest risk for AD. Future work will include APOE4 males, increase the sample size and compare CBF with non‐carriers (e.g., APOE3/APOE2). Restoration of CBF may pave a way to mitigate or prevent AD developments for APOE4 carriers.