bluuebunny/crossref_metadata_2025_split huggingface dataset:
In vivo testing of the role of Alzheimer’s disease coding variants
Authors: Sasner Michael , Oblak Adrian L. , Garceau Dylan , Kotredes Kevin P. , Preuss Christoph , Pandey Ravi S. , Uyar Asli , Lamb Bruce T. , Carter Gregory W. , Howell Gareth ,   MODEL‐AD Center
Published: December 2020

AbstractBackgroundNumerous AD risk loci and variants have been identified by large‐scale genetic studies, but few have been functionally verified and models to study their mechanism of action are lacking. The Model Organism Development and Evaluation for Late‐onset AD (MODEL‐AD) Center was created to develop, characterize, and distribute more precise preclinical models for late‐onset AD (LOAD) by engineering these disease‐associated variants into mouse models, and characterizing the resulting phenotypes using clinically relevant assays.MethodDiverse criteria including replication in multiple studies, predicted pathogenicity of variant, sequence conservation between human and mouse, and expression in relevant cell types were used to prioritize risk variants, which were then engineered into a mouse model that expresses the AD risk variants APOE4 and Trem2*R47H. Primary screening was done by transcriptomic analysis using the nanoString Mouse AD Panel at 4, 8, and 12 months.ResultBioinformatics studies enabled us to prioritize coding variants in the Abca7, Clasp2, Mthfr, Mtmr4, Plcg2, Shc2, Slc6a17, Snx1, and Sorl1 loci. Knockouts of Abca7, Ceacam1, Il1rap, and Plcg2 have also been created to model human loss of function variants. Transcriptomic analysis demonstrated that the Abca7*A1527G and Mthfr*C677T models exhibited some age‐dependent similarities to transcriptomic changes seen in post‐mortem samples from the AMP‐AD cohort. These will move on to deep phenotyping out to 24 months of age. Analysis of other models are still in progress and will be presented. Humanized APP and Tau (MAPT) models are also in progress.ConclusionWe have prioritized Abca7*A1527G and Mthfr*C677T models to be comprehensively characterized up to 24 months of age in the MODEL‐AD program. We will discuss our approach to prioritize genetic variants, develop novel models relevant to LOAD, and use clinically relevant measures to determine which models are most useful for translational studies. All models are made available for both academic and for‐profit use from The Jackson Laboratory, and all validation data will be shared via the AMP‐AD knowledge portal. For more information see www.model‐ad.org.
Integration of Alzheimer’s disease genetics and myeloid genomics reveals novel disease risk mechanisms
Authors: Novikova Gloriia , Marcora Edoardo , Kapoor Manav , TCW Julia , Renton Alan E. , Efthymiou Anastasia M. , Abud Edsel M. , Bendl Jaroslav M. , Cheng Haoxiang M. , Fullard John F. , Roussos Panos , Poon Wayne W. , Hao Ke , Goate Alison M. 
Published: December 2020

AbstractBackgroundGenome‐wide association studies (GWAS) have identified more than forty loci associated with Alzheimer’s disease (AD), but the causal variants, regulatory elements and genes remain largely unknown, impeding a mechanistic understanding of AD pathogenesis.MethodWe used an integrative genomic approach to determine the epigenomic annotations enriched for AD risk variants and applied a summary‐data based Mendelian Randomization to link myeloid enhancer activity to target gene expression regulation and AD risk modification.ResultWe show that AD risk variants are specifically enriched in active enhancers of monocytes, macrophages and microglia, nominate candidate AD risk enhancers and identify their target causal genes (including AP4E1, AP4M1, APBB3, BIN1, CD2AP, MS4A4A, MS4A6A, PILRA, RABEP1, SPI1, SPPL2A, TP53INP1, ZKSCAN1, and ZYX) in sixteen loci. Fine‐mapping of these enhancers nominates candidate functional variants that likely modify disease susceptibility by regulating causal gene expression specifically in myeloid cells. In the MS4A locus we identified a single candidate functional variant within an CTCF binding site, that is predicted to alter chromatin looping and MS4A gene expression. We used human induced pluripotent stem cells (hiPSC)‐derived microglia to provide experimental validation of this putative causal variant.ConclusionCombined, these results strongly implicate dysfunction of myeloid cell endo‐lysosomal pathways involved in clearance of lipid rich debris in the etiology of AD.
Does suppressing one’s emotions increase the risk of all‐cause dementia among older adults?
Authors: Lisko Inna , Hall Anette , Håkansson Krister , Neuvonen Elisa , Kulmala Jenni , Ngandu Tiia , Solomon Alina , Kivipelto Miia 
Published: December 2020

AbstractBackgroundAn increasing body of evidence is showing that psychological risk factors are associated with Alzheimer’s disease (AD) and other dementias. However, limited data exists on the effects of suppressing one’s emotions on dementia/AD risk. The aim of the study is to explore if suppressing one’s emotions is associated with a risk of all‐cause dementia in a population‐based sample of older adults.MethodThe study uses data from a Finnish population‐based Cardiovascular Risk Factors, Aging and Dementia (CAIDE) study. In 1998, altogether 1137 individuals aged 65 to 79 years (mean 70.9 years) without dementia/AD responded to an inventory on ways of coping, where it was asked to describe how they usually respond to adverse events in life. For the statement “I suppressed my emotions from others”, the response options ranged from 4 (fully agree) to 1 (fully disagree). Data on all‐cause dementia incidence were derived from clinical diagnoses during follow‐up in 2005–2008 and from a national register till the end of year 2009. Cox proportional hazards model was used in the analyses which were adjusted for age, gender, APOE ε4 allele, smoking, obesity and education.ResultIndividuals who reported to fully agree on suppressing their emotions had nearly five times higher risk of developing dementia/AD as compared to those who fully disagreed on suppressing their emotions (Hazard ratio [HR] 4.93, 95% Confidence Interval [CI] 1.11–21.93). For those who fairly well agreed (HR 2.05, 95% CI 0.48–8.84) and quite strongly disagreed (HR 1.51, 95% CI 0.33–6.88) on suppressing their emotions the results were statistically non‐significant.ConclusionWhen facing adverse events in life, suppressing one’s emotions appears to be associated with an increased risk of developing dementia/AD. Further studies are needed to explore the mechanisms behind the found association.
Autistic spectrum behaviors in late‐life dementia are associated with an increased burden of neurofibrillary tangles in the frontal lobe
Authors: Rhodus Elizabeth K. , Barber Justin M. , Bardach Shoshana H. , Nelson Peter T. , Jicha Gregory A. 
Published: December 2020

AbstractBackgroundPrevious clinical studies have described autism spectrum‐like behaviors in approximately 16% of late‐onset dementia cases. The neuropathologic substrate for such behaviors is currently unknown, but may shed light on shared neuroanatomic and molecular pathways involved in these otherwise distinct forms of brain dysfunction. This study investigates the hypothesis that subjects with late onset dementia associated with autism‐like behaviors will exhibit increased pathologic features in both the frontal and parietal association cortices.MethodAn age, education, and gender‐matched case‐control design was used. Subjects were recruited from the University of Kentucky Alzheimer Disease Center longitudinal autopsy cohort. Subjects had a diagnosis of MCI or dementia at the time of completion of the Gilliam Autism Rating Scale‐2 (GARS‐2) in addition to standard clinical, genetic, and cognitive assessments (n = 148). Those who have come to autopsy demonstrating either no evidence of (n = 24) or a high level of (n = 19) autism‐like behaviors on the GARS‐2 were included. Comprehensive neuropathologic evaluation included assessment of all common late‐life dementia pathologies using both semiquantitative rating scales and digital quantitative measures of global and regional pathological features.ResultBetween group analyses demonstrated no significant differences in age, education, gender, clinical diagnosis, or apoE4 status. High‐autism vs. no‐autism cases scored significantly higher on the Clinical Dementia Rating scale (p < 0.05). Approximately 80% of cases had a primary pathologic diagnosis of Alzheimer’s disease, with the remaining 20% of individuals demonstrating pathologic features consistent with LATE (16%), cerebrovascular (2%), or Lewy body disease (2%). No cases had frontotemporal lobar degeneration (FTLD) as a primary or comorbid pathology. Quantitative measures of neurofibrillary tangles and tau burden were higher in the frontal lobes of high‐autism subjects compared to the matched no‐autism controls (p < 0.02).ConclusionThese data are the first to link autism‐like behaviors to increased levels of tau and neurofibrillary pathology in the frontal lobes at autopsy in subjects with late‐life dementia. Yet, the present data demonstrate that FTLD pathology is not a major contributor to such behaviors in a community‐based cohort of late‐life dementia. Further work understanding potential links between tau‐mediated neurodegeneration and autism‐like behavior is warranted.
The Alzheimer's Prevention Registry: Accelerating recruitment and enrollment into Alzheimer's‐focused studies
Authors: High Nellie M , Kettenhoven Cassandra L , Graf Hayley , Reiman Eric M , Tariot Pierre N , Langbaum Jessica B 
Published: December 2020

AbstractBackgroundThe Alzheimer’s Prevention Initiative (API) is a collaborative program conducting preclinical Alzheimer’s disease (AD) trials in people who are at elevated risk of developing AD symptoms. To support these and other trials, we developed the web‐based Alzheimer’s Prevention Registry (“APR”) program to provide resources to the AD scientific community, aiming to accelerate recruitment and enrollment into studies and complement local efforts.MethodAdults age 18+ are eligible to join APR at www.endALZnow.org. At enrollment, individuals provide their name, email address, zip/postal code and year of birth; after enrollment they provide additional demographic information at their convenience with the option to select “prefer not to answer.” The APR team works with researchers to promote AD‐focused studies to members via its website and email. APR members receive email communication for engagement purposes and are notified when new study opportunities are available. Members interested in a study fill out an online contact form with their name, email address and phone number, review and acknowledge the study’s eligibility criteria and authorization for APR to share their contact information with the enrolling study team. The APR team provides enrolling studies with a secure dashboard for tracking referrals.ResultThe APR launched in May 2012; as of January 2020, >347,000 have joined. APR members have a mean age of 63.3 years (SD 11.7), are predominately female (75%), self‐report being cognitively unimpaired (94%), and 50% report a family history of AD/dementia. To date, the APR has promoted 82 AD‐focused studies, results from which will be presented. Only anecdotal enrollment metrics are available prior to the launch of the online contact form, however web‐traffic metrics that are available from our promotions of online studies (e.g., TRC‐PAD, Brain Health Registry) suggest >16,000 APR members expressed interest in joining these studies. The 6‐month pilot phase of the online contact form included 7 studies and referred 320 APR members.ConclusionEnrollment into the APR continues to increase, as does the number of studies the APR promotes to its members. We are exploring novel approaches for increasing enrollment and engagement of members, and collaborating with researchers and sponsors to help promote studies in their communities.
Clinico‐genetic study of two Japanese pedigrees with hereditary spastic paraparesis and Alzheimer's disease
Authors: Rumore Roberto , Montecchiani Celeste , Gaudiello Fabrizio , Miele Marialuisa , Kawarai Toshitaka , Orlacchio Antonio 
Published: December 2020

AbstractBackgroundMutations in the SPG4/SPAST gene are the major cause of hereditary spastic paraplegias (HSPs), a group of genetic disorders leading to progressive spasticity and weakness of the lower limbs. Alzheimer's disease (AD) is a degenerative disorder of the central nervous system. Early‐onset familial AD (EOFAD) accounts for 3‐5% of all AD cases and denotes families in which onset is reliably before age 60 to 65 years and often before age 55 years. The present study reports a second Japanese pedigree in which a SPG4/SPAST mutation co‐segregates with HSP and EOFAD.MethodWhole exome sequencing (WES), Sanger sequencing, Multiplex Ligation dependent Probe Amplification (MLPA) analysis, bioinformatics, neurological evaluation, diagnostic imaging, and pathological assessment. An SPG4/SPAST Japanese family with similar genotype‐phenotype findings was already described by our research team. Haplotype analysis was conducted on the two pedigrees.ResultOne Japanese man was diagnosed as certainly affected by slowly progressive autosomal dominant HSP, according to the Harding criteria. The age at onset of the first motor symptoms was 31 years. At 52 years, phenotype was complicated by cognitive impairment; a diagnosis of probable EOFAD following the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer’s Disease and Related Disorders Association (NINCDS‐ADRDA) criteria was formulated. The case was definite Alzheimer’s disease (autopsy proven): the brain pathology revealed plaques with a congophilic core and neuritic pathology. Both the brother and the son of the proband revealed the same initial symptoms of dementia and HSP was diagnosed, respectively, at age 55 and 34 years. WES revealed in all the patients a heterozygous change in SPAG4/SPAST. MLPA analysis excluded the presence of deletions/duplications in SPG4/SPAST. Haplotype analysis disclosed a founder effect for the mutation in the two families sharing the same clinico‐genetic characteristics. Bioinformatic analyses and population study confirm a pathogenetic role of such mutation. Screening of PS1, PS2, and bAPP genes did not reveal any coding mutation. No affected subject carried out APOE genotype ε4/ε3 or ε4/ε4.ConclusionThis work describes the second Japanese family with a SPAG4/SPAST mutation and association of HSP and EOFAD. A possible founder effect was confirmed by haplotype analysis.
Precise morphological mapping of high plex neurodegenerative and neuroinflammation protein targets in human and mouse FFPE brain tissue with the GeoMx™ digital spatial profiler
Authors: Rosenbloom Alyssa , Bahrami Arya , Kuhar Jamie , Miller Kelly , Liang Yan , Geiss Gary , Beechem Joseph M. 
Published: December 2020

AbstractBackgroundNeurodegenerative diseases, including Alzheimer’s, Parkinson’s, and amytrophic lateral sclerosis (ALS), affect millions of people worldwide and represent an increasing burden in terms of healthcare economics and societal impact. The investigation and characterization of the abundance, specific spatial distribution and co‐localization of neurodegenerative and neuroinflammatory targets within the human brain are critical for the advancement of our understanding of progressive degenerative disease.MethodNanoString’s GeoMx Digital Spatial Profiler (DSP) platform allows for simultaneous analysis of >70 proteins from discrete regions of interest (ROI) in FFPE tissue sections, providing morphological context to high plex molecular analysis. The assay relies upon antibody probes coupled to photocleavable oligonucleotide tags. After hybridization of probes to slide‐mounted formalin fixed paraffin‐embedded (FFPE) tissue sections, the oligonucleotide tags are released from discrete regions of the tissue via UV exposure. The size and shape of the UV exposure pattern is adjustable allowing for precise investigation into rare or specific cell populations, disease microenvironments, or neural sub‐regions. Released tags are quantitated on the standard nCounter® platform, and counts are mapped back to tissue location, yielding a spatially‐resolved digital profile of analyte abundance.ResultsIn this study, we validate the GeoMx Human Neural Cell Profiling Core panel (∼20‐plex, RUO) and five add‐on Modules (∼10‐plex each, RUO) covering Alzheimer’s Pathology, Parkinson’s Pathology, Autophagy, and Glial Cell Subtyping on GeoMx DSP platform. In addition, diseased human brain tissue was mapped with fluorescent morphology markers highlighting amyloid beta plaques, microglia, and astrocytes to select ROIs for high plex profiling using the validated antibody set. In comparable studies, mouse neurodegenerative disease models were evaluated with the GeoMx Mouse Neural Cell Profiling Core panel and Alzheimer’s and Parkinson’s Pathology Modules in both FFPE and fresh frozen samples.ConclusionSpecific cell population sampling was demonstrated by masking for multiple or individual microglia, neurons, and astrocytes. Concentric masks around plaques (Contour Profiling) allowed for spatially distinct sampling of the amyloid beta plaque microenvironments. Ongoing efforts will expand the neuroscience‐specific human and mouse antibody catalogues validated for the GeoMx DSP platform.
Novel characterization of vascular amyloid in CAA via CLARITY
Authors: Nackenoff Alex , Schrag Matthew S. 
Published: December 2020

AbstractBackgroundAlzheimer’s Disease (AD) is a costly and expanding medical crisis that represents the major form of β‐amyloidosis affecting our aged population. Another form of cerebral β‐amyloidosis is Cerebral Amyloid Angiopathy (CAA), where β‐amyloid deposits into the cerebrovasculature instead of—or in addition to—distinct parenchymal plaques, independently contributing to cognitive decline. CAA is thought to produce weakened vascular network, eventually producing miniature cerebrovascular hemorrhagic events, microbleeds, and progressive deteriorating cognitive function.MethodAll previous attempts to characterize CAA microscopically have utilized thin brain sections, which are unable to discern the discrete relationship between these β‐amyloid structures and the surrounding vasculature along the entire blood vessel. We attempt to solve this limitation with the use of CLARITY, an advanced fixative technique which preserves intact cellular network structure and allows for diffusion of unfixed lipids, rendering contiguous transparent 3D tissue samplesResultThrough this technique, we have qualitatively determined the near‐ubiquitous nature of β‐amyloid deposition in CAA and gross vascular abnormalities of stratified intensity. Furthermore, we have determined that β‐amyloid is present at sites of microhemorrhage, a question that has remained controversial to dateConclusionThis methodology will allow us to evaluate specific markers associated with vascular fragility and microhemorrhage risk and map the microvascular network to identify morphological and molecular features associated with vascular fragility. This work will provide the throughput necessary to discover tractable vascular markers for novel future therapeutics for CAA, potentially generalizable to AD.
Subjective cognitive decline is associated with longitudinal cerebral blood flow reductions and gray matter atrophy in older adults
Authors: Kresge Hailey A. , Liu Dandan , Khan Omair A. , Pamidimukkala Ujwala , Cambronero Francis E. , Moore Elizabeth E. , Bown Corey W. , Pechman Kimberly R. , Hohman Timothy J. , Jefferson Angela L. , Gifford Katherine A. 
Published: December 2020

AbstractBackgroundSubjective cognitive decline (SCD), a potential harbinger of Alzheimer’s disease (AD), has been cross‐sectionally associated with neurodegeneration and cerebrovascular disease markers on brain MRI. However, longitudinal associations are less clear with few existing studies that yield inconsistent findings. Here, we related baseline SCD to longitudinal structural and hemodynamic markers of brain health in older adults free of clinical dementia and stroke.MethodsVanderbilt Memory & Aging Project participants (n=299,72±7 years, 58% male) completed a baseline SCD protocol and multimodal 3T brain MRI, including T
1‐weighted imaging (grey matter volumes) and pseudo‐continuous arterial spin labeling (cerebral blood flow (CBF)) at baseline and multiple follow‐ups (18‐months, 3‐years, 5‐years). Baseline SCD (total and subdomain memory, language, and executive functioning scores) was longitudinally related to global and regional grey matter volumes and CBF (mL/100g/min). Linear mixed effects models, with random intercepts and slopes and a follow‐up time interaction, covaried for baseline age, sex, race/ethnicity, education, diagnosis, mood, and apolipoprotein E (APOE)‐e4 status. Grey matter volume models covaried for intracranial volume. CBF models covaried for associated tissue volume.ResultsMean follow‐up time was 3.8 years. Higher total SCD predicted hippocampal volume reductions (p=0.04), increased inferior lateral ventricular volume (p<0.001; Figure 1A), and global CBF reductions (p<0.001; Figure 1B). Higher scores within each SCD domain predicted hippocampal volume reductions, increased inferior lateral ventricular volume, and global CBF reductions (p‐values<0.04). Higher executive functioning‐SCD related only to frontal and occipital CBF reductions (p‐values<0.003; Figure 1C) but not temporal CBF or lobar atrophy (p‐values>0.07). Language‐SCD predicted reduced frontal CBF (p=0.01; Figure 1D) and temporal lobe volume (p=0.02). Surprisingly, memory‐SCD was not associated with temporal lobe volume or CBF (p‐values>0.05). Sensitivity analyses excluding outliers revealed the same associations.ConclusionsHigher baseline SCD predicted multiple pathways of longitudinal brain changes, including cerebral hemodynamics and volume loss within areas first affected by AD. Executive functioning‐SCD predicted hemodynamic changes and language‐SCD related to alterations within the frontal and temporal lobes. Results suggest the relevance of considering the type of SCD, as specific domains may predict different pathologies over time with important prognostic implications. Future research is needed to understand the clinical consequences of these findings.