bluuebunny/crossref_metadata_2025_split huggingface dataset:
Assessing whole genome sequencing variation for Alzheimer’s disease in 4707 individuals from the Alzheimer’s Disease Sequencing Project (ADSP)
Authors: Peloso Gina M. , Wang Yanbing , Lin Honghuang , Sarnowski Chloé , Pitsillides Achilleas N. , Lim Elise M. , Beecham Gary W. , Hamilton‐Nelson Kara L. , Ramos Jairo , Martin Eden R. , Naj Adam C. , Thornton Timothy A. , Wang Li‐San , Boerwinkle Eric , Farrer Lindsay A. , Haines Jonathan L. , Mayeux Richard , Pericak‐Vance Margaret A. , Seshadri Sudha , Schellenberg Gerard D. , Wijsman Ellen , Fornage Myriam , Dupuis Josée , Destefano Anita L. , Kunkle Brian W. ,   Alzheimer’s Disease Sequencing Project
Published: December 2020

AbstractBackgroundThe Alzheimer’s Disease Sequencing Project (ADSP) seeks to identify genomic variants contributing to increased risk of and/or protection from Alzheimer’s disease (AD) in multi‐ethnic populations. Here we report on statistical modeling considerations and results from 4707 diverse individuals including 2076 non‐Hispanic White, 1030 Black, 1304 Hispanic, and 297 of other ancestry with whole genome sequencing (WGS) in the ADSP.MethodsA total of 4789 individuals were sequenced across 4 sequencing centers and 2 sequencing platforms. Joint calling was carried out by the ADSP data coordinating center GCAD. We evaluated a series of models to explore technical covariate adjustment related to study, sequencing center, and platform and then performed single variant association analysis for AD status adjusting for principal components associated with AD, technical covariates, and a genetic relatedness matrix, limiting to variants with a minor allele count > 30 and a missingness rate ≤ 10%. We also performed gene‐based association of rare (both MAF < 1% and MAF < 5%) coding variants.ResultsAfter quality control, we included over 95 million variants across 4707 individuals (2209 cases, 2498 controls). We replicated association at the APOE locus and identified a locus on chromosome 15 that has a suggestive association with AD status (freq = 0.8%, p‐value = 1 × 10−7). Despite joint genotype calling, adjustment for study, sequencing center and platform are necessary to control type‐I error. In gene‐based tests, we found evidence (p < 0.05) of association for 4 of 8 AD candidate genes with low‐frequency or rare variant associations implicated for AD (TREM2, ABI3, SORL1, and MAPT) as well as suggestive associations (P < 5 × 10−5) for seven genes (ZGRF1 on chr4; C1RL on chr12; NAA30 on chr14; NIPA2 on chr15; and ABCC3, BIRC5 and HIC1 on chr17).ConclusionWe explored covariate models for the WGS data from ADSP and established that despite joint calling, it is necessary to account for technical effects in the model. We found suggestive novel associations with AD status that will require confirmation.
The function and composition of brain tissue derived exosomes in human Alzheimer’s disease
Authors: Vella Laura J. , Su Huaqi , Koukoulis Tiana , Cheng Lesley , Purnianto Adityas , Beauchamp Leah , McLean Catriona , Bush Ashley I. , Masters Colin L. , Reid Gavin , Hill Andrew F. , Barnham Kevin J. 
Published: December 2020

AbstractBackgroundExosomes are extracellular vesicles (EVs) found in all bodily fluids. They carry the unique biological fingerprint of the parental cell they were released from, making them an ideal source of tissue and disease specific biomarkers and they are key players in cell‐to‐cell communication. Identification of brain derived exosomes (BDEs) in the periphery, for the purpose of AD diagnosis, requires knowledge of the composition of exosomes in the CNS. Moreover, an appreciation of the technical complexities associated with the isolation and characterisation of exosomes. We have taken a rigorous approach to the study of exosomes in AD frontal cortex. We have determined their Aβ and tau content, in addition to uncovering their omic profile.MethodEVs were isolated from human frontal cortex as previously described by us (Vella et al JEV 2017), according to ISEV guidelines. Vesicles from neurological control or AD subjects were systematically assessed for morphology, density, size distribution, proteomic, lipidomic, genomic and metal content. The potential of BDE tau to cause conversion was assessed in tau biosensor cells.ResultExosomes are hypothesised to be a source of extracellular Aβ and p‐tau in AD and responsible for the ‘spread’ of these proteins. Here, we identified a pool of extracellular p‐tau and Aβ in AD brain, not associated with exosomes. In aggregation assays however, exosomes from AD subjects caused aggregation in tau biosensor cells, despite the absence of detectable p‐tau. Findings from some of our omic approaches revealed that BDEs recapitulate the lipidomic changes in the tissue, with remodelling in PE lipids in AD BDEs relative to control. While genomic profiling identified 26 highly enriched miRNA.ConclusionWe determined the composition of brain exosomes in AD with the goal of identifying disease relevant biomarkers and identification of BDEs in the periphery. Lipid and RNA changes in AD frontal cortex were not only recapitulated in BDEs from this region but the dynamic range between disease and control tissues was extended, highlighting the advantage of this approach. Our functional studies suggest that BDEs can corrupt tau in the brain, potentially moving through the CNS in the absence of connected neuronal networks or detectable aggregated tau.
Retinal vascular occlusions are associated with increased risk for vascular dementia in APOE ε4 carriers in a community‐based cohort
Authors: Lee Cecilia S , Lee Michael L. , Gibbons Laura E , Larson Eric B , Crane Paul K 
Published: December 2020

AbstractBackgroundWe previously reported that several eye conditions were associated with increased risks of developing Alzheimer’s disease (AD). Retinal vascular occlusions (RVO, i.e. retinal vein and artery occlusions) are one of the leading sight‐threatening retinal vascular disorders. In this study, we sought to determine whether RVO are associated with increased risks of AD and other types of dementia. A few previous studies suggest that APOE is associated with RVO and vascular dementia.MethodParticipants aged ≥ 65 and dementia‐free were recruited in a prospective, observational cohort (Adult Changes in Thought [ACT] study). Self‐reported smoking history, hypertension, congestive heart failure, diabetes, and history of cardiovascular or cerebrovascular disease were obtained at study visits, and APOE genotype was obtained from consenting participants. Cognition was evaluated every two years with extensive neurological and neuropsychological testing when cognitive scores fell below normal range. All data were reviewed at consensus conferences for diagnosis of AD and various types of dementia such as vascular dementia (VasD). Eye diagnoses were obtained using ICD‐9/10 codes. We used adjusted Cox survival models to compute hazard ratios (HR) for developing dementia.ResultA total of 4,743 participants had 1,037 incident cases of AD. 439 (9.3%) participants had retinal vascular occlusions. In participants with any APOE ε4 alleles, the HR of developing VasD was 3.03 (95%CI 1.37, 6.71, p‐value=0.0064) in participants diagnosed with retinal vascular occlusions compared to those without [Figure, Table 2]. This strong relationship persisted after further adjustment for diabetes, hypertension, and cardiovascular disease. No significant association was found between retinal vascular occlusions and VasD in participants (HR=1.05 95% CI 0.54, 2.03 , p= 0.89) who were negative for APOE ε4. No associations were found between RVO and AD or all‐cause dementia.ConclusionIncreased risk of vascular dementia was found in participants diagnosed with RVO in participants who are APOE ε4 carriers. Further research about the relationship between APOE, dementia, and eye conditions is warranted.
[18F]MK‐6240 depicts early and late Braak stages of neurofibrillary tangles in preclinical and symptomatic subjects
Authors: Pascoal Tharick A. , Therriault Joseph , Benedet Andréa Lessa , Savard Melissa , Lussier Firoza Z. , Chamoun Mira , Tissot Cécile , Qureshi Muhammad Naveed Iqbal , Kang Min Su , Mathotaarachchi Sulantha , Stevenson Jenna , Massarweh Gassan , Soucy Jean‐Paul , Gauthier Serge , Rosa‐Neto Pedro 
Published: December 2020

AbstractBackgroundPostmortem Braak staging provides an index of disease stage and has therefore been incorporated as a core neuropathological criterion for the diagnosis of Alzheimer’s disease (AD). Recent in vivo studies using the tau positron emission tomography agent [18F]flortaucipir have shown low sensitivity to detect tau pathology in early Braak stages. These studies report Braak I‐II or greater in ∼20% of cognitively unimpaired elderly, in contrast to the ∼70‐90% of non‐zero Braak stage reported in postmortem studies. Here, we tested whether the novel high‐affinity tau tangles tracer [18F]MK‐6240 (6 fold > [18F]flortaucipir)can better identify individuals in the early stages of tau accumulation.MethodTo this end, we studied 301 individuals (30 young adults, 138 cognitively unimpaired (CU) elderly, 67 mild cognitive impairment (MCI), 54 AD dementia, and 12 frontotemporal dementia (FTD)) with amyloid‐b[18F]NAV4694, tau [18F]MK‐6240, magnetic resonance imaging, and clinical assessments.Results[18F]MK‐6240 discriminated AD from FTD dementia as well as predicted amyloid‐b positivity with the highest area under the curve in Braak I‐II region (=∼95‐100%)(Fig.1 and 2). [18F]MK‐6240 accumulation hierarchically followed the 6 Braak stages (Fig.3)in 98% of our population (Fig.4).91% of the elderly amyloid‐b positive and 46% of the elderly amyloid‐b negative displayed tau deposition, at least in the transentorhinal cortex (Braak I)(Fig.4). Cognition and amyloid‐b status explained most of the Braak stages variance (P<0.0001, R2=0.75). Tau deposition solely in the transentorhinal cortex was associated with an elevated prevalence of amyloid‐b, neurodegeneration, and cognitive impairment (P<0.0001). No single region‐of‐interest accurately segregated individuals into the 6 Braak stages (Fig.5). However, classification decision tree analysis suggested that a composite of transentorhinal, entorhinal, and hippocampal cortices(Braak I‐II) was the region‐of‐interest that best represented [18F]MK‐6240Braak stages (capacity of a region’ SUVR cutoff segregating individuals in 7 levels (Braak 0‐VI)) (accuracy=86.2%)(Fig.6).ConclusionOur results highlight that the hierarchical 6‐stage Braak model using [18F]MK‐6240 provides a robust index of early and late tau accumulation as well as disease stages in preclinical and symptomatic individuals. Tau positron emission tomography Braak staging using high‐affinity tracers has the potential to be incorporated in the diagnosis of living patients with AD.
Serum metabolome informs neuroimaging biomarkers for Alzheimer’s disease
Authors: Nho Kwangsik , Kueider‐Paisley Alexandra , Arnold Matthias , Dehkordi Siamak Mahmoudian , Risacher Shannon L. , Louie Gregory , Blach Colette , Baillie Rebecca , Han Xianlin , Kastenmüller Gabi , Doraiswamy P. Murali , Kaddurah‐Daouk Rima F. , Saykin Andrew J. ,   Alzheimer’s Disease Neuroimaging Initiative, Alzheimer’s Disease Metabolomics Consortium
Published: December 2020

AbstractBackgroundAccumulating evidence suggests that Alzheimer’s disease (AD) patients display metabolic dysfunction. Metabolomics is a powerful tool for studying metabolic pathways by mapping biochemical changes in AD, yet little is known about the association between circulating metabolites in blood and the “A/T/N” (amyloid‐β, tau, neurodegeneration) biomarkers for AD.MethodSerum‐based targeted metabolite levels were measured in the Alzheimer’s Disease Neuroimaging Initiative (ADNI; n = 1,531; 370 cognitively normal controls (CN), 95 significant memory concern (SMC), 271 early mild cognitive impairment (EMCI), 491 late MCI (LMCI), and 304 AD). The quality control process resulted in 139 metabolites for further analysis. We performed association analyses of circulating serum metabolites with the “A/T/N” biomarkers for AD. Biomarkers of “A” are CSF Aβ1‐42 and cortical amyloid‐β accumulation measured by Florbetapir PET, biomarkers of “T” are CSF phosphorylated tau (p‐tau), and biomarkers of “N” are atrophy on MRI and glucose metabolism on FDG PET. FDR‐based multiple comparison adjustment with the Benjamini‐Hochberg procedure was used.ResultWe found significant associations of multiple metabolites with biomarkers of amyloid‐β (“A”) and neurodegeneration (“N”) including brain amyloid deposition, glucose metabolism, and structural atrophy measured from multimodal neuroimaging scans (MRI, PET) after multiple testing adjustment. We did not observe any significant associations between metabolites and biomarkers of fibrillary tau (“T”) (Figure 1). In particular, higher levels of phosphatidylcholines (PC) were associated with greater amyloid deposition (“A”) and decreased brain glucose metabolism (“N”). Higher levels of propionyl‐L‐carnitine (C3) were associated with less amyloid deposition and increased brain glucose metabolism. Higher levels of two amino acids, two PCs, and three sphingomyelins were associated with less brain atrophy (“N”).ConclusionThis is the first study to show serum circulating metabolites are significantly associated with neuroimaging biomarkers for AD. Perturbations in PC and acylcarnitine metabolism may play a role in features intrinsic to AD including amyloid‐β deposition and neurodegeneration, but not fibrillary tau suggesting that acylcarnitines and PCs are associated with earlier stages of AD as tau spreading is more closely related to AD progression.
Genome‐wide study of the human lipidome and links to Alzheimer’s disease risk
Authors: Meikle Peter J. , Giles Corey , Cadby Gemma , Huynh Kevin , Mellett Natalie A. , Olshansky Gavriel , Smith Alexander , Nguyen Anh , Chatterjee Pratishtha , Martins Ian , Laws Simon M. , Bush Ashley I. , Rowe Christopher C. , Villemagne Victor L.L. , Ames David , Masters Colin L. , Arnold Matthias , Kastenmüller Gabi , Nho Kwangsik , Saykin Andrew J. , Baillie Rebecca , Han Xianlin , Inouye Michael , Martins Ralph N. , Kaddurah‐Daouk Rima F. , Moses Eric ,   Busselton Health Study, AIBL and ADNI research groups
Published: December 2020

AbstractBackgroundDysregulation of lipid metabolism is as an important – and modifiable – risk factor for the initiation and progression of Alzheimer’s disease (AD). Although lipid metabolism is established as crucial to numerous biological processes, the genetic factors that influence inter‐individual variation are still not well understood. To address this issue, we apply an integrative approach to link genetic variants with altered lipid metabolism and AD.MethodLipidomic profiling was performed using liquid chromatography coupled electrospray‐ionization tandem‐mass spectrometry on 4,492 genotyped individuals from the Busselton Family Health Study. We performed genome‐wide association analysis of 596 lipid species and 33 lipid classes using linear‐mixed models, correcting for age, sex, their interactions, 10 genomic principal components and an empirical genetic relatedness matrix. To account for lipoprotein mediated associations, the analysis was repeated with HDL‐C, triglycerides and total cholesterol as covariates. Additionally, collider bias was avoided by conditioning using multi‐trait‐based conditional and joint analysis. Validation of genome‐wide significant associations is supported by replication in the Australian Imaging, Biomarker & Lifestyle Study of Ageing (n = 1,112) and Alzheimer’s Disease Neuroimaging Initiative (n = 757) cohorts.ResultOver 70,000 genome‐wide significant (p<5e‐08) associations were identified, with 451 lipid species having at least one significant association. Approximately 70% of the observed associations are independent of lipoprotein measures. We observed associations (p<1.0E‐6) between lipid species and seven loci containing genes previously identified as risk factors for AD, including ApoE, ABCA7 and SLC24A4. We further identify 1252 variants (92 independent gene regions) that associated (p<5.0E‐8) with the 71 lipid species we identified as significantly associated with incident AD in a combined meta‐analysis of the AIBL and ADNI cohorts.ConclusionBy linking lipid species to AD, through genetic associations, we highlight potential therapeutic targets for monitoring, prevention and treatment.
Alteration of perivascular spaces in early cognitive decline
Authors: Sepehrband Farshid , Barisano Giuseppe , Sheikh‐Bahaei Nasim , Choupan Jeiran , Cabeen Ryan P , Crawford Malcolm S , Mack Wendy J , Chui Helena C , Ringman John M , Toga Arthur W ,   Alzheimer’s Disease Neuroimaging Initiative
Published: December 2020

AbstractBackgroundVascular contributions to early cognitive decline are increasingly recognized, prompting further investigation into the nature of related changes in perivascular space (PVS). Here we investigated the association between PVS volume fraction and early cognitive decline, neurofibrillary tau and Amyloid‐b uptake and APOE status.MethodData were obtained from the ADNI‐3 database. A total of 685 participants with magnetic resonance imaging (MRI) data were assessed, and 596 participants (326 female [54.6%]) with complete data that passed quality control and inclusion criteria were included (cognitively normal participants age: 73.04 ± 7.36; mild cognitive impairment participants age = 75.56 ± 8.16). PVS volume fraction and brain volume were estimated from MRI using an automated in‐house pipeline; Amyloid‐b and Tau status were determined from PET images and CSF samples; Demographic, cognitive information and cardiovascular risk factors were also collected. Cognitive assessment scores were used to categorized individuals into cognitively normal and mild cognitive impairment subjects. Analysis models were adjusted for age, sex and years of educations.ResultA significantly lower PVS volume fraction in mild cognitive impairment was observed compared to the cognitively normal group in both left (p=0.00047) and right (p=0.0009) anterosuperior medial temporal lobe (Figure 1). PVS volume fraction of the centrum semi‐ovale of the white matter was higher in mild cognitive impairment compared to cognitively normal participants, but not statistically significant after adjusting for age, sex, education and brain volume (p=0.07). PVS volume fraction in anterosuperior medial temporal lobe was significantly associated with Tau PET standardized uptake value ratio in right entorhinal cortex (beta (SE) = ‐0.02 (0.007); p=0.006). PVS volume fractions across different regions were independent of Amyloid load or APOE e4 status.ConclusionWe show that, compared to a cognitively normal sample, individuals with early cognitive dysfunction have altered PVS presence and distribution, irrespective of Amyloid‐b. Surprisingly, we noted decreased PVS presence in the anterosuperior medial temporal lobe, which was associated with neurofibrillary tau tangle deposition in the entorhinal cortex, one of the hallmarks of early Alzheimer’s disease pathology. Our results suggest that anatomically‐specific alteration of the PVS may provide an early biomarker of cognitive impairment in aging adults.
The effects of mesial temporal tau in Ab‐negative cognitively normal older adults
Authors: Groot Colin , Dore Vincent , Robertson Joanne S , Burnham Samantha C , Savage Greg , Ossenkoppele Rik , Rowe Christopher C , Villemagne Victor LL 
Published: December 2020

AbstractBackgroundMany older adults have some degree of tau aggregation, which is often regarded as a part of the process of aging. We assess the effects of mesial temporal tau on neocortical tau and on cognition in Ab‐negative, cognitively healthy older adults.MethodSubjects were 47 cognitively healthy subjects from the AIBL cohort who had negative Ab‐PET scans and underwent [18F]flortaucipir‐PET to examine tau load. Regional tau was assessed using the MeTeR template and we determined mesial temporal (Mecomprising entorhinal cortex, hippocampus, parahippocampus and amygdala) tau‐positivity at SUVR>1.2 (n=10/47 [21.3%]). The associations between Me‐tau, voxelwise tau‐burden and cognition (MMSE, composite memory, composite non‐memory and the pre‐Alzheimer’s cognitive composite) were assessed. Furthermore, we examined the effect of Me tau on age and Ab burden.ResultVoxelwise contrasts between Me+ and Me‐ subjects revealed that Me+ subjects had more tau in the neocortex (Figure 1). Furthermore, Me+ subjects had worse performance compared to Me‐ subjects on all cognitive tests assessed (Figure2). Me‐tau was marginally associated with higher age, but there was no association with Aβ burden (Figure 3).ConclusionThese results indicate that, within a group of Ab‐negative subjects performing within normal ranges of cognitive performance, high Me tau is associated with more neocortical tau, suggesting that Me tau is a harbinger of tau in the neocortex. This high Me‐tau is associated with worse cognition and while likely age‐related (PART) might not be as benign as the term “ageing” implies.
The effects of peripheral lipoprotein metabolism on cerebrovascular inflammation in APP/PS1 mice
Authors: Button Emily B. , Boyce Guilaine K. , Wilkinson Anna , Stukas Sophie K. , Hayat Arooj , Cheng Wai Hang , Wadsworth Brennan J. , Fan Jianjia , Robert Jerome , Martens Kris M. , Wellington Cheryl L. 
Published: December 2020

AbstractBackgroundAlthough Alzheimer’s disease (AD) is characterized by amyloid beta (Aβ) plaques and neurofibrillary tangles, most AD patients also exhibit cerebrovascular dysfunction. Therefore, strategies promoting cerebrovascular resilience have potential as therapeutic or preventative interventions against AD. High‐density lipoproteins (HDL) have several known beneficial functions on peripheral vessels. Further, increased plasma HDL concentrations have been associated with reduced dementia risk and HDL supplementation reduces both amyloid pathology and cognitive deficits in AD model mice. We therefore hypothesized that HDL may promote cerebrovascular health to protect against AD. We investigated the effects of HDL specifically on the cerebrovasculature in APP/PS1 mice, an AD model, using two methods.MethodsFirst, we reduced plasma HDL levels by creating APP/PS1 mice genetically deficient for apolipoprotein (apo)A‐I, the primary protein component of HDL. Second, we treated 12‐month old APP/PS1 mice with a non‐brain penetrant liver X receptor (LXR) agonist for seven days to selectively upregulate the HDL biogenesis pathways in peripheral tissues. We measured cognitive deficits using cued and contextual fear conditioning tests. Fluorescent amyloid staining was used to assess vascular amyloid deposition. Immunofluorescent imaging evaluating glial fibrillary acidic protein (GFAP) and intercellular adhesion molecule 1 (ICAM‐1) association with CD31 positive area was used to assess vessel‐associated astrogliosis and endothelial inflammation, respectively.ResultsAt 12 months of age, apoAI‐null mice had increased cognitive deficits in cued and contextual fear conditioning tests, increased vascular amyloid burden, increased vessel‐associated astrogliosis, and increased brain endothelial cell inflammation. Seven days of LXR agonist treatment had no effect on amyloid pathology or astrogliosis. However, LXR agonist‐treated APP/PS1 mice displayed reduced cognitive deficits in cued fear conditioning tests and reduced endothelial cell inflammation.ConclusionsCirculating HDL promotes cerebrovascular health in APP/PS1 mice by limiting both Aβ‐induced vascular inflammation and vascular Aβ deposition resulting in reduced amyloid pathology and cognitive deficits.