bluuebunny/crossref_metadata_2025_split huggingface dataset:
Differential effects of APOE2 and APOE4 alleles on PET‐measured amyloid‐β and tau deposition in older individuals without dementia
Authors: Grothe Michel J. , Salvadó Gemma , Groot Colin , Moscoso Alexis , Gispert Juan Domingo , Schöll Michael , Ossenkoppele Rik 
Published: December 2020

AbstractBackgroundThe APOE4 allele is the best‐established genetic risk factor for sporadic Alzheimer’s disease (AD), whereas the APOE2 allele has been linked to decreased AD risk. Although the most prominent neurobiological effect of the APOE polymorphism appears to relate to altered amyloid‐β (Aβ) deposition, recent PET imaging evidence has also pointed to Aβ‐independent APOE4 effects on increased medial temporal tau deposition. Here, we investigated whether APOE2 has a reversed (i.e. protective) association with PET‐measured tau deposition.MethodFrom the ADNI cohort we identified 467 APOE‐genotyped individuals without dementia (31% with mild cognitive impairment (MCI); 53% female) who underwent tau ([18F]flortaucipir) and Aβ ([18F]florbetapir or ([18F]florbetaben) PET as well as a structural MRI scan. 257 were APOE3/3 homozygotes, 45 had an APOE2/3 genotype, 160 were APOE3/4 or APOE4/4. Five individuals with a APOE2/4 genotype were excluded from the analysis. Linear models, controlled for age, sex, education, and diagnosis, were used to compare genotype groups on multimodal imaging biomarkers, including entorhinal cortex (ERC) flortaucipir standard uptake value ratio (SUVR, inferior cerebellum reference), cortical Aβ load expressed as centiloid values, and hippocampal volume on MRI. On the basis of an emerging literature highlighting female‐specific risks for developing AD, we also studied sex*APOE interactions on biomarker outcomes.ResultCompared to APOE3/3, APOE2/3 carriers had significantly reduced Aβ burden (14.2 vs 25.5 centiloids, p=0.021), but did not differ in ERC tau (1.166 vs 1.148 SUVR, p=0.52) or hippocampal volume (p=0.82)(Fig‐1). These effects did not differ between males and females, and similar results were obtained when using alternative medial/inferior temporal tau regions‐of‐interest. By contrast, APOE4 carriers showed both significantly increased Aβ (48.3 centiloids, p<0.001) and ERC tau burden (1.249 SUVR, p<0.001), but no difference in hippocampal volume (p=0.33). In combined regression models, Aβ load fully mediated the APOE4 effect on ERC tau in males (APOE4: t(188)=0.6/p=0.52; Aβ: t(188)=5.3/p<0.001), whereas in females APOE4 retained a minor direct effect (t(217)=2.2/p=0.03) in addition to the prominent effect of Aβ (t(217)=10.6/p<0.001).ConclusionWe demonstrate a relatively minor Aβ‐independent effect of APOE4 on medial temporal tau deposition, which was observed in females only. Our data do not support a corresponding protective effect of APOE2.
A single ascending dose study in healthy volunteers to assess the safety and PK of LY3372689, an inhibitor of O‐GlcNAcase (OGA) enzyme
Authors: Kielbasa William , Phipps Krista M , Tseng James , Natanegara Fanni , Cheng Eden , Monk Scott A. , Bundgaard Christoffer , Kevin Donnelly B. , Nuthall Hugh Norman , McDonald Nicholas , Lindsay‐Scott Peter , Dreyfus Nicolas , Hawk Mai Khanh , Warner Susan , Biglan Kevin , Gilmore Julie A. , Zhang Xiaoyu , Mergott Dustin J. , Lowe Stephen L. 
Published: December 2020

AbstractBackgroundLY3372689, an O‐GlcNAcase (OGA) enzyme inhibitor, is being developed as a potential treatment for tauopathies, including Alzheimer’s disease. OGA inhibition is proposed to delay the progression of tau‐related diseases by slowing the accumulation of hyper‐phosphorylated, insoluble tau filaments. Herein we report the first clinical study that assessed safety and pharmacokinetics (PK) of LY3372689 after single oral doses in healthy volunteers (HV).MethodThe phase 1 clinical trial (NCT03819270) was a single ascending dose, randomized, crossover, placebo controlled, investigator‐ and subject‐blind study. Each HV received up to 3 escalating single doses of LY3372689 or placebo over 3 study periods with an approximately 7‐day follow‐up period after each dose, such that a total of 6 LY3372689 dose levels were evaluated. Safety was assessed by adverse events (AE), safety laboratories, electrocardiograms, vital signs, physical exams, and neurological exams. Plasma PK was assessed up to 48 hours after LY3372689 administration.ResultA total of 23 HV (15 males, 8 females; 22 – 63 years) participated in the study, of which 18 completed and 5 did not complete due to loss to follow up procedures or did not meet randomization criteria. LY3372689 was generally well tolerated up to the maximum dose administered. There were no serious AE reported and no subjects discontinued the study because of an AE. A total of 13 treatment‐emergent AE reported by 5 subjects considered as possibly related to study treatment were mostly mild in severity, and included pain of skin, headache, limb discomfort, pain in extremity, chest discomfort, muscle fatigue, nausea, and rash macular. The PK of LY3372689 supported daily dosing and was generally dose proportional based on AUC and Cmax.ConclusionLY3372689 demonstrated an acceptable safety and PK profile following single oral doses of LY3372689 in HV, which supports further investigation of LY3372689 as a potential treatment for tauopathies.
Discrepancies in the detection of early impairment in elderly individuals: Implications for the clinic and research
Authors: Ritter Aaron , Kaylegian Jaeson , Calvin Kirsten , Ivey Brooke , Cummings Jeffrey L. , Shan Guogen , Caldwell Jessica Z.K. 
Published: December 2020

AbstractBackgroundWomen’s lifelong advantages in verbal memory persist well into the early stages of Alzheimer’s disease (AD) and may delay AD diagnosis. This has important implications for clinical trials, which frequently use verbal memory tests for eligibility. We examined whether discrepancies between neuropsychological testing and a semi‐structured clinical interview provides enhanced ability to detect early AD, particularly in women. We also examined whether these discrepancies provide meaningful information about disease progression and/or underlying AD biomarkers.MethodData was retrospectively analyzed from the Center for Neurodegeneration and Translational Neuroscience (CNTN), a longitudinal, natural history study of elderly individuals. Participants were cognitively normal (CN—with and without subjective cognitive impairment), or diagnosed with mild cognitive impairment (MCI) or mild dementia. We looked for discrepancies between memory tests (Rey Auditory Verbal Learning Test, Brief Visuospatial Memory Test‐Revised) and the Clinical Dementia Rating (CDR) using baseline data from 163 consecutive individuals. Discrepancies were defined as: (1) Neuropsychologically worse (NP worse): CDR=0 and impairments in ≥2 memory scores; or a CDR=0.5 and impairments in ≥5 memory scores. (2) Clinically worse (CDR worse): CDR=0.5 and 0 memory impairments; or CDR=1 and 0 memory impairments.ResultThe overall discrepancy rate was 36% (22% NP worse; 13% CDR worse). In both directions, discrepancies were more common when the participant was male. NP worse individuals were also more often amyloid positive (66%) than CDR worse (43%). When examined longitudinally, participants with discrepancies more often progressed diagnostically (e.g., CN to MCI or MCI to mild dementia) than those without discrepancies. NP worse individuals were almost twice as likely to progress than CDR worse. We found no effects of study partner characteristics (time spent together, gender, education or rate) on discrepancy rates.ConclusionIn our sample, we found a high rate of discrepancy between CDR and memory scores. Memory impairment more often anticipated cognitive decline and better identified those with underlying AD biomarkers than the CDR. Discrepancies were more common in men than women. Further research is needed to account for sex differences in early AD and should be incorporated in clinical trial design.
Early adult to midlife trajectory of inflammation and midlife cognition
Authors: Yaffe Kristine , Gross Myron , Levine Deborah A , Jacobs David R , Bahorik Amber L 
Published: December 2020

AbstractBackgroundLate‐life inflammation, often measured by peripheral biomarkers, has been linked to risk of developing dementia and preclinical cognitive decline. Little is known about early adulthood inflammation and if this could influence cognition earlier in life. Furthermore, few studies have investigated repeated measures of inflammation.MethodWe studied 1920 adults (mean age 33.3 ±3.5, 53% female, 62% white) who were enrolled in the Coronary Artery Risk Development in Young Adults study. We used latent class analysis to identify inflammation trajectories using repeated C‐reactive protein (CRP) measurements (≥3 CRP assessments) over almost two decades. At midlife (mean age 55.4 ±3.5), we assessed cognition using the Digit Symbol Substitution Test (DSST), Stroop Test, Rey Auditory Verbal Learning Test, Montreal Cognitive Assessment, and fluency tests. Logistic regression was used to evaluate the association between inflammation trajectories and poor cognitive performance, defined as a score ≥1 standard deviation below the cohort mean for each test.ResultThree early to mid‐adult inflammation trajectories were identified: consistently low (34% [n=676]), moderate/increasing (15.0% [n=150]), and consistently high (51% [n=1094]). Those participants in the moderate/increasing or high trajectories had about a two‐fold greater risk (adjusting for age, race, sex, and education) of poor cognitive performance on processing speed and executive function tasks compared to those in the consistently low trajectory. Further adjustment for physical activity, smoking, alcohol, hypertension and diabetes led to similar results (DSST: moderate/increasing OR=2.11 95%CI 1.22‐3.65, high OR=1.52 95%CI 1.07‐2.15; Stroop: high OR=1.68 95%CI 1.16‐2.44). There were no differences by trajectory in odds of poor cognitive performance on memory or global cognition domains.ConclusionHigh or moderate/increasing early to mid‐adult inflammation trajectory was associated with an almost 2‐fold higher odds of worse executive function and processing speed in midlife. These findings suggest that inflammation is an important association for cognitive aging and may begin much earlier in life than previously known.
Intergenerational interactions between people with dementia and children up to the age of five in care homes—what are the outcomes and how are they measured?: A systematic review
Authors: Sakure Jelena , Livingston Gill , Beeke Suzanne 
Published: December 2020

AbstractBackgroundIntergenerational projects in care homes are often run for people with dementia and children of pre‐school and Reception age. These projects are thought to be beneficial for people with dementia and the children involved. We systematically review existing research on the different models of such projects and the effect of these on communication.MethodWe searched six electronic databases (Medline, PsychINFO, CINAHL, Scopus, Web of Science, CENTRAL (Cochrane Library)). We searched from inception to present and did not limit the language. Two researchers decided independently on whether references fitted inclusion criteria. We included qualitative and quantitative studies of intergenerational programmes for children not older than 5 years and people with dementia in care homes. Our search terms were adapted for each source and included subject headings and keywords for dementia, children/intergenerational activities and long‐term care settings. We involved a steering group of stakeholders in the discussion of included studies and the synthesis of extracted data.ResultsWe report on the impact of intergenerational activities on people with dementia and children, highlighting the domains of verbal and non‐verbal communication. We document the links of these outcomes with the settings, programme types and facilitation contexts in which they occur. We also discuss reported methods for measuring outcomes of intergenerational activities.ConclusionWe present the existing evidence and give a new interaction and communication‐focused perspective on long term care‐based intergenerational programmes for people with dementia and children up to the age of five. We make recommendations about further research.
β‐amyloid and tau drive early Alzheimer’s disease decline while glucose hypometabolism drives late decline
Authors: Hammond Tyler C , Xing Xin , Ma David W , Nho Kwangsik , Crane Paul K , Elahi Fanny M , Ziegler David , Liang Gongbo , Cheng Qiang , Jacobs Nathan , Lin Ai‐Ling ,   Alzheimer's Disease Neuroimaging Initiative (ADNI)
Published: December 2020

AbstractBackgroundOver the past several decades, treatment development for Alzheimer’s disease (AD) has been largely focused on modifying amyloid‐beta (Aβ), but no drugs that modify the pathophysiological processes underlying the disease have been FDA approved; it is therefore possible that Aβ may not be the optimal target for treating AD. The NIA‐AA consortium has proposed the use of amyloid, tau, and neurodegenerative (A/T/N) biomarkers in diagnosis and treatment of AD. However, it remains unclear whether each arm of the A/T/N framework has an equally weighted contribution to the progression of AD or rather a stage‐dependent importance to AD development.MethodsHere we use random forest, a machine learning algorithm, in participants from the ADNI dataset (Table 1) to predict AD cognitive decline using integrated biomarkers from the A/T/N framework: Aβ‐PET, CSF‐pTau, and FDG‐PET and MRI‐Structural, respectively (Table 2). We chose random forest for its high prediction accuracy and interpretability. We also analyzed the relationship between A/T/N biomarkers and memory composite and executive functioning composite scores.ResultsWe show that the A/T/N biomarkers have stage‐dependent importance to AD development, with Aβ and phosphorylated‐tau (pTau) better predicting early dementia status (i.e. mild cognitive impairment) and neurodegeneration, especially low glucose uptake, better predicting later dementia status (i.e. clinical AD) (Table 3). We show a similar pattern when correlating markers to performance on memory and executive functioning tests.ConclusionsOur results provide evidence that AD treatments may need to be stage‐oriented to match the natural disease progression. (Figure 1) Aβ and tau may be appropriate targets early in the disease course, but brain metabolic restoration should be explored as a treatment target later on in the disease process.
Association of cerebrovascular risk burden with mild cognitive impairment, dementia and brain vascular pathologies
Authors: Song Ruixue , Xu Hui , Pan Kuan‐Yu , Qi Xiuying , Buchman Aron S , Bennett David A , Xu Weili 
Published: December 2020

AbstractBackgroundTo examine the association of cardiovascular risk burden assessed by Framingham General Cardiovascular Risk Score (FGCRS) with incidence of mild cognitive impairment (MCI) and dementia, and brain vascular pathologies.MethodsWithin the Rush Memory and Aging Project, 1203 cognitively intact participants were identified at baseline and followed up to 21 years to detect incident MCI and dementia. FGCRS was assessed at baseline and categorized into tertiles (the lowest, middle, and the highest). MCI and dementia were diagnosed following standard criteria. During the follow‐up, 423 participants died and underwent autopsies for neuropathological assessments. Data were analyzed using Cox regression model, linear regression and logistic regression.ResultsDuring the follow‐up, 457 participants developed MCI and 192 developed dementia. FGCRS, as continuous variable, was dose‐dependently related to the incidence of MCI and dementia. Compared to the participants with the lowest tertile of FGCRS, those with the highest tertile had the multi‐adjusted hazard ratio (HR) of 1.34 (95% CI 1.04‐1.73) for MCI and 1.49 (95% CI 1.01‐2.21) for dementia. Further, FGCRS was dose‐dependently associated with gross chronic cerebral infarctions (odds ratio [OR] 1.08, 95% CI 1.01‐1.15) and cerebral atherosclerosis (OR 1.09, 95% CI 1.00‐1.18), but not with other brain pathologies.ConclusionHigher cardiovascular risk burden is associated with an increased risk of MCI and dementia. Cerebral infarctions and atherosclerosis might underlie this association.
Translating genetic risk variants in disease‐associated enhancers into novel mouse models of Alzheimer’s disease
Authors: Preuss Christoph , Chen Xi , Chen Kathleen , Theesfeld Chandra , Cofer Evan , Uyar Asli , Cary Gregory A. , Pandey Ravi S. , Garceau Dylan , Kotredes Kevin P. , Logsdon Ben , Mangravite Lara M. , Howell Gareth , Sasner Michael , Troyanskaya Olga , Carter Gregory W. 
Published: December 2020

AbstractBackgroundThe enrichment of late‐onset Alzheimer’s disease (LOAD) GWAS variants in noncoding regions of the genome reveals new potential for modeling disease risk. Yet, identifying noncoding causal variants and the cell types in which they are functional remains challenging. Translating noncoding variants into novel mouse models can elucidate phenotypic effects of those variants through specific perturbations of gene enhancers associated with LOAD risk.MethodWe developed a multi‐tier approach to translate noncoding GWAS risk variants into novel mouse models of LOAD. First, we used publicly available GWAS summary statistics and eQTL data from the AMP‐AD consortium (ROS/MAP, Mayo Clinic) across two brain regions (DLPFC, TCX) to prioritize LOAD risk variants. Then, a deep learning approach (DeepSEA) was implemented to identify regulatory variants in conserved enhancers that are likely to disrupt expression of nearby candidate genes in both human and mouse. Further, ATAC‐seq data from human and mouse was integrated to predict cell‐type specific effects of the prioritized regulatory elements. Finally, the top‐predicted disease‐associated variants were used to develop novel mouse models as part of the MODEL‐AD initiative.ResultOur integrative approach for prioritizing disease‐associated variants revealed a set of conserved risk variants that mediate the expression of nearby LOAD candidate genes in a cell type‐specific manner. These included several well‐known LOAD risk loci (BIN1, PT2KB, SCIMP, CD2AP). In addition, we identified a genome‐wide significant risk variant (rs4575098, p = 2.05 × 10(‐11), Jansen et al. 2019), which decreased expression of the novel candidate FCER1G in the brain of LOAD patients (ROS/MAP eQTL p = 1.81 × 10(‐05), beta = ‐0.27). This highly conserved variant resides in a microglia specific enhancer and overlaps with a binding site of the transcriptional regulator PU.1 (SPI1). We created a 2kb enhancer deletion mouse model for the FCER1G associated variant and knock‐in models for variants linked to increased expression in three well‐known GWAS loci (BIN1, SCIMP, PT2KB). We provide initial functional characterization for our novel models based on RNA‐seq data.ConclusionOur findings expand the list of LOAD candidate genes likely to be impacted by noncoding variants and provide a novel set of mouse models to study their effects in vivo.
Human glia‐specific functional dysregulations affected by APOE ε4 risk of Alzheimer's disease
Authors: T.C.W. Julia , Qian Lu , Liang Shuang A. , Pipalia Nina H. , Chao Michael J. , Shi Yang , Bertelsen Sarah , Kapoor Manav , Marcora Edoardo , Sikora Elizabeth , Holtzman David M. , Maxfield Frederick R. , Zhang Bin , Wang Minghui , Poon Wayne W. , Goate Alison M 
Published: December 2020

AbstractBackgroundApolipoprotein E (APOE) is the strongest genetic risk factor for late‐onset Alzheimer's disease (AD). APOE ɛ4/ɛ4 homozygosity increases AD risk by >15‐fold. Although its association with AD is well‐established, the mechanisms underlying this genetic risk on particular brain cell types remains elusive. We hypothesized that the APOE ε4/ε4 genotype contributes to disease risk through cell autonomous mechanisms in glia.MethodWe used three models: human induced pluripotent stem cells (hiPSCs), post‐mortem brains and human APOE‐targeted replacement (TR) mice. We have differentiated microglia, astrocytes, cortical neurons and brain microvascular endothelial cells from hiPSC derived from non‐isogenic and isogenic cohort of cells selected based on APOE genotype. We also deconvoluted AD vs control whole brain transcriptome by cell types to confirm the findings from iPSCs in human brain tissue. Primary mouse microglia and astrocytes were purified from APOE‐TR mice. Global transcriptomic analyses were performed to identify APOE ɛ4 impact on particular cell type and to compare species differences. We validated predicted functional pathways in vitro using isogenic hiPSC lines using gas chromatograph‐mass spectrometry, fluorescently tagged cholesterol efflux assay, protein biochemistry and Luminex multiplex immunoassay.ResultGene set enrichment and pathway analyses of whole transcriptome profiles showed that APOE ε4 is associated with dysregulation of cholesterol homeostasis in human glia but not mouse astrocytes and microglia. Elevated matrisome signaling associated with chemotaxis, glial activation and lipid biosynthesis in APOE ε4 mixed neuron/astrocyte cultures parallels altered pathways uncovered in cell‐type deconvoluted transcriptomic data from APOE ε4 glia and AD post‐mortem brains. Experimental validation of the transcriptomic findings showed that isogenic APOE ε4 is associated with increased lysosomal cholesterol levels and decreased cholesterol efflux, demonstrating decoupled lipid metabolism. APOE ε4 glia also secrete higher levels of proinflammatory chemokines, cytokines and growth factors, indicative of glial activation.ConclusionThus, CNS cell type based models allowed us to elucidate APOE ε4‐driven cell autonomous effects; APOE ε4 induces human glia‐specific dysregulation in reactivity of the cells and associated lipid metabolism that may initiate AD risk.