bluuebunny/crossref_metadata_2025_split huggingface dataset:
APOE loss‐of‐function variants: Compatible with longevity and associated with resistance to Alzheimer’s Disease pathology
Authors: Guen Yann Le , Chemparathy Augustine , Chen Sunny , Leong Lesley , Gorzynski John John , Xue Guangxue , Belloy Michael E , Kasireddy Nandita , Tauber Andres Peña , Williams Kennedy , Wingo Thomas S. , Lah James J. , Jayadev Suman , Hales Chadwick M , Peskind Elaine R , Child Daniel D , Keene C Dirk , Le Cong , Ashley Euan , Yu Chang‐En , Greicius Michael D 
Published: December 2023

AbstractBackgroundThe ε4 variant of APOE is the strongest genetic risk factor for late‐onset Alzheimer’s disease (AD). It remains unclear if the ε4 protein increases AD risk through a gain of abnormal function, or whether it functions less well than the ε3 protein. Framed bluntly: Would knocking down ε4 in an ε4 carrier increase or decrease AD risk?MethodWe searched whole‐exomes and whole‐genomes from ∼47,000 older controls and AD cases in the Alzheimer’s Disease Sequencing Project (ADSP) looking for early loss‐of‐function variants on APOE. Five of 26,605 older controls carried a loss‐of‐function variant while only one of 20,856 AD cases did (Figure.1A/B). We reasoned that if ε4 does not function as well as ε3, then loss‐of‐function of either ε3 or ε4 should have an ε4‐like impact on risk. However, if ε4 is inherently detrimental, loss‐of‐function of ε4, specifically, should have a protective effect.ResultLoss of ε3 was seen in two cognitively healthy ε3 homozygotes, last assessed at ages 82 and 88. This suggests that the ε3/null effective genotype is not a strong driver of AD risk. Subject 6‐nominally ε3/ε4 but effectively ε4/null ‐developed symptoms at 75 and died at 87 with autopsy‐confirmed AD, with an age‐at‐onset similar to typical ε3/ε4 (μ = 73.5y), but later typical than ε4/ε4 (μ = 69.7y). This suggests that the loss of ε3 does not result in an ε4‐like phenotype, as seen with Subjects 3 and 5. The most illustrative phenotypes are seen in Subjects 1 and 2 who are nominally ε3/ε4 but effectively ε3/null. Subject 2 was cognitively healthy at 79, with normal levels of amyloid and tau in cerebrospinal fluid at 76, while 2/3rds of ε3/ε4 are amyloid‐positive by 75. Subject 1 was assessed as cognitively normal at 90, died the same year, and had no amyloid pathology, and no amyloid deposits in the cerebral blood vessels, making him a prominent outlier compared to 1700 ε3/ε4 individuals in NACC (Figure.1C).ConclusionTaken together, these results provide the strongest human genetics evidence yet available to support the hypothesis that ε4 drives AD risk through a gain of abnormal function and that reducing ε4 should be expected to reduce AD risk.
Studying TLR9 loss‐of‐function in iPSC of patients with deleterious mutation
Authors: Cacace Rita , Frydas Alexandros , van Broeckhoven Christine 
Published: December 2023

AbstractBackgroundToll‐like Receptor 9 (TLR9) is an essential innate and adaptive immune component. In human it is predominantly expressed in B cells and in plasmacytoid dendritic cells (pDC). We have previously identified a novel heterozygous variant in TLR9 (p.E317D), located in the CpG‐DNA binding pocket, co‐segregating with Alzheimer’s disease (AD) in an early‐onset (EO) Flanders‐Belgian family. We showed that p.E317D decreases the TLR9 CpG‐induced signaling efficiency in HEK293 cells, suggesting loss‐of‐function (LoF). Cytokine profiling of human wild‐type peripheral blood mononuclear cells (PBMCs), upon TLR9 activation, revealed a predominantly anti‐inflammatory response. The cytokines released suppressed inflammation and promoted phagocytosis of Aβ42 oligomers in human induced pluripotent stem cells (iPSC)‐derived microglia. In this study, we aim to investigate the mutation effect in patients derived bio‐samples with the hypothesis that failure of the innate immune system to clear Aβ, rather than an overproduction of the Aβ peptides, is likely the disease mechanism in TLR9 LoF mutation.MethodIPSc were generated from two p.E317D mutation carriers from the Flanders‐Belgian family. Isogenic and knock‐out (KO) TLR9 iPSC lines were obtained by CRISPR‐based genome editing. Optimization of the derived‐pDC differentiation protocol in a feeder‐free culture methods and derived‐pDC characterization were performed.ResultDifferentiation of pDC was optimized in an iPSC control line. The formation of embryoid bodies (EB) was followed by induction of hematopoietic progenitor cells (HPCs) using timed addition of specific factors. HPCs were matured into pDCs through the addition of master regulators of cell faith (FLT3L, SCF and GM‐CSF). Derived‐pDC expressed specific cell surface markers, CD123, CD304, ILT3, DR6 and HLA‐DR and showed high expression levels of TLR9.ConclusionThe generation of derived‐pDC will allow us to test TLR9 response to its ligand in mutation carriers compared to isogenic cell lines. Furthermore, we will be able to test the effect of the complete loss of TLR9 in KO cell lines form the same patients. These cells, upon treatment with TLR9 ligands will produce specific conditioned media that will be used in additional investigations, among others, to treat iPSC‐derived microglia in presence of Aβ42 oligomers, to better understand the effect of LoF p.E317D mutation.
VIVIAD, A Phase 2b Study Investigating Varoglutamstat in Patients with MCI or Mild AD: Analysis of Baseline Cognition Data
Authors: Wenzkowski Christine , Schaeffer Michael , Fuchs Katharina , Weber Frank , Li Yanqi , Miller Claire Prener , Bihlet Asger Reinstrup , Alexandersen Peter , Axelsen Tobias Melton , Harrison John E , Vijverberg Everard G.B. 
Published: December 2023

AbstractBackgroundVaroglutamstat (PQ912) is an oral, small molecule inhibitor of glutaminyl cyclase, preventing the formation of neurotoxic N3pE amyloid. A Phase 2a study (NCT02389413, Scheltens et al., 2018) reported encouraging first evidence of varoglutamstat’s disease‐modifying activity, most importantly with statistically significant changes from baseline in working memory after only 12 weeks of treatment.MethodVIVIAD (NCT04498650, Vijverberg et al., 2021) is an informed multicenter, randomized, placebo‐controlled, double‐blind, parallel group dose‐finding Phase 2b study in 250 patients with Mild Cognitive Impairment (MCI) and early Alzheimer´s disease (AD). Treatment duration varies between 48 and 96 weeks depending on the time of inclusion, with participants receiving 300mg or 600mg varoglutamstat, or placebo, twice‐daily (BID). The participants’ disease status at time of inclusion was confirmed by Abeta1‐42 and phospho‐tau CSF biomarker profiles, various cognition tests including MMSE, DSST/WAIS‐IV Coding test (WAIS‐IV), and A‐IADL‐Q. Primary outcome is a composite score of the cognitive domains attention and working memory using the Cogstate Neuropsychological Test Battery (Cogstate NTB).ResultEnrollment has been completed, with a total of N = 259 patients randomized. The 300mg BID varoglutamstat arm was switched to 600mg BID based on positive independent Data Safety Monitoring Board review in June 2022. As of April 14, 2023, 23 patients had completed 96 weeks of treatment. The study will continue until the last patient has completed 48 weeks of treatment with the corresponding follow‐up visit. While most AD trials focus on cognitive tests assessing memory deficits rather than working memory and attention, VIVIAD uses WAIS‐IV to select patients with rescuable cognitive deficits in the target domains. In contrast to MMSE, WAIS‐IV performance shows a reasonably good correlation with the primary outcome measures. Comparing baseline data of male and female participants showed no significant gender differences except for Abeta1‐42 levels.ConclusionThe use of MMSE and DSST/WAIS‐IV together with CSF biomarkers is a valuable tool in identifying and recruiting patients with MCI or mild AD. The strategy of recruiting individuals with evidence of baseline deficits on the WAIS‐IV Coding test has successfully enriched the study cohort with respect to deficits in attention and working memory, enabling reliable assessment of potential cognitive improvement after treatment.
BCAT proteins: A metabolic link between Type II Diabetes and Alzheimer’s Disease
Authors: Lush Marie , Moraes Marcela Usmari , Conway Myra 
Published: December 2023

AbstractBackgroundAberrant energy pathways compounded by dysregulated cellular redox plays a pivotal role in the pathogenesis of Alzheimer’s disease (AD) but the underlying mechanisms are not clear. Clinical and epidemiological data show that those with Type II Diabetes Mellitus (T2DM) have a 65% increased risk of developing AD (Arvanitakis et al., 2004). Our group and others have shown that serum branched chain amino acids and the branched chain aminotransferase proteins (BCAT) are increased in subjects with AD and T2DM, which has been linked with dysregulated autophagy and metabolic reprogramming. Here, we explore how changes in cellular redox regulate and influence metabolic‐related pathology changes associated with AD.MethodsSHSY‐5Y cells were used as a neuronal model to observe the effects of BCATc dysregulation in neuronal metabolism. Cells were transfected with our BCATc overexpression constructs and metabolite load assessed using LC‐MS/MS. Activity of glycolytic enzymes GAPDH and enolase were assessed, and overall glycolytic rate characterised using a Seahorse XF analyser. Oxidative stress was measured using the HyPer‐7 molecular probe (Bousolov et al, 2004) and cells were visualised using confocal microscopy. Finally, Western blot analysis was performed to assess levels of BCATc in the presence of increasing glucose (+/‐ 100 nM insulin) and hydrogen peroxide treatments and to demonstrate changes in levels of β‐amyloid and hyperphosphorylated tau.ResultsHere we show that BCATc overexpression increases the level of glucose and fructose, whilst decreasing GAPDH, enolase activity and glycolytic rate (p < 0.05). There was an observable increase in hydrogen peroxide generation (p<0.001), while levels of amyloid precursor protein (P<0.01), β‐amyloid (p>0.05) and hyperphosphorylated tau (p<0.05) were significantly increased. In addition, levels of BCATc increased dose‐dependently following hydrogen peroxide treatments (p < 0.001) and decreased in the presence of excess glucose (+ 100 nM insulin) (p<0.05).ConclusionOur results demonstrate that the reprogramming of BCAT as a result of hallmarks of T2DM such as excess dietary‐derived nutrient signals and a concurrent increase in oxidative stress, are associated with aberrant processing and aggregation of β‐amyloid and tau protein and are likely to contribute to the pathophysiology of AD.
Interim phase 1 part A results for ALN‐APP, the first investigational RNAi therapeutic in development for Alzheimer’s disease
Authors: Cohen Sharon , Ducharme Simon , Brosch Jared R. , Vijverberg Everard G.B. , Apostolova Liana G. , Sostelly Alexandre , Goteti Sasikiran , Makarova Nune , Avbersek Andreja , Guo Weinong , Bostwick Bret , Mummery Catherine J. 
Published: December 2023

AbstractBackgroundGenetic‐driven deregulation of the amyloid pathway and overproduction of downstream amyloid‐β are known to cause early‐onset Alzheimer’s disease (EOAD)1. ALN‐APP is an investigational intrathecally (IT) administered RNAi therapeutic designed to reduce upstream intracellular and extracellular amyloid precursor protein (APP) levels by lowering APP mRNA. As a result, we hypothesize that ALN‐APP may alter the cascade of events that result in neurodegeneration, potentially slowing, halting, or reversing Alzheimer’s disease progression.MethodALN‐APP‐001 (NCT05231785) Part A is an ongoing randomized, double‐blind, placebo‐controlled, Phase 1 single‐ascending dose study in patients with EOAD. Patients are required to have disease onset at age <65 years, Clinical Dementia Rating® global score of 0.5 or 1.0, and Mini Mental State Examination score >20. Patients are being evaluated over 6 months, with further follow‐up of up to 6 months as needed. The primary endpoint is the safety and tolerability of ALN‐APP. Secondary objectives include the evaluation of pharmacokinetics and pharmacodynamic effects of ALN‐APP.Result12 patients were enrolled and randomized 2:1 to receive ALN‐APP or placebo in 25mg and 75mg dose cohorts. Baseline characteristics are shown in Table 1. Mean (SD) duration on study was 6.7 (1.7) months for cohort 1 (25mg) and 2.0 (1.0) months for cohort 2 (75mg). Dose‐dependent reductions of soluble APPα and APPβ (sAPPα and sAPPβ) levels in cerebrospinal fluid (CSF) at day 15 were observed following a single dose of ALN‐APP, with mean reductions from baseline of 55% (sAPPα) and 69% (sAPPβ), and maximum reductions of 71% (sAPPα) and 83% (sAPPβ) in the 75mg cohort (n = 4) (Table 2). All adverse events (AEs) by data cut‐off on 01/17/2023 were mild or moderate (Table 3), with no AEs deemed related to study drug by the investigators. Additional cohort data will be presented at the meeting.ConclusionThis first clinical study of a CNS‐administered RNAi therapeutic demonstrates target engagement of APP, with reductions in CSF sAPPα and sAPPβ. To date, ALN‐APP remains generally well tolerated with all reported AEs mild or moderate. These interim results support further evaluation of ALN‐APP in patients with EOAD.Reference:1. Hampel H et al. Molecular Psychiatry (2021). 26:5481‐5503.
History of preoperative COVID‐19 infection and postoperative cognitive change among older adults undergoing major elective surgeries
Authors: Sanborn Victoria , Enos Sara J , Tremont Geoffrey , Bedrosian Hannah E , Dousis Hunter M , Daiello Lori A 
Published: December 2023

AbstractBackgroundEmerging evidence suggests that recovery from COVID‐19 infection may be associated with cognitive decline and possibly, incident dementia. Older adults undergoing major surgeries are at heightened risk for postoperative delirium and delayed cognitive recovery; however, it is unknown whether preoperative COVID‐19 infection is associated with worse perioperative cognitive outcomes. Therefore, the objective of this study was to investigate relationships between history of preoperative COVID‐19 infection and cognitive change following major elective surgery.MethodThe study population consisted of cognitively normal adults, ≥ 65years, enrolled in the Cognitive Recovery After Elective Surgery (CREATES) study, an ongoing investigation of BBB function and perioperative cognition. Participants who completed preoperative baseline and 2‐month postoperative assessments were included in the analyses. Cognitive performance (global function (MoCA) and age‐ and education‐adjusted letter fluency, category fluency, learning, memory) at baseline was compared with 2‐month postoperative test results in the entire sample and among those with/without preoperative COVID‐19. Between‐group differences were analyzed using independent samples t‐tests, chi‐square analyses, and repeated measures ANOVAs.ResultA total of 34 participants (mean age, 75 [SD] 4.9 years; 83% White; 54% orthopedic surgery) were included. Of these, 10 reported a preoperative, non‐hospitalized COVID‐19 infection and 24 did not have preoperative COVID‐19. No cases of postoperative delirium were observed. In the full sample, there was evidence of cognitive improvement in letter fluency (F = 5.53, p = 0.03, η2 = 0.18) and memory (F = 4.42, p = 0.04, η2 = 0.12), relative to preoperative baseline. On the MoCA, a global cognitive measure, 86% scored within normal range (MoCA ≥ 26) 2 months after surgery. COVID sub‐groups did not differ on baseline demographics, family history, medical, or cognitive variables (all p’s<0.5). There was no effect of time on change in cognitive test scores (all p’s<0.05) at the 2‐month postoperative assessment.ConclusionIn this modest sample of older surgical patients, history of preoperative COVID‐19 infection was not associated with cognitive decline after surgery; however, postoperative improvement on some cognitive tests was observed in the full sample. Future research in larger populations including biomarkers of neuroinflammation is needed to determine whether older adults with history of COVID‐19 infection are at additional risk of cognitive decline following surgery.
Early metformin initiation was not associated with incident dementia: a population‐based cohort study
Authors: Wu Che‐Yuan , Wang Christa , Saskin Refik , Swardfager Walter 
Published: December 2023

AbstractBackgroundMetformin is the first‐line pharmacotherapy for type 2 diabetes. Although metformin was previously suggested to prevent dementia, most existing epidemiologic studies did not adequately address immortal time bias or confounding due to disease severity. We aim to determine the association of metformin with dementia risk using various bias mitigation strategies.MethodThis population‐based retrospective cohort study utilized data housed at ICES (https://www.ices.on.ca/). Using a validated algorithm for diabetes (Specificity = 99.1%, PPV = 91.4%), residents of Ontario, Canada ≥66 years newly diagnosed with diabetes from January 1, 2008 to December 31, 2017 entered the cohort. We excluded potential type 1 diabetes or advanced diabetes cases by excluding people with insulin as the first received glucose‐lowering medication. To select people at an early disease stage who could either initiate metformin or start lifestyle interventions alone, we excluded people with hemoglobin A1c <6.5% or ≥8.0% or estimated glomerular filtration rate (eGFR) <45 mL/min/1.73m2. Using a landmark analysis to address immortal time bias, the exposure was classified into “metformin monotherapy initiation within 180 days after new diabetes diagnosis” or “no glucose‐lowering medications within 180 days”. To mitigate reverse causality, a 1‐year lag period was applied to the end of the 180‐day landmark period, and therefore follow‐up started 1.5 year after cohort entry. Incident dementia was ascertained using a validated algorithm for Alzheimer’s disease and related dementias (Sensitivity = 79.3%, Specificity = 99.1%). Adjusted hazard ratios (aHR) and confidence intervals (CI) were obtained from propensity‐score weighted Cox proportional hazard models.ResultCompared to no or delayed metformin initiation (N = 22,369; 1,768 events; 117,414 person‐years), metformin initiation within 180 days (N = 12,331; 978 events; 65,761 person‐years) showed no association (aHR [95% CI] = 1.047 [0.956‐1.147]) with dementia risk over mean follow‐up of 5.28 years. The sensitivity analysis with a 1‐year landmark period also showed no association (aHR [95% CI] = 1.040 [0.942‐1.148]) when comparing metformin initiation within 1 year (N = 13,902; 1,047 events; 68,404 person‐years) to no or delayed initiation (N = 19,078; 1,433 events; 91,917 person‐years).ConclusionEarly metformin initiation was not associated with a lower dementia risk. The present study does not support metformin as a drug to prevent dementia.
Locus coeruleus hyperactivity in middle age may be associated with better cognitive performance
Authors: Riley Elizabeth , Swallow Khena , Anderson Adam , De Rosa Eve 
Published: December 2023

AbstractBackgroundMeasuring the health of the locus coeruleus (LC), the brainstem site of the first cellular damage in Alzheimer’s Disease (AD) pathogenesis, is of particular interest for early diagnosis. In both rodents and humans (Elman 2017; Kelberman 2023; Malatt 2022; Weinshenker 2008), increased tonic firing rates have been noted in middle age. This occurs prior to the hypoactivity and reduced functional and structural connectivity associated with cognitive aging (Jacobs 2015; Kelberman 2022; Langley 2022; Prokopiou 2022) . Understanding the mechanism or function behind LC hyperactivity in middle age may be key to identifying individuals on pathological aging trajectories.MethodParticipants (29 younger, 18 middle‐aged, 24 older) performed a dual attention task in the scanner with multi‐echo fMRI and concurrent pupillometry. Cognition was assessed with NIH Toolbox Cognitive Battery (Fluid Composite) and sorted into high (>50th percentile) or low (<50th) categories. Age groupings were determined by a pupillary behavior data analysis.Results
Pupil (Fig. 1): using a linear mixed effects model to predict the dynamic range‐normalized pupillary response area under the curve (AUC) from age group and trial type, there was a significant effect of age and significant age*trial type interactions. Middle‐aged adults had larger responses than other groups. Using a model to predict AUC from cognitive category and trial type, there was a significant interaction between cognitive category and trial type, with the high cognitive group having larger target and distractor responses.
Blood‐Oxygen‐Level‐Dependent (BOLD) (Fig. 2): using a linear mixed effects model to predict LC BOLD response from age group and trial type, there was no significant effect of age but a significant age*trial type interaction. Middle‐aged adults had larger distractor responses and older adults had smaller target responses. Using a model to predict BOLD response from cognitive category and trial type, there was no significant effect of category, but there was a significant interaction between category and trial type, with the high cognitive group having larger target and distractor responses.ConclusionsElevated LC BOLD and pupillary responses to target trials in middle age are associated with better cognitive performance. LC hyperactivity may be adaptive in middle age.
URBAn Native Elders: Risk and Protective Factors for Alzheimer’s Disease and Related Dementias ‐ Overview and Methods
Authors: Nelson Lonnie A , Mednansky Sage W. , Pham‐Lake Camille , Bryne Charlotte , Jones Jacob , Valenzuela Yenny Gabriela , Rivas Rhiannon , Cuellar‐Rocha Priscilla , West Cynthia , Lee Sunny T. , Ali Tauqeer , Collier Ann , Mortenson Ryan , Suchy‐Dicey Astrid M , Muller Clemma , Buchwald Dedra 
Published: December 2023

AbstractBackgroundOver 86% of American Indian and Alaska Native elders live in urban metropolitan areas, yet the extant epidemiological data on cognition and aging in this racial and ethnic population has been collected in reservation communities and may have limited generalizability to the larger population. Multi‐faceted, high quality data are needed to assess risk and protective factors in this underserved and understudied population.MethodWe intend to collect medical history, lifestyle and behavioral history, neurocognitive battery, anthropometric measures, blood and urine samples, cranial 3T MRI, rsfMRI, and wrist actigraphy data from 1200 urban‐dwelling Native elders (age 55 and older) across 5 major metropolitan areas: Anchorage, AK; Seattle, WA; San Bernardino, CA; Phoenix, AZ; and Oklahoma City, OK. This initial cohort will be the first in a NIA‐funded longitudinal cohort study to evaluate the brain and cognitive health of this population as they advance in age.ResultOriginally funded in the summer of 2019, data collection was initially delayed due to the pandemic, but was initiated at one site (Phoenix) in the summer of 2021 and is now underway at all 5 field sites, with a total of 260 participants enrolled as of the time of this writing.ConclusionThis study represents the largest effort to characterize the cognition and brain health of a generalizable sample of urban‐dwelling American Indian and Alaska Native elders to date.