bluuebunny/crossref_metadata_2025_split huggingface dataset:
Association of DNA methylation from the temporal cortex and cerebellum with AD‐related neuropathology and biochemistry
Authors: Oatman Stephanie R , Allen Mariet , Quicksall Zachary , Reddy Joseph S. , Carrasquillo Minerva M. , Wang Xue , Liu Chia‐Chen , Yamazaki Yu , Nguyen Thuy , Heckman Michael G. , Martens Yuka A , Zhao Na , DeTure Michael , Murray Melissa E. , Kanekiyo Takahisa , Dickson Dennis W. , Bu Guojun , Ertekin‐Taner Nilufer 
Published: December 2022

AbstractBackgroundAlzheimer’s disease (AD) is a progressive neurodegenerative disorder neuropathologically characterized by amyloid‐β (Aβ) plaques and tau neurofibrillary tangles often measured by Thal phase and Braak stage, respectively. Frequently, Aβ also deposits in the brain vasculature with severity categorized by a cerebral amyloid angiopathy (CAA) score. Assessment of these and related endophenotypes can reveal biological insights into the phenotypic variability in AD. We hypothesize that, amongst AD patients, severity of neuropathology and brain levels of AD‐related proteins are influenced by variation in DNA methylation (DNAm), the identification of which may uncover biological pathways for AD pathogenesis. To test this, we performed epigenome‐wide association studies (EWAS) using DNAm from the temporal cortex (TCX) and cerebellum (CER) with AD‐related neuropathology measures (Braak, Thal, and CAA) and brain levels of five proteins (apoE, Aβ40, Aβ42, tau, and p‐tau).MethodsDNAm from autopsy‐confirmed AD cases available through the Mayo Clinic Brain Bank was measured by reduced representation bisulfite sequencing (RRBS) from 471 brain samples, 200 of which had both TCX and CER measures. Bisulfite converted reads were sequenced on the Illumina High Seq4000 and quality filtered. Neuropathology scoring was performed by an experienced neuropathologist. TCX levels of five AD‐related proteins from three fractions (buffer‐soluble, detergent‐soluble, and insoluble) were measured by ELISA (Liu et al. 2020). Individual CpG methylation ratios were tested for association with each neuropathological and biochemical measure using the R package CpGassoc.ResultsWe identified multiple epigenome‐wide significant CpGs unique to each AD‐related measure. Comparisons between the TCX and CER revealed region specific CpG associations. The effects of sex, age at death, APOE genotype, and presence of genetic variants for each significant CpG association were also identified.ConclusionsAlthough all neuropathological and biochemical measures tested reflect core AD pathologies, our results demonstrate unique associations of epigenetic factors with these individual phenotypes, suggesting that their variability may be governed by distinct epigenetic processes. Discovery of DNAm changes that underlie specific neuropathological or biochemical outcomes can enhance our understanding of AD pathophysiology and may lead to the identification of novel gene or pathway targets for the different facets of this complex condition.
APOE‐targeted epigenome therapy for late onset Alzheimer’s disease
Authors: Kantor Boris , Rittiner Joseph , Nicholls Peter J , Chiba‐Falek Ornit 
Published: December 2022

AbstractBackgroundThere is an urgent need to refocus Alzheimer’s disease (AD) drug discovery on new targets and shifting the paradigm of AD DRUG DEVELOPMENT towards precision medicine. Apolipoprotein E gene (APOE) is the strongest and most reproduceable genetic risk factor for late‐onset Alzheimer’s disease (LOAD), and thus holds promise as a potential therapeutics target for LOAD. In this study we developed an epigenome therapy platform to reduce APOE expression generally and APOEe4 specifically by targeted modification of the epigenome landscape within APOE locus.MethodsOur gene therapy strategy is based on CRISPR/deactivated (d)Cas9 editing technology fused with an effector molecule and delivered by lentiviral (LV) vehicle. Our gRNAs were designed to target regulatory elements in the APOE promoter and in exon 4 overlapping the SNP that define the APOEe4 allele. We evaluated our epigenome therapy platform in vitro using human hiPSC‐derived neurons and in vivo by stereotactic injection of reporter gene into the hippocampus of mice.ResultsThe LV dCas9‐repressor vector showed decreased APOE‐mRNA and protein overall levels in hiPSC‐derived neuronal model. To specifically target the APOEe4 allele we utilized the VRER‐dCas9 protein. Evaluation of the system specificity showed a reduction in APOE‐mRNA levels in the hiPSC‐derived neurons with the e4 allele while there was no effect in the isogeneic hiPSC‐derived neurons homozygous for the e3 allele. Moving onto in vivo studies in mice administration of LV dCas9‐repressor vector and the GFP reporter gene into the hippocampus showed 50‐70% decrease in GFP expression demonstrating promising preliminary data. Collectively, our results provided in vitro and in vivo proof‐of‐concept for the utility and efficacy of the APOE‐targeted epigenome therapy.ConclusionsOur epigenome therapy strategy for fine‐tuning of APOE expression based on dCas9 technology is translational toward the development of a therapeutics approach to prevent and/or delay LOAD onset. Furthermore, the technology offers the opportunity to refine the platform for the development of gene‐specific and even allele‐ and cell‐type‐ specific therapies, and by that enables the advancement of strategies for precision medicine in LOAD.
Non‐specific elevation of plasma phosphorylated tau181 during neurological illnesses affecting consciousness
Authors: Thanapornsangsuth Poosanu , Ongphichetmetha Tatchaporn , Hemachudha Thiravat 
Published: December 2022

AbstractBackgroundPhosphorylated tau (p‐tau)181 has become a promising blood‐based biomarker for Alzheimer’s disease (AD), however, most prospective diagnostic studies excluded participants with other neurological illnesses. We studied the agreement of plasma p‐tau181 and cerebrospinal fluid (CSF) markers, according to AT(N) framework to evaluate the practicality of implementing blood‐based AD diagnosis.MethodPlasma and CSF were simultaneously collected in subjects presenting with alteration of consciousness to the King Chulalongkorn Memorial Hospital, Bangkok, Thailand. Plasma p‐tau181 was measured using the single‐molecule array. CSF biomarkers were classified according to the AT(N) framework.ResultAmong 69 participants enrolled in the study, the median (IQR) age was 57 (28.5‐75) years, 32 (46.4%) were male, and 4 (5.8%) had AD. Plasma p‐tau181 yielded area under the curve (AUC) of 0.86, although its correlation with CSF p‐tau181 was relatively weak (Rho=0.42, p<0.001). Based on the Youden’s index, the optimal cut‐off point showed sensitivity, specificity, and overall agreement of 0.75, 0.85, and 0.84, respectively. Among subjects with negative CSF biomarkers of AD, plasma p‐tau181 was elevated beyond the usual cut‐offpoint derived from our memory clinic patients undergoing positron emission tomography in many, resulting in a poor specificity of 0.65.ConclusionPlasma p‐tau181 showed inadequate performance for diagnosing AD in patients with other neurological illnesses and warrant great caution if used.
Becoming physically active or maintaining physical activity during midlife is associated with biomarkers of amyloid‐beta, microglia, and temporal lobe integrity
Authors: Akinci Muge , Deulofeu Carme , Palpatzis Eleni , Peña‐Gomez Cleofé , Fuentes‐Julian Sherezade , Operto Grégory , Garcia Marina , Milà‐Alomà Marta , Shekari Mahnaz , Kollmorgen Gwendlyn , Suridjan Ivonne , Wild Norbert , Blennow Kaj , Zetterberg Henrik , Gispert Juan Domingo , Suárez‐Calvet Marc , Sánchez‐Benavides Gonzalo , Grau‐Rivera Oriol , Arenaza‐Urquijo Eider M 
Published: December 2022

AbstractBackgroundPhysical activity (PA) has a beneficial effect on brain health in older age. Whether and how changes in PA during midlife are linked to brain health later in life remains understudied. In adults at risk for Alzheimer’s disease (AD), we investigated the change in PA during midlife in relation to biomarkers of AD pathology, microglia, and brain integrity.MethodsA questionnaire investigating the minutes of PA per week was administered to 273 cognitively unimpaired participants at baseline and after a follow‐up of 4.1 (±0.8) years. The change in PA minutes/week between the two time points was calculated. Participants were classified in groups based on their activity levels at the two time points (active≥150 minutes, inactive<150 minutes): (1) maintained‐PA groups: active/active, inactive/inactive and (2) changing‐PA groups: inactive/active, active/inactive. During the follow‐up, participants had available CSF amyloid‐β42/40, phosphorylated‐tau and sTREM‐2 measured using either the exploratory Roche NeuroToolKit or the Elecsys® immunoassays, amyloid PET, and structural MRI (AD signature [medial temporal lobe structures] thickness and hippocampal volume). We conducted multiple regression analyses with AD, microglia, and brain integrity biomarkers as outcome measurements and the change in PA minutes between the two time points as predictor, to assess dose‐dependent effects within the whole group, and maintained‐PA and changing‐PA groups separately. Furthermore, we investigated the associations of maintenance and change in activity status (PA groups) on the outcome measurements. All models were adjusted by age, sex, APOE‐ε4 status, education, and time interval between baseline and follow‐up.ResultsThe associations observed were group‐specific: increased minutes of PA was associated with greater AD signature thickness in the active/active group (p = 0.05) and greater hippocampal volume in the inactive/active group (p = 0.046). In the maintained‐PA groups, being active/active predicted higher CSF amyloid‐β42/40 (p = 0.024). In the changing‐PA groups, decreased minutes of PA predicted higher sTREM2 (p = 0.036) and brain amyloid‐β burden (p = 0.021). Additionally, the active/inactive group showed higher sTREM2 (p = 0.033) and brain amyloid‐β burden (p = 0.013).ConclusionsOur results suggest that becoming or staying physically active during midlife is associated with lower amyloidosis, microglia activation, and preserved temporal lobe integrity. The results further suggest a dose‐dependent effect of PA on brain health.
Microglial proteins Iba1 and TSPO (PBR) are differentially altered in the temporal cortex and cerebellum according to Braak stage
Authors: Garland Emma F , Dennett Oliver , Hartnell Iain James , Nicoll James AR , Bottlaender Michel , Boche Delphine 
Published: December 2022

AbstractBackgroundMicroglia are the resident immune cells in the brain and contribute to the neuropathology of Alzheimer’s disease (AD) by mechanisms not completely known. Iba1 is a microglial marker associated with homeostatic and motility functions. Whereas TSPO (PBR) is a marker of the mitochondrial membrane in microglia, macrophages and endothelial cells and is proposed to be associated with the activated subtype of microglia.MethodTo assess both Iba1 and PBR, we retrieved human temporal cortex and cerebellum samples from 57 cases at different stages of the disease, based on the Braak staging (Group 0‐II n=19, Group III‐IV n=20, Group V‐VI n=18), using immunohistochemical analysis. Additionally, a V‐Plex Mesoscale Discovery (MSD) analysis was performed to assess the inflammatory environment.ResultThere was a significant increase in PBR percentage load (P<0.001) across the Braak stages in the temporal cortex (average load 0.93%) but not in the cerebellum (average load 0.76%). Conversely, there was a significant increase in cerebellar Iba1 load (average load 0.96%, P=0.012) but not in the temporal cortex (average load 1.12%). Furthermore, it was observed that Iba1 forms clusters, putatively around amyloid plaques, whereas this phenomenon was not seen with the PBR marker. The only significant inflammatory molecule was the cytokine IL15 in the temporal cortex (P=0.024), which increased across all Braak stages. However, when the MSD data was correlated with the Iba1 and PBR markers it showed that GM‐CSF was significantly correlated with PBR in the temporal cortex (P<0.0099) and IL‐16 was significantly correlated with Iba1 in the cerebellum (P<0.0012).ConclusionThis emphasises the outcome that, in AD, PBR may contribute to inflammation in the temporal cortex and Iba1 may be correlated to inflammation in the cerebellum. The findings indicate that TSPO relates to microglial activation in the brain which is Braak‐stage specific and consequently supports the use of TSPO ligands for positron emission tomography (PET) imaging of Alzheimer’s disease‐relevant microglial activity in vivo. Moreover, the absence of an increase in PBR load in the cerebellum could qualify this structure as a reference region for PET quantification.
The impact of social health on global cognition and cognitive domains: An individual participant level data meta‐analysis of longitudinal cohort studies of cognitive ageing
Authors: Samtani Suraj , Mahalingam Saly , Lam Ben C. P. , Lipnicki Darren M. , Costa Erico , Xiao Shifu , Guerchet Maëlenn , Preux Pierre‐Marie , Skoog Ingmar , Scarmeas Nikolaos , Kim Ki Woong , Riedel‐Heller Steffi G. , Hamid Tengku Aizan , Numbers Katya T. , Ganguli Mary , Crowe Michael G , Ng Tze Pin , Sachdev Perminder S. , Brodaty Henry ,   Cohort Studies of Memory in an International Consortium (COSMIC) and Social Health And Reserve in the Dementia patient journal (SHARED) consortium
Published: December 2022

AbstractBackgroundThe Social Health and Reserve in the Dementia patient journey (SHARED) project is an international collaboration investigating the association between social health and cognitive function. We conducted an individual participant‐level meta‐analysis of the associations between social health variables and cognitive function (global cognition, memory, language, and executive function).MethodWe obtained individual participant level data (N = 38,641, mean age = 70.5 years, 58.49% female) from 13 longitudinal cohort studies of ageing (12 studies from the COSMIC consortium and the English Longitudinal Study of Ageing). Linear mixed models examined the impact of social health factors, namely relationship status, cohabitation, interactions with friends/family, community group engagement, perceived social support, loneliness, and having a confidante, on global cognition and cognitive domains (memory, language, and executive function).ResultAfter controlling for age, sex, and education, we found significant associations between social health variables and slower cognitive decline over time (Mean follow up = 4.99 years, SD = 3.71 years). Compared to being single, being in a relationship was associated with slower decline in global cognition (b = 0.0132, 95% CI: 0.0044, 0.0220), and language (b = 0.0180, 95CI%: 0.0015, 0.0346). Living with others was associated with slower decline in global cognition (b = 0.0089, 95% CI: 0.0039, 0.0139), and memory (b = 0.0155, 95%CI: 0.0031, 0.0279). Compared to never interacting with friends/family, weekly interactions were associated with slower decline in global cognition (b = 0.0178, 95% CI: 0.0021, 0.0335) and memory (b = 0.0198, 95% CI: 0.0094, 0.0302). Other social variables (community group engagement, loneliness and having a confidante) were not associated with cognitive decline.ConclusionGood social health (specifically, being in a relationship, living with others, and interactions with friends/family) was associated with slower cognitive decline. Further research is required to investigate the causal pathways from social health to cognitive health.
Shared genetic components between brain regions identify potential therapeutic targets for Alzheimer’s disease by integrative proteomic analysis
Authors: Liu Andi , Manuel Astrid M. , Dai Yulin , Fernandes Brisa S. , Enduru Nitesh , Jia Peilin , Zhao Zhongming 
Published: December 2022

AbstractBackgroundGenome‐wide association studies (GWAS) have identified >30 genetic loci associated with Alzheimer’s disease (AD). However, how those variants impact protein expression in different brain regions remain elusive. Large‐scale quantitative proteomic datasets of AD postmortem brain tissues have become available with the breakthrough of high‐throughput mass spectrometry‐based technologies. Thus, we utilized these datasets to understand brain region‐specific molecular pathways underlying AD pathogenesis and their potential drug targets.MethodWe extended our multi‐omics network‐based tool, Edge‐Weighted Dense Module Search of GWAS (EW_dmGWAS), to integrate genetic variants with brain region‐specific proteomic profiles. We performed this analysis by leveraging publicly available AD GWAS statistics of 472,868 individuals (Schwartzentruber et al., 2021) and protein expression profiles covering 190 parahippocampal gyrus (PHG) samples from the Mount Sinai Brain Bank (MSBB) and 192 dorsolateral prefrontal cortex (DLPFC) samples from the Religious Orders Study and Memory and Aging Project (ROSMAP). The resulting modules were evaluated using a scale‐free network index. We highlighted key overlapped genes between region‐specific top module genes (TMGs) and further examined region‐specific differentially co‐expressed genes to identify investigational AD drug targets. Gene set enrichment analyses were performed to assess the functions and cell‐type‐specificity of region‐specific TMGs.ResultThe EW_dmGWAS analyses prioritized 52 TMGs from PHG and 58 TMGs from DLPFC. The TMGs in both regions were found to be enriched in excitatory neurons through cell‐type‐specific enrichment analysis (combined p‐value = 0.03 in PHG; combined p‐value = 0.09 in DLPFC). We found four key overlapped genes with high genetic risk (gene‐level FDR < 0.05), CLU, PICALM, PRRC2A, and NDUFS3. In addition, the differentially co‐expressed drug target analysis pinpointed three potentially drug‐targetable genes, APP, SNCA, and VCAM1, in PHG but none in DLPFC. Additional enrichment analyses of TMGs revealed region‐specific biological processes and drug signatures, including disulfiram in PHG (‐log2FDR = 9.5).ConclusionOur network‐based analyses of PHG and DLPFC proteomic profiles prioritized potential key shared genetic factors, which were further proved to play possible roles in the excitatory neurons in AD pathology. Our drug signature analyses validated three known investigational drugs targets, suggesting our findings might serve as a repurposing strategy for AD.
Delays in access to an Alzheimer’s treatment for individuals dually eligible for Medicare and Medicaid in the U.S.
Authors: Mattke Soeren , Jun Hankyung , Chu Samantha , Hanson Mark 
Published: December 2022

AbstractBackgroundPrior research has predicted substantial wait times for access to a disease‐modifying Alzheimer’s treatment because of the combination of a highly prevalent disease and a complex diagnostic process. Access could be particularly limited for individuals dually eligible for Medicare and Medicaid in the U.S. in some states. Medicaid programs cover Medicare cost‐sharing requirements for their indigent members, but under the so‐called “lesser of” policy, states may elect to pay only up to the Medicaid rate which is typically less than the Medicare rate. In states with that policy, providers will only receive the lower Medicaid rate, which is known to reduce appointment availability. We estimate the effect of the policy on wait times.MethodWe use a Markov model to predict wait times for dually eligible and regular Medicare beneficiaries. Counts of both groups by age, sex and states came from Census data and Medicare enrollment records, specifics of each state’s Medicaid policy from published data and inquiries to states, and prevalence and incidence data as well as price elasticity of supply from published data.ResultAt total of 35 states and the District of Columbia have a “lesser of” policy and pay less than the Medicare rate for elective specialty care. The average wait time for dually eligibles is between 5.9 and 48.5 months with an average of 17.5 compared to between 3.6 and 42.5 with an average of 13.8 for regular Medicare beneficiaries in those states. Conversely, wait times are indistinguishable in states without that policy, as Figure 1 illustrates. As Figure 2 shows, the difference means that duals have a 30.3% higher average wait times than regular Medicare beneficiaries with a range of 61.2% in DC and 1.2% in Georgia.ConclusionThe “lesser of” policy is likely to reduce access for the socio‐economically disadvantaged group of dually eligibles, who also suffer from a higher disease burden. The delays would translate into avoidable disease progression and mortality, raising concerns about health equity.
Ubiquitin‐proteasome system dysfunction induced by Alzheimer's disease‐linked Ab oligomers
Authors: Cozachenco Danielle , Ribeiro Felipe Campos , Fortuna Juliana , Lourenco Mychael V. , De Felice Fernanda G. , Ferreira Sergio T. 
Published: December 2022

AbstractBackgroundBrain accumulation of the amyloid‐β peptide (Aβ) is a pathological hallmark of Alzheimer’s disease (AD). Considerable evidence indicates that soluble Ab oligomers (AβOs) cause synapse failure/loss and cognitive decline in AD. Evidence further indicates that the ubiquitin‐proteasome system (UPS) is inhibited in AD brains, likely leading to impaired synaptic plasticity and memory. However, the mechanisms underlying UPS dysfunction in AD remain to be elucidatedMethodHere, we investigated proteasome activity in primary hippocampal cultures and in isolated hippocampal synaptosomes from mice that received an intracerebroventricular (i.c.v.) infusion of AβOs. We further investigated the possible protective actions of UCH‐L1, an enzyme that enhances proteasome‐mediated degradation of target proteins, against the impact of AβOs on hippocampal neurons and memory.ResultExposure to AβOs resulted in decreased proteasome activity in primary hippocampal cultures and in isolated hippocampal synaptosomes. Synaptosomes isolated from the hippocampi of AβO‐infused mice were also inhibited compared to hippocampal synaptosomes from control, vehicle‐infused mice. Treatment with exogenous recombinant UCH‐L1 prevented oxidative stress in AβO‐exposed hippocampal neurons and memory deficit in AβO‐infused mice.ConclusionThese results indicate that AβOs inhibit the proteasome, notably at synapses, and suggest that boosting proteasomal proteolysis prevents AβO‐induced neuronal damage and memory deficit.