bluuebunny/crossref_metadata_2025_split huggingface dataset:
Modifiable dementia risk factors associated with distinct subjective and objective cognitive outcomes
Authors: Rosická Anna M , Teckentrup Vanessa , Pringle Andrew , Gallagher Eoghan , Hanlon Anna K , Lawlor Brian , Naci Lorina , Gillan Claire M 
Published: December 2023

AbstractBackgroundA range of potentially modifiable environmental, social, and lifestyle factors are estimated to contribute to over a third of dementia cases worldwide. Leading theories propose that these risk factors have different risk‐conferring mechanisms. For example, social isolation, hypertension, and exercise may respectively impact most on cognitive reserve, neurodegeneration, and inflammation. If true, this may support the development of more personalised preventative strategies, depending on risk profiles. Here, we aimed to address this by gathering multiple forms of cognitive assessment in a large sample, across lifespan.MethodN = 2831 users of a free smartphone app, Neureka (aged 18‐82, M(SD) = 46.84(14.7)), completed questionnaires about their background, health, and lifestyle. Additionally, they completed subjective and objective assessments of their cognitive status, via questionnaires (subjective memory problems, attitude to own ageing, and cognitive fluctuations) and cognitive tests (working memory, processing speed, cognitive flexibility, and model‐based planning), respectively. We tested the differential cognitive correlates of previously established risk factors using univariate regressions, controlling for age and gender.ResultLower education and socio‐economic status (SES) were associated with worse cognitive status across all domains (all p<.05). However, the association between SES and subjective cognition (β = 0.38–0.51) was more than twice that of objective cognition (β = 0.05–0.09), while this was not the case for education (β = 0.15–0.32 for subjective and β = 0.10–0.16 for objective cognition). Subjective measures were also more sensitive to depression, loneliness, hearing handicap, age‐related hearing loss, and tinnitus (all p<.01 for subjective and .001<p<.75 for objective cognition). In contrast, cardiovascular factors like diabetes, hypertension, stroke, and smoking were associated with comparable impacts on objective and subjective cognition. Overall, there was little evidence for risk factor correlates of different aspects of objective cognition (e.g., working memory vs. processing speed).ConclusionObjective and subjective cognition have dissociable associations with certain potentially modifiable risk factors for dementia. This may aid in our understanding of the distinct mechanisms through which they confer risk for dementia. The objective cognitive assessments gathered, model‐based planning, memory, processing speed and flexibility, yielded remarkably similar associations with risk factors, suggesting a common mechanism through which they are linked to risk factors for dementia.
Genome‐wide identification of modifiers of age‐at‐onset for Alzheimer’s disease in African American populations
Authors: Nuytemans Karen , Guo Shengru , La Jong Ok , Naj Adam C. , Gao Xiaoyi Raymond , Li Yi‐Ju , Martin Eden R. ,   the Alzheimer Disease Genetics Consortium
Published: December 2023

AbstractBackgroundSeveral studies have attempted to identify genes for age‐at‐onset (AAO) of Alzheimer’s disease (AD) through genome‐wide linkage and genome‐wide association studies (GWAS). While these efforts have thus far focused predominantly on non‐Hispanic white (NHW) populations, we present here the first GWAS to identify genetic contributors to AAO in African Americans (AA) using AA genotype and phenotype data from the Alzheimer’s Disease Genetics Consortium (ADGC).MethodWe combined data from 13 AA prospective and case‐control ADGC datasets, excluding family‐based datasets. Genotype data underwent standard quality control and were imputed to the TOPMed R5 reference panel using the Michigan Imputation Server. Data were merged across cohorts using QCTOOL and GTOOL, filtering out variants with MAF≤0.005). We performed two analyses: case‐only linear mixed‐model regression with AAO as outcome (LMM); and survival analysis using Cox proportional‐hazards frailty modeling (COXPHF) with time‐to‐AD‐onset (AAO in cases and censoring of controls at age‐at‐last‐exam). Both models were adjusted for sex, principal components capturing population substructure, and APOE‐ε4 dosage with a random cohort effect.ResultWe examined 2,262 AA AD cases, including 1,561 females (69%) with mean (SD) AAO of 77.7 (8.1) years. The APOE‐adjusted COXPHF analyses identified twelve genome‐wide significant regions (P<5×10−8), the most significant in ABCA7 (P = 3.57×10−10), known to be associated with AD risk in AAs. In the LMM analysis, we observed strong novel associations with variants in CCDC141 on chr2q31.2 (Pmin = 2.93×10−9). In silico analyses of LD structure and functional potential suggest SESTD1, a gene involved in synaptic regulation, as driving the CCDC141 locus signal. Nine of 12 COXPHF loci were driven by African‐specific variants (MAF<0.0002 in gnomAD Non‐Finish Europeans). These significant loci identified in the AA COXPHF or LMM analyses were not significant (P>0.05) in equivalent analyses in NHW ADGC cohorts (9,220 AD cases/10,350 controls; Li et al. Alz Dement 2023), except for the ABCA7 locus (NHW P<0.0002).ConclusionIn a large ADGC African American dataset, we confirmed AAO associations in the APOE region and ABCA7 and observed evidence for potential novel AD AAO loci including SESTD1; many of which might be African‐ancestry specific.
Evaluation of the cognitive enhancing properties of diosmin in lipopolysaccharide‐induced memory impairment in mice
Authors: Adeniyi Funmilayo Racheal , Adeoluwa Olusegun Adebayo , Adeoluwa Gladys Onyinye , Adeoye Rachel , Ibifiri Precious Jack 
Published: December 2023

AbstractBackgroundCognitive impairment is a major feature of many neurodegenerative disorders such as Alzheimer’s disease, dementia etc. The progressive cognitive decline in Alzheimer’s disease (AD) can be attributed to the fact that current anti‐Alzheimer’s drug only treat AD symptoms without completely reversing cognitive impairment in AD patients. Therefore, it is imperative to develop new therapeutic remedies that can improve memory and ameliorate cognitive impairment in AD patients. Disomin is a flavone with antioxidant, anti‐inflammatory and anti‐apoptotic properties. This study evaluated the neuroprotective effects of diosmin on LPS‐induced cognitive impairment in mice.MethodThirty‐six Swiss mice were randomly divided into six groups (n = 6). Group 1 received vehicle, group 2 received vehicle, groups 3 to 5 received diosmin (50, 100 and 200 mg/kg, p.o.) respectively group 6 received donepezil (50 mg/kg, p.o.). Sixty minutes after the treatment with the vehicle/Diosmin/Donepezil, lipopolysaccharide (LPS) (250ug/kg, i.p.) was administered daily to groups 2 to 6 for seven days. Twenty‐four hours after treatment on day 7, mice were subjected to Y‐maze test and the Novelty object recognition test (NORT) to assess their spatial and non‐spatial working memory. Subsequently, the mice were sacrificed and their brain samples were harvested for biochemical analysis (TNF‐alpha, Interferon gamma and interleukin‐12), immunohistochemical examinations (Amyloid beta, BDNF, IBA‐1, NLRP3 expression) and Golgi staining procedure for morphological alterations.ResultOur data shows that diosmin increased percentage alternation in Y‐maze test and discrimination ratio in NORT compared with the control group. Diosmin significantly (p<0.05) decreased TNF‐alpha, Interferon gamma and interleukin‐12 and reduced neurodegeneration in the CA1 region of the hippocampus & dendate gyrus when compared with the control group.ConclusionDiosmin reversed LPS‐induced cognitive impairment, which can be attributed to its neuroprotective and anti‐inflammatory properties.
Shared and disparate transcriptomic signatures associated with cortical atrophy change in genetic behavioral variant frontotemporal degeneration
Authors: Shen Ting , Vogel Jacob W , Van Deerlin Vivianna M , Dratch Laynie , Lee Eddie B , Phillips Jeffrey S , Grossman Murray , Massimo Lauren , Irwin David J. , McMillan Corey T 
Published: December 2023

AbstractBackgroundCortical atrophy is a common manifestation in behavioral variant frontotemporal degeneration (bvFTD). Distinct atrophy patterns across different form of genetic bvFTD may be shaped by their different underlying biology. This study aimed to use an integrative imaging transcriptomics approach to identify shared and disparate transcriptomic signatures associated with cortical thickness changes in bvFTD with mutations in C9orf72, GRN, and MAPT.MethodWe extracted cortical thickness for 124 sporadic bvFTD patients, 32 C9orf72‐bvFTD, 11 GRN‐bvFTD, and 13 MAPT‐bvFTD mutation cases. Cortical thickness differences were computed between genetic and sporadic bvFTD patients, adjusted for age, sex and disease duration. Normative gene expression profiles were extracted from the Allen Human Brain Atlas. Partial least squares regression model was used to rank all genes by their correlation between gene expression and cortical thickness differences in each genetic form of bvFTD. Functional and cell‐type enrichment analyses were then conducted to explore underlying biological processes of top‐ranked genes.ResultRelative to sporadic bvFTD, cortical thickness was decreased in temporal regions in C9orf72‐bvFTD, frontotemporal regions in MAPT‐bvFTD, and cortical atrophy was more extensively distributed in GRN‐bvFTD. We identified sets of genes that were positively or negatively associated with cortical thickness differences for each genetic form of bvFTD. Enrichment analyses indicated that genes negatively associated with GRN‐bvFTD atrophy were mainly involved in synaptic pathways and neuron projection development. These GRN‐bvFTD negatively associated genes were enriched in neurons, while the positively associated genes were mainly enriched in glial cells (Figure 1). The genes positively associated with MAPT‐bvFTD atrophy were involved in synaptic pathways and cognition‐related terms, and were preferentially expressed in neurons (Figure 2). Furthermore, an oligodendrocyte precursor cell enriched gene, Protocadherin‐15 (PCDH15), was found to be negatively associated with cortical thickness change in both C9orf72‐bvFTD and GRN‐bvFTD.ConclusionSpatial distribution of cortical structural change in each genetic form of bvFTD might be modulated by the expression of genes that were involved in common and different functional pathways, coupled with different cellular signatures. Identification of shared and disparate transcriptomic signatures will contribute to further understanding of potential genetic basis of heterogeneity for different genetic forms of bvFTD.
Associations of antihypertensive medication (AHM) consumption and drug‐drug interaction with Statin and Metformin with reduced Alzheimer’s disease and related dementias (ADRD) risk among hypertensive patients with mild cognitive impairment (MCI) using high volume claims data
Authors: Lundin Sori Kim , Hu Xinyue , Feng Jingna , Lundin Karl Kristian , Chen Yong , Tao Cui 
Published: December 2023

AbstractBackgroundWhile hypertension is a modifiable risk factor of Alzheimer’s disease and related dementias (ADRD), limited studies have been conducted on drug effectiveness of antihypertensive medications (AHMs) on ADRD progression from mild cognitive impairment (MCI) or on drug‐drug interactions of AHMs with drugs for other risk factors such as type 2 diabetes and hypercholesterolemia.Method128,683 unique hypertensive patients with MCI on US‐based Optum claims data were identified. Diuretics, beta blockers (BBs), calcium channel blockers (CCBs), angiotensin‐converting enzyme inhibitors (ACE inhibitors), and angiotensin II receptor antagonists (ARBs) were identified as five major AHM classes. Baseline characteristics were compared. Cox proportional hazards (PH) models were used to study the association between specific AHM exposure and the progression from MCI to ADRD while controlling for demographic variables, comorbidities, and use of Statin and Metformin. To examine the association of AHM‐Statin or AHM‐Metformin interaction with ADRD progression, we also investigated models controlling for aforementioned confounders, as well as drug‐drug interaction terms.ResultThe study included 100,678 patients who were taking at least one class of AHM and 28,005 who were not taking any AHMs. AHM users had higher ratios for the comorbidities (all P≤0.039) and consumption of Metformin and Statin (both P<0.001) compared to non‐users. Users of each major AHM class showed significantly lower risk of developing ADRD compared to non‐users of that specific drug class (adjusted hazard ratio (aHR): 0.96‐0.98; all P≤0.048). Within patients on monotherapy (using only one AHM drug), no specific AHM class had significantly lower risk of ADRD diagnosis compared to other AHM drug classes (aHR: 0.97‐1.11; all P≥0.053). Use of Diuretics or CCBs in combination with Metformin consumption (aHR: 0.89, 0.91, respectively) showed lower risk of MCI to ADRD progression than that under Metformin non‐consumption (aHR: 0.97, 0.98), whereas use of any of the five major AHMs under Statin consumption (aHR: 0.91‐0.94) all showed lower risk than that under Statin non‐consumption (aHR: 0.98‐1.04).ConclusionAll five major AHM classes show a protective effect against ADRD progression among hypertensive patients with MCI. Also, AHMs combined with consumption of Metformin or Statin showed a stronger protective effect compared to non‐consumption.
Alzheimer’s disease biomarkers of amyloid and tau influence white matter neurite alterations in dementia with Lewy bodies: a NODDI study
Authors: Mak Elijah , Reid Robert I. , Przybelski Scott A. , Lesnick Timothy G. , Schwarz Christopher G. , Senjem Matthew L. , Raghavan Sheelakumari , Vemuri Prashanthi , Jack Clifford R. , Min Hoon‐Ki , Jain Manoj K. , Miyagawa Toji , Forsberg Leah K. , Fields Julie A. , Savica Rodolfo , Graff‐Radford Jonathan , Jones David T. , Botha Hugo , St. Louis Erik K , Knopman David S. , Ramanan Vijay K , Graff‐Radford Neill R , Ferman Tanis J , Petersen Ronald C. , Lowe Val J. , Boeve Brad F. , O'Brien John T , Kantarci Kejal 
Published: December 2023

AbstractBackgroundCo‐morbid Alzheimer’s disease (AD) pathology in the form of amyloid‐β plaques and tau neurofibrillary tangles are frequently observed in people with probable dementia with Lewy bodies (DLB). Neurite Orientation Dispersion and Density Imaging (NODDI) is an emerging technique to characterize white matter (WM) tissue microstructure, although NODDI alterations and associations with AD biomarkers remain undefined in DLB. The objectives of this study are to compare NODDI and DTI parameters between DLB and controls and (ii) evaluate the pattern of DTI and NODDI changes associated with amyloid and tau deposition.MethodConsecutive patients within the DLB spectrum (n = 45), including probable DLB (n = 32) and probable Mild Cognitive Impairment with Lewy bodies (MCI‐LB) (n = 13) from the Mayo Clinic ADRC underwent multi‐shell diffusion MRI, [18F]‐Flortaucipir and [11C]‐PiB PET. A comparison group of 45 age‐ and gender‐matched clinically unimpaired controls (CU) was included. Voxelwise non‐parametric permutation models were used to determine pair‐wise group differences and assess the associations of AD biomarkers with fractional anisotropy (FA), mean diffusivity (MD), tissue‐weighted neurite density index (tNDI; NDI x (1 – Free water fraction)) and orientation dispersion index (ODI), controlling for age. Complementary analyses were performed using regions‐of‐interest (ROI) obtained from the JHU atlas.ResultCompared to CU, the DLB spectrum group exhibited widespread decreases in FA and tNDI and increases in MD and ODI, with the most pronounced effects in the cingulum bundles, uncinate, inferior and superior longitudinal fasciculi (Fig. 1). Greater [18F]‐Flortaucipir uptake was also associated with lower FA and tNDI, and higher MD and ODI in the DLB spectrum compared to CU, independently of age and [11C]‐PiB uptake (Fig. 2). In contrast, no associations were found between [11C]‐PiB uptake and any of the DTI or NODDI parameters. Complementary ROI analyses corroborated these findings.ConclusionWidespread loss of WM integrity was observed on DTI and NODDI in probable DLB and prodromal DLB. These findings were associated with greater cortical tau, but not with amyloid‐β deposition. Although alpha‐synuclein pathology underlies the loss of WM integrity in DLB, amyloid‐independent tau pathology may also be an important influence on white matter integrity within the DLB spectrum.
Genome‐wide mapping implicates 5‐hydroxymethylcytosines in diabetes and Alzheimer’s disease
Authors: Zhang Zhou , Beadell Alana , Capuano Ana W. , Bennett David A. A , He Chuan , Zhang Wei , Arvanitakis Zoe 
Published: December 2023

AbstractBackgroundDiabetes mellitus (DM) is a recognized risk factor for dementia including Alzheimer’s disease (AD). Because DM is a potentially modifiable risk factor, a greater understanding of the mechanisms linking DM to the clinical expression of AD may provide insights into the much‐needed dementia therapeutics or intervention approaches. Epigenetic analysis offers a powerful approach, and previous studies including our team’s exploration in circulating cell‐free DNA (cfDNA) suggested that the under‐investigated 5‐hydroxymethylcytosines (5hmC) is now emerging as a promising measure to investigate in DM‐related conditions.MethodWe used samples and data from the Rush Memory and Aging Project. Using the 5hmC‐Seal technique, we performed genome‐wide profiling of 5hmC in cfDNA samples (n = 74) from antemortem blood samples and brain tissue (n = 75) genomic DNA from postmortem prefrontal cortex tissue from 80 deceased individuals across four groups: AD (neuropathologically defined), DM (clinically defined Type 2 DM), DM with AD (AD+DM), and non‐AD/non‐DM controls. Differential analysis and machine learning approaches were used to investigate 5hmC signatures associated with different conditions and summarize epigenetic scores to evaluate diagnostic potential for AD in cfDNA. Pathway enrichment analysis was performed on differential 5hmC signatures to explore biological mechanisms underlying DM‐associated AD.ResultWe identified distinct 5hmC signatures and biological pathways, including Wnt signaling and inflammatory mediator regulation of TRP channels, as well as amino sugar and nucleotide sugar metabolism, that are associated with AD or AD+DM compared to non‐AD/non‐DM controls or DM alone. We further demonstrated the potential diagnostic value of 5hmC profiling in circulating cfDNA. Specifically, a 4‐gene model showed capacity for distinguishing AD+DM from DM (AUC [area under the curve] = 82.7%; 95% CI [confidence interval], 67.6‐97.9%), while an 11‐gene model distinguished AD from non‐AD/non‐DM controls (AUC = 90.0%; 95% CI, 80.4‐99.6%).ConclusionGenome‐wide 5hmC profiling uncovered epigenetic features and biological pathways related to nucleotide sugar metabolism that link DM to DM‐associated AD. Our findings also demonstrated the potential of utilizing 5hmC in circulating cfDNA as diagnostic biomarkers or disease monitoring tools, with the ultimate goal of preventing or ameliorating DM‐associated AD dementia and improving clinical outcomes. This study was supported partially by the NIH (RF1AG074549, R01AG17917).
Perceived needs for mobile interventions among Spanish language Latino family caregivers of persons living with dementia
Authors: Melero‐Dominguez Maria , Jain Felipe A , Madarasmi Saira , Gutierrez‐Ramirez Paulina , Ramirez‐Gomez Liliana A. 
Published: December 2023

AbstractBackgroundSupportive and caregiver skills programs for Spanish language Latino caregivers of persons living with Alzheimer’s disease and related dementias (SLDCs) have been developed and researched primarily using in‐person delivery. However, in‐person interventions are limited by scalability constraints due to barriers such as time, cost of travel to intervention sites, and COVID‐19 containment measures. There is a tremendous need for caregiver interventions for SLDCs that can be delivered remotely by smartphone, the most accessible means for SLDCs to connect to the internet. A mobile application combining caregiver skills literacy, stress reduction tools, and chat‐based support groups might help fill this gap. However, whether SLDCs perceive a need for such an application is unclear. This research aimed to assess perceived needs and preferences for mobile intervention among SLDCsMethodWe conducted two virtual focus groups with 12 SLDCs (aged 37 to 87, 83% female) from the Greater Boston area to determine preferences for smartphone‐based intervention. Participants answered semi‐structured questions during the group and completed questionnaires individually regarding smartphone application usage. Topics included needs for caregiver skills, relaxation tools, and chat‐based social support. Data analysis was conducted with an inductive and deductive mixed‐methods approach.ResultOpinions regarding the potential utility of a smartphone application that would combine caregiver skills, relaxation tools, and a smartphone chat for SLDCs were positive and demonstrated that such an application would serve unmet needs. Although only one participant had previously used a caregiver literacy app, all SLDCs expressed a desire to receive caregiver skills resources via mobile application. While just two (16.7%) had utilized a relaxation app, six (50%) felt that having access to relaxation instructions would be beneficial. Finally, an unmet social support need was identified, which caregivers felt would be possible to meet through chatroom‐based functionalities. Several participants felt the chat room would require facilitation by someone with expertise in dementia caregiving.ConclusionA mobile intervention could help meet the needs of SLDCs for caregiver skills, relaxation training, and social support. Further studies using participatory research should focus on the development and feasibility of a mobile application that provides these features.