bluuebunny/crossref_metadata_2025_split huggingface dataset:
Sex/gender differences in subjective cognitive decline’s association to cognition and depression
Authors: Joyce Jillian , Chapman Silvia , Gifford Katherine A. , Shagalow Shaina , Waltrip Leah H. , Zeiger Peter , Kann Michael , Ravichander Aanya , Rizer Sandra , Marder Karen , Jefferson Angela L. , Cosentino Stephanie 
Published: December 2023

AbstractBackgroundDespite the fact that women are more likely to develop Alzheimer’s disease (AD) than men, and develop pathological changes at an earlier age, women often receive diagnoses later. This disparity is possibly due to women’s verbal memory advantage, and the fact that verbal memory tests are often the gold‐standard for diagnostics. Further, a recent meta‐analysis found that female sex/gender was associated with greater depression which is often a differential diagnosis for dementia (Eikelboom 2022). Understanding sex/gender differences in Subjective Cognitive Decline (SCD) is critical to closing the care gap, as SCD is thought to be a preclinical stage of AD where intervention may be most effective. Integration of challenging cognitive testing, including non‐verbal memory tests, along with measurement of depression, is key for defining this preclinical stage. In this study, we compare SCD’s associations with non‐verbal and verbal list‐learning and depression as a function of sex/gender.Method97 cognitively unimpaired older adults were recruited for this study. Participants completed surveys regarding SCD and depression (Geriatric Depression Scale [GDS]) and cognitive testing. Non‐verbal memory was assessed with the Biber Figure Learning Test – Extended (BFLT‐E), a challenging non‐verbal figure‐learning test. Verbal memory was assessed with the Loewenstein‐Acevedo Scales for Semantic Interference and Learning (LASSI‐L). Both tests are associated with early AD changes. Linear regressions were conducted and stratified by sex/gender to assess the relationships of cognition and mood with SCD. Models of cognitive performance included age and education as covariates.ResultVerbal list‐learning (LASSI‐L) predicted SCD in men (R2= .416, β = ‐.390, p = .017), but not in women (R2
= .217, β = ‐.173, p = .167). Non‐verbal figure‐learning, as measured by the BFLT‐E, predicted SCD in women (R2
= .267, β = ‐.342, p = .006), but not in men (R2
= .175, β = ‐.334, p = .078). Similarly, depression predicted SCD in women (R2
= .109, β = .330, p = .007), but not in men (R2
= .003, β = .055, p = .763).ConclusionResults demonstrate that in AD risk states such as SCD, cognitive dysfunction may manifest differently for women than men. Clinical care settings should consider integration of non‐verbal memory tests such as BFLT‐E along with regular screening of depression in order to address the inequities in diagnostics for women.
Microbial infection and associated inflammasome in the retina of Alzheimer’s disease patients
Authors: Gaire Bhakta Prasad , Koronyo Yosef , Rentsendorj Altan , Fuchs Dieu‐Trang , Subedi Lalita , Jallow Ousman , Black Keith L , Arditi Moshe , Crother Timothy R , Koronyo‐Hamaoui Maya 
Published: December 2023

AbstractBackgroundRecent advances in Alzheimer’s disease (AD) research revealed that AD pathology is not confined to the brain but also occur in the neurosensory retina. Data have further suggested parallels between retinal and brain AD biomarkers. While the exact etiology of AD pathogenesis is undefined, an emerging theory has linked AD with microbial infection as a plausible cause for AD progression. The presence of several microbes including Chlamydia pneumoniae (Cp), Borrelia burgdorferi, Porphyromonas gingivalis, and Toxoplasma gondii have been reported in the post‐mortem brain of AD patients and murine models. However, the existence and role of microbial infection in AD retina has never been studied.MethodWe employed a range of histological, biochemical, and genetic techniques to detect bacterial infection and other associated biomarkers in postmortem retinas of patients with mild cognitive impairment (MCI) or AD dementia, compared to retinas from age‐matched individuals who displayed normal cognition (NC). We assessed the presence and burden of Cp and correlated with gliosis, inflammasome, and apoptosis markers.ResultWe discovered the presence of Cp inclusions in postmortem retinas of patients with MCI and AD as compared to age‐ and sex‐matched NC individuals. Our experimental evidence revealed Cp‐infected retinal neuronal cells in AD patients, with no increase in retinal Cp infection in MCI versus CN and a significant 4‐fold increase in of Cp immunoreactivity in retinas of AD patients versus MCI and CN subjects. These data possibly indicate that Cp infection mainly occur during the dementia phase of AD and is less observable at the early functional impairment stages of AD. Retinal microglia were found to aggregate around and engulf Cp‐infected cells. Alongside Cp infection, retinal tissues from MCI and AD patients exhibited increased NLRP3 inflammasome and gliosis. Our data suggest Cp‐triggered inflammasome activation, that can lead to neuronal degeneration. We further found a relationship between the severity of retinal Cp infection and brain pathology; retinal Cp burden was associated with brain neurofibrillary tangles, neuropil threads, Braak stage.ConclusionCp‐triggered chronic inflammation could be a detrimental process leading to retinal degeneration in AD, suggesting potential new therapeutic avenues involving early antibiotic treatment or inflammasome attenuation.
Genetic and Environmental Influences of Plasma Biomarkers and Their Relation to APOE status and Mild Cognitive Impairment
Authors: Gillespie Nathan A. , Panizzon Matthew S. , Elman Jeremy A. , Neale Michael C. , Reynolds Chandra A. , Franz Carol E , Kremen William S. 
Published: December 2023

AbstractBackgroundBefore onset of Alzheimer’s dementia, aggregation of amyloid‐beta (Aβ) is thought to drive accumulation of Tau, followed by neurodegeneration (indexed here by neurofilament light chain [NFL]). Why or how Aβ increases Tau accumulation remains unclear. Using genetically informative twins aged 61.4 to 73.3 years, we sought to: (1) identify genetic and environmental influences on plasma Aβ (Aβ40, Aβ42, Aβ42/40), total Tau (t‐Tau), and NFL; (2) determine if their genetic and environmental influences are correlated with one another; (3) determine if Aβ40 and Aβ42 causally impact Tau levels; (4) measure associations between biomarkers and APOE‐ε4 status; and (5) measure associations between these biomarkers and mild cognitive impairment (MCI).MethodData were from 1,035 male twins in the Vietnam Era Twin Study of Aging. Average age was 67.1 years (SD = 2.6). Twin models were used to estimate heritability, genetic and environmental correlations, model the direction of causation between biomarkers, and associations with APOE‐ε4 status. Mixed effect linear regressions were applied to regress MCI on biomarkers.ResultHeritability for Aβ40, Aβ42, t‐Tau and NFL ranged from 43% to 51%, whereas Aβ42/40 heritability was not significantly different from zero. Phenotypic correlations between t‐Tau and Aβ40 (rP = 0.01) and Aβ42 (rP = 0.14) were small. Genetic correlations between t‐Tau and Aβ40 (rG = ‐0.05) and Aβ42 (rG = 0.05) were also very small. In contrast, genetic correlations between NFL and Aβ40 and Aβ42 were higher (rG ranging = 0.31‐0.37). We found no evidence to suggest that Aβ40 or Aβ42 causally impacts t‐Tau. APOE‐ε4 accounted for a significant, but very small amount of variance in Aβ40 and Aβ42. Finally, none of the biomarkers was significantly associated with MCI, which affected 15.1% of the sample.ConclusionBoth Aβ40 or Aβ42 appear heritable, but have very little phenotypic and genetic association with t‐Tau. The associations between the amyloid‐beta biomarkers and t‐Tau are mostly explained by non‐shared environmental factors, and the direction of causation is unclear. The small associations between APOE‐ε4 and the biomarkers, including their lack of association with MCI, may stem from the low sensitivity of plasma biomarkers, the relatively young age or the low proportion of MCI cases in this community‐dwelling sample.
Proteomics correlates of amyloid beta and tau in CSF: A monozygotic twin study
Authors: Visser Pieter Jelle , Braber Anouk , Campo Marta , Teunissen Charlotte E. , Tijms Betty M. 
Published: December 2023

AbstractBackgroundEarly Alzheimer’s disease (AD) is characterised in cerebrospinal fluid (CSF) by a decreased concentration of amyloid beta 1‐42 and an increased concentration of total tau (t‐tau). Insights in early AD development may provide clues for primary and secondary prevention. We aimed to investigate which other proteins were associated with abnormal amyloid beta 1‐42 and t‐tau in cognitively normal monozygotic twins. We tested to what extend proteins associated with abnormal amyloid and t‐tau have a common genetic background by performing cross‐twin cross‐trait (CTCT) analysis.MethodWe included 126 twins (54 pairs) from the EMIF‐AD PreclinAD study. We assessed 690 proteins by OLINK multiplex panels and t‐tau, abeta42, abeta40 by ELISA. We used the abeta42/40 ratio as measure of amyloid pathology. We correlated the abeta42/40 ratio and t‐tau levels with the other proteins. For proteins that showed an association with abeta42/40 or t‐tau we performed Cross‐Twin Cross‐Trait (CTCT) analysis by correlating the concentration of abeta42/40 or t‐tau in one twin with the concentration of the protein in the co‐twin (figure 1). Enrichment analysis was performed using Gene Ontology.ResultAverage age was 70 years. A lower abeta42/40 ratio was associated with increased levels of 114 proteins. These proteins were enriched for neurogenesis (p = 1.7E‐9) and apoptosis (p = 1.7E‐10). Only one protein showed a CTCT association. A lower abeta42/40 ratio was associated with lower levels of just 3 proteins. Increased t‐tau levels were associated with increased concentrations of 414 proteins. These proteins were enriched for nervous system development (p = 9.7*10‐21) and included 103 of the 114 proteins that correlated negatively with abeta42/40. Of the 414 proteins, 335 correlated with t‐tau in CTCT analysis. One of these proteins was BACE1 (see figure 2). Increased t‐tau levels were also associated with lower levels of 21 proteins which were enriched for leukocyte migration (p = 5.47*10‐3), of which 5 correlated with t‐tau in CTCT analysis.ConclusionA lower Abeta42/40 ratio and higher t‐tau level were both associated with an increased concentration of neuroplasticity related proteins. CTCT analysis showed that only t‐tau and plasticity proteins shared a common genetic architecture supporting the role of t‐tau in aberrant plasticity.
Innate immunity protein IFITM3 is involved in Alzheimer’s disease‐associated microglial response
Authors: Jain Tanya , Frost Georgia , Li Yueming 
Published: December 2023

AbstractBackgroundAlzheimer’s disease (AD) is the most common neurodegenerative disorder that has complex neuropathology which includes an accumulation of amyloid beta (Aβ) plaques, hyper‐phosphorylated tau tangles, and neuroinflammation. Amyloid plaques consist Aβ peptides, which are sequentially cleaved by α or β‐secretase and then γ‐secretase (GS) from amyloid precursor protein (APP). Our lab has previously identified interferon response protein IFITM3 as a GS modulatory protein that is upregulated in the human AD brain as well as in the 5xFAD mouse brain. We have shown that IFITM3 regulates GS activity in neurons, and a deficit in IFITM3 results in decreased GS cleavage of APP, leading to reduced amyloid plaque deposition in the 5xFAD mouse.MethodWe have generated 5xFAD;IFITM3−/−;TREM2−/− mice and have established stem cell‐derived IFITM3‐/‐ microglial cells. We have used a panel of mouse behavioural and immunohistochemical tests and in vitro microglial assays to investigating the function of IFITM3 in the phagocytic clearance of Aβ by microglia, its interplay with TREM2 and downstream signaling in the context of neuroinflammation.ResultWe have found that IFITM3 is highly expressed and inducible in glial cells, particularly astrocytes and microglia. We have shown that 5xFAD;IFITM3−/− mice have partially rescued cognition compared to 5xFAD mice, and have an upregulation of several microglial genes. In our in vitro microglial model, we have found that IFITM3−/− microglia display enhanced uptake of Aβ peptide, enhanced lysosomal degradation, and enhanced TREM2 expression and signalling.ConclusionWe have determined a novel role of IFITM3 in microglia using cellular assays and mouse models. We have also found evidence of an interplay of IFITM3 with TREM2.
Quantification of the Brain Iron Metabolism in the Cognitively Declined Adults Using 7T MRI
Authors: Alipour Akbar 
Published: December 2023

AbstractBackgroundThe extracellular aggregation of beta‐amyloid (AB) plaques is one of the hallmark pathology of Alzheimer’s diseases (AD) that develops years prior to clinical symptoms. However, inconsistency in the rate of cognitive decline among subjects with AB pathology and ineffectiveness of anti‐amyloid therapeutics to mitigate cognitive impairment suggest that other parameters, such as patterns of brain iron, may impact the risk of cognitive decline. In this study we leveraged improved MRI signal at 7T to explore susceptibility changes in the iron‐enriched regions among individuals with AD/MCI and healthy controls (HCs) through quantitative susceptibility mapping (QSM) with unprecedented resolution.MethodIn vivo MRI experiment was performed in AD/MCI and age‐matched healthy subjects. Scanning was conducted on a 7T MRI scanner using 1Tx/32Rx Nova head coil. To calculate QSM, a 3D high‐resolution spoiled gradient echo (GRE) sequence was used (voxels size = 0.3×0.3×1.5 mm3). QSM was used to measure susceptibility in the major iron‐enriched structures (Fig. 1), including red nucleus (RN), substantia nigra (SN), globus pallidus (GP), Caudate nucleolus (CN), putamen (PT), and dentate nucleus (DN).ResultWe found a significantly higher magnetic susceptibility in GP and DN in patients with AD/MCI compared with HCs (Fig. 2). Overall mean susceptibility values for the RN, SN, CN, GP, PT, and DN in AD/MCI and HCs is summarized in Table 1. In AD/MCI the highest susceptibility values were found in the GP (233.5±12.7) and DN (214.7±10.4), verses 174.6±11.8 and 168.9±11.6 for GP and DN in the HCs, respectively. There were small differences in the susceptibility values between the other ROIs.ConclusionWe reported an initial result for QSM at 7T in the AD/MCI subjects and appropriate age matched HCs. The main aim of the study was to investigate whether susceptibility values measured using ultra‐high resolution QSM differ in the iron‐enriched regions between these two populations. A significant susceptibility value was reported in the AD/MCI compared with the HC in GP and DN regions. This observation clearly deserves further investigations in larger cohorts.
Food Insecurity and Executive Function among Older Mexican Adults: Indirect Effects through Depressive Symptoms
Authors: Saenz Joseph , Renteria Miguel Arce , Avila Jaqueline Contrera 
Published: December 2023

AbstractBackgroundRecent work has linked food insecurity with worse cognitive outcomes, with executive function being a domain affected most consistently. The mechanisms underlying this association are largely unknown and few have investigated how changes in food insecurity over time (never food insecure, newly food insecure, formerly food insecure, or chronically food insecure) relate with cognitive outcomes. Food insecurity is also related with worsening depressive symptoms, which may impact executive function. This study evaluates how changes in food insecurity in late‐life relate with executive function, and whether this association is mediated by depressive symptoms among older adults in Mexico.MethodData includes the 2012‐2015 Mexican Health and Aging Study (MHAS) and 2016 Mex‐Cog subsample of the MHAS (n = 1,581 age 55+). Food insecurity was classified as never food insecure (not food insecure in 2012 or 2015), newly food insecure (food insecure in 2015 but not 2012), formerly food insecure (food insecure in 2012 but not 2015), or chronically food insecure (food insecure in 2012 and 2015). Executive function and depressive symptoms (CES‐D) were obtained from the Mex‐Cog. Direct/indirect (through depression) effects of food insecurity were tested using structural equation modeling with bootstrap confidence intervals controlling for demographic and socioeconomic confounders.ResultApproximately half of the sample were never food insecure, 16% were newly food insecure, 15% were chronically food insecure, and 18% were formerly food insecure. SEM results indicated partial mediation. Significant direct effects were observed, with chronic and former food insecurity related with 0.12 and 0.11 standard deviations lower executive function, respectively, compared to the never food insecure. Both chronic and former food insecurity exhibited significant indirect effects via depressive symptoms with indirect effects making up 21% and 15% of the total effects of chronic and former food insecurity on executive function.ConclusionFood insecurity may represent an important modifiable risk factor for poorer executive function outcomes. Although food insecurity had a direct impact on executive function, part of its detrimental effect was through worsening depressive symptoms. This study highlights the importance of considering experiences of food insecurity over time and the co‐existence of both food insecurity and depressive symptoms.
Interpretable Deep Learning and MultiOme data repurposing in Alzheimer’s target and drug discovery: NIA Artificial Intelligence and Machine Learning Consortium
Authors: Cheng Feixiong 
Published: December 2023

AbstractBackgroundHigh‐throughput DNA/RNA sequencing technologies have rapidly led to a robust body of genetic and genomic data in the Alzheimer’s Disease Sequencing Project (ADSP); however, approaching AD with a simplistic single‐target approach has been demonstrated effective for developing symptomatic therapies but ineffective when attempted for disease modification. Therapeutic approaches by specifically modulating genetic risk genes are essential for development of disease‐modifying treatments in AD. However, existing data, including genetics, genomics, transcriptomics, proteomics, and interactomics, have not yet been fully utilized and integrated to explore the roles of targeted therapeutic development for AD.MethodWe will introduce how our team combines tools from artificial intelligence (AI), network medicine, endophenotype models, multi‐omics (genomics, transcriptomics, and proteomics), and electronic health records (EHRs), to identify potential drug targets and repurposable drugs for AD. The fundamental premise of our method is that AD risk genes exhibit distinct functional characteristics compared to non‐risk genes and, therefore, can be distinguished by their aggregated human brain‐specific functional genomic features from various quantitative trait loci (X‐QTL), including expression QTL (eQLT), protein QTL (pQTL), splicing QTL (sQTL), methylation QTL (meQTL), and histone acetylation QTL (haQTL).ResultVia applying our deep learning model to the latest AD GWAS data, we identified 156 putative AD‐risk genes that were differentially expressed in AD‐associated microglia and astrocytes from large single‐nuclei RNA‐sequencing data of human postmortem brains with AD. Combining network‐based prediction and retrospective case‐control observations with 10 million individuals, we identified that usage of four drugs (ibuprofen, gemfibrozil, cholecalciferol, and ceftriaxone) is significantly associated with reduced likelihood of AD incidence, after adjusting for various confounding factors. Importantly, gemfibrozil (an approved lipid regulator) is significantly associated with reduced risk of AD compared to simvastatin (another approved anti‐lipid medicine under Phase II AD trials), using an active user design (odds ratio 0.57, 95% CI 0.51‐0.63, P < 0.0001).ConclusionFrom a translational perspective, the deep learning and network‐based approaches presented here, if broadly applied would significantly catalyze effective treatment development in AD and other neurodegenerative diseases from the human genome sequencing findings.
Exploring Biomarker Signatures of the Peripheral Immune Response in Alzheimer’s Disease: NIA Artificial Intelligence and Machine Learning Consortium
Authors: Bekris Lynn M. 
Published: December 2023

AbstractBackgroundAlzheimer’s disease (AD) has been linked to multiple immune system‐related genetic variants. Triggering receptor expressed on myeloid cells 2 (TREM2) genetic variants are risk factors for AD and other neurodegenerative diseases. In addition, a soluble TREM2 (sTREM2) isoform is elevated in cerebrospinal fluid in the early stages of AD and is associated with slower cognitive decline in a disease stage‐dependent manner. Multiple studies have reported an altered peripheral immune response in AD. Less is known about the relationship between peripheral sTREM2 and an altered peripheral immune response in AD. The overall objective of this study was to explore the relationship between plasma sTREM2 and inflammatory activity in AD. The hypothesis of this exploratory study was that sTREM2‐related inflammatory activity differs by AD stage or ATN Research Framework category.MethodCohorts included participants from the Cleveland Clinic‐based Dementia with LewyBody Consortium (DLBC), the Lou Ruvo Center for Brain Health Aging and Neurodegenerative Disease biobank (LRCBH‐biobank) and the Cleveland Alzheimer’s Disease Research Center (CADRC). Patients were clinically characterized based on cerebrospinal fluid AD‐related biomarkers, clinical symptoms, and consensus review. Analytes measured included: plasma sTREM2 and a panel of 38 inflammatory factors (Luminex/Millipore). Linear regression, Spearman correlation, Correlation Matrices, and Network analyses were some of the methods utilized.ResultWe observed different patterns of inflammatory activity across AD stages. Notably, fractalkine showed a significant relationship with sTREM2 across different analyses in the control groups (cognitively normal and A‐T‐N‐) that was lost in later AD‐related stages (MCI or AD and A+T‐N‐, A+T+N‐ and A+T+N+). Although multiple other inflammatory factors either differed significantly between groups or were significantly correlated with sTREM2 within specific groups, three inflammatory factors (fibroblast growth factor‐2, GM‐CSF, and IL‐1β) were notable because they exhibited both lower levels in AD, compared with mild cognitive impairment, and a disease stage alteration in the relationship with sTREM2. Additionally, preliminary analyses indicate sex differences in peripheral TREM2‐related inflammatory activity.ConclusionThese findings suggest that sTREM2‐related inflammatory activity alterations are AD stage specific and potentially sex specific. This novel information could enhance therapeutic strategies focused on targeting the immune response in AD.