bluuebunny/crossref_metadata_2025_split huggingface dataset:
Sleep in People with Dementia and Their Caregivers
Authors: Manning Carol A , Youngkin Anna E , Quigg Mark S 
Published: January 2025

AbstractBackgroundThere is mounting evidence that difficulties with sleep including insomnia, sleep quality, and sleep fragmentation contribute to Alzheimer’s disease risk including formation of beta‐amyloid. Disrupted sleep is common in people with dementia (PWD). Primary unpaid caregivers (CGs) of PWD may also have disrupted sleep as a result of their caregiving roles. It is clear that CGs experience CG burden, stress and depression. The interplay of CG‐PWD dyads and the impact of behavior, cognition and sleep in the PWD on the CG are relatively understudied.MethodEight dyads consisting of individuals diagnosed with Alzheimer’s Disease (AD) (PWD) and their CGs were recruited from the Virginia Alzheimer’s Disease Center (VADC) Clinical Cohort. Diagnosis of AD in the VADC cohort was made by team consensus using neuroimaging, biomarker, neurological and neuropsychological data. All participants had wrist actigraphy measured for 14 days and overnight polysomnography (PSG) done in a sleep lab. Dyad members were in separate rooms during PSG.Dyads members independently completed the Montreal Cognitive Assessment 12, the Geriatric Depression Scale 13, Epworth Sleepiness Scale 14, and the Quality of Life in Alzheimer’s Disease scale 15 (QOL). CGs only completed the Preparedness for Caregiving Scale 16 and the Zarit Burden Interview and the Neuropsychiatric inventory.ResultNeither activity nor rest over 14 days differed within dyads. Relative to PWD, CGs experienced shorter total sleep, lower sleep efficiency, and longer sleep onset. CG and PWD depression and QOL did not differ between dyad members. Importantly, poorer CG sleep was associated with higher CG burden and greater PWD neuropsychiatric symptoms but not with degree of cognitive impairment in the PWD.ConclusionResults suggest that sleep in CGs can be more impaired than the PWDs they are caring for even when sleeping separately. Importantly, behavioral disturbance may be more problematic than PWD cognitive impairment level in CG sleep. These may have implications for ability to care for the PWD potentially impacting nursing home placement. Furthermore, PWD sleep characteristics may impact longer‐term CG health and well‐being.
Sex Differences in Neuropsychiatric Symptoms Associated with Alzheimer’s Disease in Down Syndrome
Authors: Shaka Sophia E. , Krinsky‐McHale Sharon J. , Silverman Wayne , Pulsifer Margaret B. , Rosas H. Diana , Lai Florence , Lott Ira T. , Hom Christy L. 
Published: January 2025

AbstractBackgroundAdults with Down syndrome (DS) have increased risk for developing Alzheimer’s disease (AD). Several studies have found that the onset of new neuropsychiatric and behavioral symptoms in DS is associated with AD progression. There is evidence in the neurotypical population that AD‐related apathy is more severe among males, while females display higher prevalence of depression, psychosis, and delusions. The current study investigates sex differences in AD‐related neuropsychiatric symptomology in adults with DS. It is hypothesized that men will have greater frequency or severity of AD‐related apathy compared to women while women will display more AD‐related depression.MethodA total of 155 adults with DS from the Alzheimer’s Disease in Down Syndrome (ADDS) study (43.3% female, Mage = 50.26, SD = 7.20) received cognitive testing. Their care providers completed questionnaires that measured psychiatric and/or behavioral symptoms: the Neuropsychiatric Inventory Questionnaire (NPI‐Q), the Reiss Screen for Maladaptive Behavior (RSMB), and the Dementia Questionnaire for People with Learning Disabilities (DLD). AD clinical status was determined through consensus decisions by the research team based on cognitive and functional scores. 113 participants were classified as cognitively stable and 42 had possible/probable AD dementia. Participants with mild cognitive impairment or of uncertain clinical status were excluded.ResultThere were no significant main effects for sex on any of the measures examined. However, there was a significant interaction between sex and clinical status on the DLD Activity & Interest scale, adjusting for age, sex, and clinical status (F(4, 154) = 4.055, p = 0.46, η2 = 0.20). While cognitively stable men and women had similar scores on this scale, men with dementia had significantly greater problems in this area of functioning than women with dementia.ConclusionAD appears to affect men and women differently after the transition to dementia. Affected males engage in fewer activities and are less interested in their surroundings than females, suggesting greater apathy or withdrawal, despite the lack of sex differences in depressive symptomology during the preclinical and clinical stages of AD. Possible neurobiological reasons will be discussed as well as how individuals with DS and AD may need tailored support based on sex differences in psychiatric and behavioral symptoms.
Study of the irisin hormone on metabolism and mitochondrial dynamics in experimental models of Alzheimer’s disease
Authors: Fonseca Ariene Soares , Chauvet Mariana Gomes , Ferreira Sergio T , Lourenco Mychael V 
Published: January 2025

AbstractBackgroundAge‐related decrease glucose utilization, coupled with insulin resistance, are key features of AD, resulting in reduced glucose utilization/catabolism and oxidative stress generation. Irisin, an exercise‐induced hormone promoting mitochondrial biogenesis in adipocytes via PGC‐1α, stimulates thermogenic pathways, increases energy expenditure and induces browning of adipose tissue. Further, irisin expression was shown to trigger neuroprotection in AD models.MethodHere, we assessed whether irisin could prevent potential metabolic deficits induced by soluble Aβ oligomers (AβOs) in hippocampal slices and in C57BL/6 mice.ResultOur results indicate that irisin produced only subtle changes in the metabolic profile without clearly altering the protein content associated with mitochondrial dynamics in the AβOs‐exposed hippocampus.ConclusionOur data suggest that other mechanisms may possibly contribute to the neuroprotective effects of irisin in AD models.
Lessons from Ten Years of Validation of Targets Identified by the Accelerating Medicines Partnership in Alzheimer’s Disease (AMP‐AD)
Authors: Ehrlich Michelle E. 
Published: January 2025

AbstractBackgroundThe Accelerating Medicines Partnership in Alzheimer’s Disease (AMP‐AD) is a public‐private partnership linking NIH, the FDA, pharmaceutical companies, and nonprofit organizations in an interactive, collaborative program utilizing transcriptomics, genomics, metagenomics, proteomics, and metabolomics to provide data for computational analysis, that, in turn, enables promising targets to be ranked by a combination of omic scores and druggability. This ranking informs the selection of targets for validation.MethodHuman postmortem samples were obtained from Mount Sinai, ROSMAP (Religious Orders Study and Rush Memory and Aging Project), Mayo Clinic (Florida), and Columbia University. The validation systems were mouse and fly models of AD pathology and human induced pluripotent stem cells (hiPSCs). Target genes were up‐ or down‐ regulated or mutated to determine whether AD‐related phenotypes were altered.ResultTargets selected for validation by AMP‐AD included genes expressed in neurons (e.g., VGF, REST, ATP6V1A), microglia (e.g., BIN1, TYROBP, TREM2, SYK, MSN, INPP5D), or astrocytes (e.g., PLEXNB1, GJA1). As expected, phenotypes were improved by decreasing levels of proteins that are abnormally elevated in AD or by increasing the levels of proteins that are abnormally decreased in AD. Qualitative and quantitative variability in effects of target manipulation may be attributable to duration or stage of disease at the time of intervention, and/or to the cell type that expresses each target. AD‐related changes were used to predict therapeutic directionality, but up‐ and down‐regulation sometimes had similar effects. Plaque load changes did not reliably predict changes in other aspects of the phenotype. Paradoxically, manipulation of some targets (e.g., ABI3) caused amyloidosis and tauopathy to change in different directions.ConclusionValidation experiments in multiple systems support the AMP‐AD approach for selecting druggable targets for the treatment of AD. Future work will focus on validation of additional targets and close collaboration with the Target Enablement to Accelerate Therapy in AD (TREAT‐AD) Consortium to develop pharmacologic agents derived from these discoveries.
Unravelling the mechanisms of aducanumab on efficacy of Aß clearance by iPSC‐derived human microglia in 2D and 3D cell cultures
Authors: Lin Ada J. , Wendt Stefan , Brennan Declan , Nygaard Haakon B. 
Published: January 2025

AbstractBackgroundAntibodies targeting amyloid beta (Aß) have recently been developed as promising treatments for Alzheimer’s Disease (AD). Aducanumab was the first to receive limited FDA approval in 2021 offering much needed new treatment options for AD patients. Aducanumab clears aggregated Aß in the brain, presumably through microglial phagocytosis, although the exact cellular and molecular mechanisms of its effect remain incompletely understood. We employed iPSC‐derived microglia in 2D and 3D cultures to study the mechanisms by which aducanumab facilitates Aß clearance in the brain.MethodiPSC‐derived microglia were studied in both 2D and 3D environments. Microglia plated in 2D were treated with pHrodo conjugated oligomeric Aß42 and aducanumab and imaged live for 24 hours to monitor short term changes. Cells and supernatant were collected for ELISA afterwards. For 3D cell culture, neurospheres were formed from iPSC‐derived neuronal progenitor cells, which grew to consist of mature neurons and astrocytes. Microglia were added to the neurospheres and infiltrated into the 3D tissue, followed by longer Aß and aducanumab treatment. Both the neurospheres and the surrounding 2D microglia were imaged afterwards, and the supernatant was collected for Aß ELISA.ResultLive imaging 2D microglia over 24 hours indicated that microglia treated with aducanumab have significantly higher levels of phagocytosed Aß and at a faster rate. Intriguingly, immunostaining for fibrillar Aß revealed that aducanumab decreased the amount of highly aggregated intracellular Aß. In the neurospheres, microglia are the primary cell type phagocytosing Aß. Aducanumab did not cause a significant reduction of Aß in the 3D tissue but prevented the formation of larger Aß aggregates, which may in turn facilitate microglia mediated Aß clearance.ConclusionAducanumab acutely increases the ability of iPSC‐derived microglia to phagocytose Aß and may also prevent Aß aggregation. 3D neurospheres can be used to study more functional impacts of aducanumab on neuronal function. Further analysis of phagocytosed Aß using biochemical techniques after anti‐Aß antibody treatment will help to determine the precise molecular mechanisms of its effects.
MIAMI‐AD (Methylation in Aging and Methylation in AD): an integrative knowledgebase that facilitates explorations of DNA methylation across sex, aging, and Alzheimer’s disease
Authors: Wang Lily , Lukacsovich David , O'Shea Deirdre , Huang Hanchen , Zhang Wei , Young Juan I , Chen X. Steven , Dietrich Sven‐Thorsten , Kunkle Brian W. , Martin Eden R. 
Published: January 2025

AbstractBackgroundAlzheimer’s disease (AD) is a common neurodegenerative disorder with a significant impact on aging populations. DNA methylation (DNAm) alterations have been implicated in both the aging processes and the development of AD. Given that AD affects more women than men, it is also important to explore DNAm changes that occur in each sex.MethodWe created the MIAMI‐AD, a comprehensive database containing manually curated summary statistics from 97 published tables in 37 studies, all of which included at least 100 participants. There are four main sections: Genome‐wide Query, Gene Query, CpG Query, and Epigenetic Clock Query.ResultMIAMI‐AD enables easy browsing, querying, and downloading DNAm associations at multiple levels – at individual CpG, gene, genomic regions, or genome‐wide, in one or multiple studies. Moreover, it also offers tools to perform integrative analyses, such as comparing DNAm associations across different phenotypes or tissues, as well as interactive visualizations. Using several use case examples, we demonstrated that MIAMI‐AD facilitates our understanding of age‐associated CpGs in AD and in revealing sex‐specific DNAm differences in AD.ConclusionMIAMI‐AD (https://miami‐ad.org/) facilitates integrative explorations to better understand the interplay between DNAm across aging, sex, and AD. This open‐access resource is freely available to the research community, and all the underlying data can be downloaded.
Neuronal mTORC1 is required for acute Aβ‐induced cognitive dysfunction
Authors: Hussong Stacy A , Williams Kylie M , Galvan Veronica 
Published: January 2025

AbstractBackgroundPrevious studies have found that mechanistic target of rapamycin complex 1 (mTORC1) activity is significantly increased in Alzheimer’s disease (AD) patients and mouse models of AD. Additionally, inhibition of mTORC1 with systemic rapamycin treatment ameliorates AD‐like phenotypes in several AD mouse models. However, the specific contribution of neuronal mTORC1 signaling in driving AD phenotypes has not yet been explored. In this study, we use an innovative neuron‐specific knockdown mTORC1 mouse model to determine whether neuronal mTORC1 signaling contributes to cognitive dysfunction in response to acute amyloid β (Aβ) exposure.MethodsFor these experiments, we used an innovative mouse model that expresses an inducible, neuron‐specific Cre recombinase in Raptorff/fl mice. Raptor is a required component of mTORC1, thereby this Cre‐lox system results in a neuronal mTORC1 knockdown mouse. Cre expression was induced at 6 months of age. To create Aβ1‐42 oligomers, Aβ1‐42 was reconsitituted in a 10% DMSO in PBS solution (220µM) and incubated at 37°C for 48 hours. Littermate control (wildtype, Cre non‐transgenic) and neuronal mTORC1 knockdown mice were given a single intraventricular injection of vehicle (10% DMSO in PBS) or oligomerized Aβ1‐42 (5µL of 220µM Aβ1‐42) to acutely induce AD‐like cognitive deficits. Cognitive behavior was assessed by Y‐maze and contextual fear conditioning 7‐10 days after acute Aβ1‐42 exposure.ResultsWildtype control mice acutely exposed to Aβ1‐42 had significantly impaired spatial working memory (Y‐maze, p<0.01) as well as significant deficits in contextual memory (fear conditioning, p<0.05). However, we found that mice with reduced neuronal mTORC1 signaling injected with Aβ1‐42 did not exhibit cognitive deficits in either spatial working memory or contextual memory as compared to vehicle‐treated wildtype controls. Furthermore, we found that mice with reduced mTORC1 signaling acutely exposed to Aβ1‐42 had significantly improved cognitive outcomes as compared to Aβ‐injected, wildtype, control mice (Y‐maze, p<0.05; fear conditioning, p<0.05).ConclusionNeuronal mTORC1 is required for acute Aβ‐induced cognitive dysfunction. Therefore, reduction of mTORC1 signaling in neurons with systemic rapamycin treatment contributes to the amelioration of Aβ‐induced cognitive dysfunction in AD mouse models.
In vivo TurboID labeling for paired proteomic and transcriptomic profiling of neurons and astrocytes
Authors: Ramelow Christina C , Xiao Hailian , Cheng Lihong , Kumar Prateek , Dammer Eric B. , Sampson Maureen , Nelson Ruth S , Malepati Sneha , Quo Qi , Bagchi Pritha , Duong Duc M , Seyfried Nicholas T , Sloan Steven A , Rangaraju Srikant 
Published: January 2025

AbstractBackgroundOur group has developed the innovative proximity labeling cell‐type specific in vivo biotinylation of proteins (CIBOP) approach to quantify cell‐specific in vivo proteomic and transcriptomic signatures that may lead to identify novel therapeutic targets for Alzheimer’s disease (AD) pathogenesis. CIBOP uses TurboID, a biotin ligase, selectively expressed in the cell type of interest using a conditional Cre/lox genetic strategy to label the cytosolic proteome. Using mass spectrometry (MS)‐based proteomics, we have found that TurboID biotinylates many RNA‐binding and ribosomal proteins. We extended the CIBOP approach to obtain representative cell type‐specific transcriptomes and proteomes.MethodWe crossed cell‐specific Cre lines (astrocytic: Aldh1l1‐Cre‐ert2 and neuronal: Camk2a‐Cre‐ert2) and Rosa26TurboID/wt floxed mice for cell‐specific proteomic labeling (astrocyte‐CIBOP and neuron‐CIBOP). CIBOP and control (Cre‐only) mice received tamoxifen, followed by biotin‐containing water. While maintaining RNA‐protein interactions, cortical tissue was lysed, biotinylated proteins were enriched via streptavidin beads, and RNA and proteins were eluted. Immunofluorescent microscopy (IF), biochemical assays, MS‐based proteomics, and RNA‐sequencing were completed to confirm cell‐specific molecular profiling. Concordance analysis of paired proteomes and transcriptomes from CIBOP mouse brains was conducted.ResultWestern blot analysis of the cortex confirmed biotinylation of the cellular proteome of CIBOP mice when compared to controls. Cell‐type specificity was further validated by IF images showing that biotin‐labeled proteins colocalized with corresponding astrocytic (e.g., GFAP and NDRG2) or neuronal markers (e.g., MAP2 and beta‐tubulin‐3). RNA gel electrophoresis displayed high levels of RNA from CIBOP brain streptavidin pulldowns and low RNA yield from control pulldowns. MS‐based proteomics and RNA‐sequencing analysis showed upregulation of astrocytic proteins (e.g., Hepacam, Glu, Aqp4, Plpp3) and genes (e.g., Sox9, Aqp4, Gfap, Apoe) from astrocyte‐CIBOP brain. In contrast, upregulation of neuronal proteins (e.g., Map2, Ncam1, Mapt) and genes (e.g., Pdyn, Tmem130, Ptpn7) was observed in neuron‐CIBOP brain samples, confirming specificity.ConclusionTogether, these results validate the CIBOP approach to capturing the cortical Aldh1l1‐positive astrocytic and Camk2a‐positive neuronal proteome and transcriptome. Our innovative in vivo cell type‐specific and native‐state dual‐omics approach provides complementary transcriptomic and proteomic information that can extend to AD models to investigate disease mechanisms, discover new biomarkers, and identify therapeutic targets.
Family history of AD and memory problems associated with worse subjective memory, not objective memory, in cognitively normal individuals
Authors: Hou Mingzhu , Jagust William J. , Chen Xi 
Published: January 2025

AbstractBackgroundFamily history of Alzheimer’s disease (AD) or undiagnosed memory problems is linked to an increased risk of dementia. Subjective memory complaints are also more common among individuals with positive family history, which could be indicative of heightened awareness of memory deficits in these people. Here, we conducted an online study in cognitively normal individuals across the lifespan and aimed to examine whether the presence of family history is linked to worse objective memory performance that mediates the lower subjective memory in these individuals.MethodParticipants’ objective memory was measured online by an object‐scene‐pair memory task that assessed their memory in different domains. Here we focused on the d prime (ZHit‐ZFA) for the object‐scene pairs, while other measures yielded similar results. Participants’ subjective memory was assessed by Memory Functioning Questionnaire (MFQ). We focused on the two most commonly used measures from this questionnaire, the general question and the frequency of forgetting subscale, as the primary measures of subjective memory. Participants’ family history was based on self‐report information using a comprehensive family history questionnaire. Family history positivity was defined as any family member having been diagnosed with AD or having undiagnosed memory problems.ResultsAmong 273 participants (aged 22‐70 yrs), 71.4% reported no family history (N = 195). In the 78 reports of positive family history, 14.7% was parent only (N = 40), 1.1% was sibling only (N = 3), 9.9% was other family member only (N = 27), 2.6% was parent & another member (N = 7); 0.4% was parent & sibling & another member (N = 1) (Fig.1). Individuals with family history reported having more memory problems (general, p = .032; Fig.2a) and more often forgetting (frequency of forgetting, p = .004; Fig.2b), after controlling for age and gender, despite having equivalent objective memory performance (p = .295; Fig.2c). These associations remained significant while further controlling for actual memory performance in the same model (Fig.3).ConclusionOur findings suggest that, contrary to our hypothesis, family history of AD and memory problems is associated with worse subjective memory, but not objective memory, in cognitively normal individuals. Low subjective memory in people with family history may reflect their general worry about dementia that is not based on actual cognition.
Psychological profiles associated with cortical thickness changes in middle‐aged adults
Authors: Bartrés‐Faz David , Demnitz‐King Harriet , Cabello‐Toscano María , Vaqué‐Alcázar Lídia , Saunders Rob , Cattaneo Gabriele , Bargalló Núria , Tormos‐Muñoz Josep M. , Sánchez Javier Solana , Pascual‐Leone Alvaro , Marchant Natalie L. 
Published: January 2025

AbstractBackgroundPsychological factors such as repetitive negative thinking, proneness to experience distress, and perceived stress are associated with increased risk of neurodegeneration and clinical dementia, whereas having a sense of life‐purpose, self‐reflection, and dispositional mindfulness may be protective. However, whether combinations of these risk and protective factors may inform distinct psychological profiles, which may be differential associated with age‐related health outcomes is currently unknown.MethodWe included 742 middle‐aged (mean age 51.4 (SD:7.0), 51.1% women) healthy individuals from the Barcelona Brain Health Initiative. All participants underwent a psychological assessment of individual risk and protective factors based on previous literature (Figure 1). An initial 3T MRI was acquired for all participants, with follow‐up MRIs conducted for 533 participants (average follow‐up 2.3 years). Latent profile analysis (LPA) was used to identify statistically distinct psychological profiles from risk and protective factors and MRIs were automatically processed with FreeSurfer v6.0 (maps p < 0.05, corrected for family‐wise error).ResultLPA revealed a 3‐profile solution: Profile 1 (n = 190, 25.6%) was characterized by lower levels of positive or protective psychological factors; Profile 2 included individuals showing higher negative or psychological risk factors (n = 149, 20.1%); and Profile 3 reported high protective and moderately low risk factors (n = 403, 50.3%; Figure 1). Age‐, gender‐, and education‐adjusted results revealed that compared to Profile 3, individuals in Profile 1 exhibited accelerated cortical thinning in the inferior and middle temporal areas, including regions within the AD cortical thinning signature. In models additionally adjusted for anxiety and depressive symptoms, Profile 1 also exhibited greater cortical thinning over time in the inferior temporal lobe region compared to Profile 2 (Figure 2A and B).ConclusionUsing a person‐centered approach to identify statistically distinct psychological profiles we found that already in middle‐age, those with lower levels of protective factors (Profile 1) exhibit accelerated cortical atrophy. This emphasizes the need for comprehensive psychological assessments in dementia prevention research, including the assessment of ‘protective’ factors in addition to the more commonly assessed ‘risk’ factors.