bluuebunny/crossref_metadata_2025_split huggingface dataset:
APOE4 impairs myelination via cholesterol dysregulation in oligodendrocytes
Authors: Tsai Li‐Huei , Akay Leyla A , Blanchard Joel , Von Maydell Djuna K , Kellis Manolis , Bennett David A. A , Davila Jose 
Published: December 2023

AbstractBackgroundAPOE4 is the strongest genetic risk factor for late‐onset Alzheimer’s disease (AD), yet the cellular and molecular mechanisms by which APOE4 contributes to AD risk remain largely unknownMethodWe performed single‐nuclear RNAsequencing from the prefrontal cortex (Brodmann’s Area 10) of thirty‐two individuals, 12 APOE3/3 and 12 APOE3/4 carriers each, and one subgroup with 8 APOE4/4 carriers, and validated hypotheses using mouse models and patient‐derived iPSC lines.ResultDifferential expression and pathway analysis revealed that APOE4 is strongly associated with dysregulation of cholesterol homeostasis across multiple cell types, with oligodendrocytes being the most impacted. Strikingly, in human and mouse brains, APOE4 oligodendrocytes contained aberrant intracellular accumulations of cholesterol, whereas in non‐carriers, cholesterol preferentially localized to the oligodendrocyte cell membrane along myelinated neuronal tracts. Mass‐spectrometry‐based lipidomic analysis further revealed that APOE4 oligodendrocytes and APOE4 human post‐mortem brain tissue had elevated levels of cholesteryl esters, associated with intracellular storage of cholesterol as lipid droplets. Cholesterol transport and bioavailability are rate‐limiting steps in axonal myelination. Consistent with this, we discovered both APOE4 human and mouse brains were hypomyelinated relative to non‐carriers. We found that a small molecule known to facilitate cholesterol transport reduced cholesterol accumulation in APOE4 oligodendrocytes, increased axonal myelination, and improved memory in APOE4 mice.ConclusionThese results provide a transcriptional atlas of cell‐type specific APOE4 effects in the human brain. Our results demonstrate that cholesterol homeostasis in oligodendrocytes is highly dysregulated in APOE4 oligodendrocytes and identify hypomyelination as a key APOE4‐associated phenotype. Collectively, these data establish a functional link between APOE4, cholesterol homeostasis, and myelination that presents new therapeutic opportunities for Alzheimer’s disease.
Association between metabolic syndrome and incident dementia: a prospective population‐based cohort study of UK Biobank participants
Authors: Qureshi Danial , Allen Naomi , Kuzma Elzbieta , Littlejohns Thomas J 
Published: December 2023

AbstractBackgroundGlobally, the prevalence of metabolic syndrome (MetS) is on the rise. Several studies indicate a potential relationship between MetS and dementia risk, however, findings remain inconclusive. We sought to investigate the association between MetS and risk of incident dementia, and further examine variations by follow‐up length, number of MetS components, and genetic risk for dementia.MethodsParticipants were selected from the UK Biobank, a prospective population‐based cohort study of half a million individuals aged 40‐69 years recruited between 2006‐2010. MetS at baseline was defined as the presence of at least three of the following five components, as per the 2009 Harmonized Criteria: elevated waist‐circumference, triglycerides, blood‐pressure and fasting‐glucose levels, and reduced HDL‐cholesterol. Incident dementia cases were identified through hospital inpatient and death registry records. Cox proportional‐hazards models were used to investigate the association between MetS and incident dementia. Models were adjusted for age, sex, ethnicity, Townsend‐deprivation index, education, household income, smoking status, alcohol intake, physical activity, and Apolipoprotein‐E (APOE)‐ε4 carrier status.ResultsWe identified 176,249 dementia‐free participants aged ≥60 years at baseline, among which 73,510 (41.7%) had MetS. Over 15 years of follow‐up (median: 12.3), 5,255 participants developed dementia. MetS was associated with a 14% increased risk of developing dementia (Fully Adjusted Hazard‐Ratio [HR]: 1.14, 95% Confidence‐Interval [CI]: 1.08, 1.21), compared to no MetS. Associations were evident only among those with ≥5 years of follow‐up (e.g., ≥10 years of follow‐up, HR: 1.18, 95%CI: 1.09, 1.28). Only the presence of four (HR: 1.23, 95%CI: 1.06, 1.42) or five (HR: 1.57, 95%CI: 1.34, 1.83) MetS components was significantly associated with an increased risk of dementia, compared to zero components. There was a statistically significant interaction (p <0.001) between MetS and APOE‐ε4. MetS was associated with dementia risk in APOE‐ε4 non‐carriers (HR: 1.28, 95%CI: 1.18, 1.39) but not in APOE‐ε4 carriers (HR: 1.04, 95%CI: 0.96, 1.12).ConclusionMetS was associated with an increased risk of incident dementia. This risk varied according to follow‐up length, number of MetS components present, and genetic risk for dementia. Early identification and management of MetS may help prevent or delay dementia onset.
CD147 associates cerebrovascular lesion with Aβ pathology in Alzheimer’s disease
Authors: Gao Feng , Zhan Yaxi , Wang Qiong , Dai Linbin , Shen Yong ,   China Aging and Neurodegenerative Initiative (CANDI) Consortium
Published: December 2023

AbstractBackgroundCerebrovascular abnormality is recognized as a major contributor to Alzheimer’s disease (AD). However, how cerebrovascular damage accelerates Aβ production/deposition remains poorly defined. CD147, a transmembrane molecule mainly expressed in cerebral small vessels, modulates γ secretase function and Aβ production in vitro. The present study was to study whether CD147 associated cerebrovascular damage with the Aβ pathology in autopsied human brains with AD, and whether CD147 in the CSF was related with CSF Aβ AD patients from China Aging and Neurodegenerative Initiative (CANDI) cohort.MethodAmounts of soluble CD147, membrane CD147 / Claudin‐5 / CD31 and insoluble Aβ43 /42 /40 from autopsied human brain tissue samples were assessed by ELISA, Luminex and MSD, respectively. In CANDI cohort, CSF Aβ40 and 42, CSF CD147, CSF Aβ43, and CSFAβ38 were measure with Simoa, Luminex, ELISA, and MSD, respectively. Linear regression models were used to evaluate the associations between CSF CD147 with cognitive decline (MMSE and cortical thickness), GFAP, NFL, Aβ burden (18F‐Flobetapir), and Aβ isoforms (Aβ43/42/40/38).ResultIn autopsied human AD brains, the lower soluble/membrane CD147 ratio was significantly associated with worse BBB integrity (lower Claudin‐5/CD31 ratio) and with higher levels of insoluble Aβ43 and Aβ42. In the CANDI cohort, lower CSF CD147 in AD patients was also significantly associated with higher level of Aβ burden. Interestingly, CSF CD147 show a stronger association with shorter Aβ isoforms (Aβ38 ≈ Aβ40 > Aβ42 > Aβ43). Decreasing CSF CD147 was significantly linked to worse cognitive function (MMSE and cortical thickness) and with higher levels of CSF GFAP and NFL. White matter hyperintensity was negatively significantly associated with CSF CD147.ConclusionCerebrovascular damage may impair the release of CD147 from vessels, thereby further exacerbate Aβ pathology via shifting the production of Aβ from longer to shorter isoforms. The findings suggest that soluble CD147 links cerebrovascular damage and Aβ pathology and cerebrovascular CD147 could be a potential therapeutic target for AD.
Associations of self‐reported psychological stress with memory and cerebrospinal fluid biomarkers of Alzheimer’s disease in middle‐aged adults
Authors: Franks Katherine H. , Bransby Lisa , Buckley Rachel F. , Yassi Nawaf , Chong Trevor T.‐J. , Lim Yen Ying , Pase Matthew P. 
Published: December 2023

AbstractBackgroundSelf‐reported psychological stress is associated with an increased risk of cognitive decline and dementia. However, it remains unclear whether stress is related to key biomarkers of Alzheimer’s disease (AD). This cross‐sectional study examined the relationship of psychological stress with memory and cerebrospinal fluid (CSF) biomarkers of AD in middle‐aged adults without dementia.MethodThe Healthy Brain Project (HBP) is a prospective web‐based study of adults aged between 40 and 70 years. A total of 2208 participants (76% female) completed the Depression, Anxiety, and Stress Scale (DASS) and Paired Associates Learning subtest of the CANTAB unsupervised on the HBP web platform. Additionally, a sub‐group of participants (n = 67; 41% APOE e4 carriers) attended an in‐person assessment where CSF samples were obtained to measure levels of amyloid‐beta (Aβ42), total tau (t‐tau), phosphorylated tau 181 (p‐tau), and neurofilament light chain (NFL). Separate linear regression analyses investigated associations of the DASS‐Stress score with memory performance and AD biomarkers. All analyses were adjusted for age, sex, education, and race.ResultIn the web‐based cohort, higher levels of self‐reported psychological stress were significantly associated with poorer memory (unstandardised β = ‐0.014, standard error [SE] = 0.004, p <.001). However, there were no significant associations between psychological stress and CSF levels of Aβ42, t‐tau, p‐tau, and NFL (all p > .05), with small effect sizes (Cohen’s f2 ≤ 0.05).ConclusionHigher levels of self‐reported psychological stress were associated with poorer memory in a large middle‐aged cohort but were not associated with AD biomarkers in a subset of participants with available CSF. One potential explanation is that non‐AD pathologies may underlie the relationship between stress and poorer memory; for example, poor coping strategies (e.g., smoking, overeating, and physical activity) might increase the risk of vascular cognitive impairment. However, it is also likely that the small sample size of the in‐clinic cohort was insufficient to detect any subtle relationships between stress and AD pathologies. Further research is needed to determine the associations between stress and the development of the clinical and biological manifestations of AD.
Iterative refinement: Developing items to build an assessment of dementia caregivers’ caregiving style
Authors: Leggett Amanda N , Miner Jennifer A , Baker Elaina , Lee Hannah , Kallen Michael A , Tsuker Sophia , Carlozzi Noelle E 
Published: December 2023

AbstractBackgroundPrior mixed‐methods research has classified 5 distinct dementia caregiving style profiles based on how caregivers vary across 5 domains: understanding of dementia, adaptability, orientation towards oneself vs. the care recipient, emotional expression, and behavioral management. Style profiles have been associated with important care outcomes, yet, for this construct to be useful, it must be measurable. Our study aims to develop the first comprehensive assessment of caregiver cognitive‐behavioral styles for clinical/service utility or self‐assessment.MethodA preliminary item pool of 188 items was developed based on prior research. A literacy review of item content was conducted. Items then went through iterative refinement including: 1) expert review (2 content experts and 1 measurement development expert, with 63 items modified and 66 deleted); 2) cognitive interviews with 7 caregivers (caregivers reviewed each domain’s item set and provided interview feedback on the items, with 4 items modified and 18 deleted); and 3) translatability review for Spanish (review of wording that could impede translation to other languages, with 28 modified and 4 deleted).ResultOur iterative item pool refinement process resulted in 99 items reflective of the 5 domains to be included in psychometric field testing: adaptability (32 items; e.g., I make adjustments to the way I provide care), behavioral management (20 items; e.g., I try to distract the person I care for when they are frustrated), emotional expression (25 items; e.g., I feel positive when it comes to handling caregiving difficulties), understanding (10 items; e.g., I recognize when I need to change how I communicate with the person I care for), and orientation to self or other (12 total; e.g., I do what is best for the person I care for, even at my own expense).ConclusionOur iterative item development process ensures that items developed for a future measure are person‐centered, clear, translatable, and relevant to empirical evidence. The developed items will be field tested among 200 caregivers. This measure is vital to the development of more effective and individualized treatment to enhance caregivers’ ability to support the PLwD, improve outcomes, and reduce the downstream burden of illness and healthcare costs.
Predicting the chance for being at‐risk of AD based on smartphone data obtained during an everyday wayfinding task in the real world
Authors: Marquardt Jonas , Mohan Priyanka , Spiliopoulou Myra , Glanz Wenzel , Butryn Michaela , Kuehn Esther , Schreiber Stefanie , Maass Anne , Diersch Nadine 
Published: December 2023

AbstractBackgroundPatients with Alzheimer’s disease (AD) often show problems in spatial navigation. However, spatial navigation is rarely investigated in real world settings and in people at early disease stages. Capitalizing on recent advancements in digital technologies, we measured the performance of healthy younger (YA) and older adults (OA), as well as older adults with subjective cognitive decline (SCD) while they solved a smartphone‐based wayfinding task.MethodUsing the novel smartphone application “Explore”, we tracked GPS data and other behavioral indicators in 24 YAs, 25 OAs, and 23 SCDs, while they were asked to find points of interest on the medical campus in Magdeburg. In our analyses, we first quantified similarities between the GPS trajectories and identified wayfinding styles using k‐medoids clustering. Next, we extracted navigation profiles with aggregated performance measures as input features (e.g., wayfinding distance and number of help function calls) in a latent profile analysis. Mixed effect models were fitted to evaluate group differences for each performance measure separately. We then fed the performance measure that showed the largest groups differences into a multinomial logistic regression model to predict age and diagnostic group in unknown users via leave‐one‐out cross‐validation.ResultThe GPS data could be clustered into three wayfinding styles. However, the correspondence to our groups was rather low (Figure 1a). In contrast, navigation profiles obtained from the latent profile analysis showed a higher correspondence (Figure 1b). Particularly the number of brief stops during navigation differed between the groups, all p ≤ .006 (Figure 2), and predicted age group, p = .015, and diagnostic group above chance, p = .004 (Figure 3). The leave‐one‐out cross‐validation confirmed the successful prediction of group membership in unknown participants, accuracy = 0.57 (chance level 0.33).ConclusionHere, we show how information about the cognitive health status of an individual can be inferred from smartphone‐data, obtained during a brief episode of a frequently performed everyday behavior. In particular, the number of short stops during wayfinding could be used to distinguish between YA, OA, and SCDs. Hence, real‐world navigation data, obtained from mobile devices, might help to identify individuals at increased risk for developing AD.
A TREM2‐activating antibody with a blood–brain barrier transport vehicle enhances microglia function
Authors: Sanchez Pascal E. 
Published: December 2023

AbstractBackgroundLoss‐of‐function variants of TREM2 are associated with increased risk of Alzheimer’s disease (AD), suggesting that activation of this innate immune receptor may be a useful therapeutic strategy.MethodHere we describe a high‐affinity human TREM2‐activating antibody engineered with a monovalent transferrin receptor (TfR) binding site, termed antibody transport vehicle (ATV), to facilitate blood–brain barrier transcytosis.ResultUpon peripheral delivery in mice, ATV:TREM2 showed improved brain biodistribution and enhanced signaling compared to a standard anti‐TREM2 antibody. In human induced pluripotent stem cell (iPSC)‐derived microglia, ATV:TREM2 induced proliferation and improved mitochondrial metabolism. Single‐cell RNA sequencing and morphometry revealed that ATV:TREM2 shifted microglia to metabolically responsive states, which were distinct from those induced by amyloid pathology. In an AD mouse model, ATV:TREM2 boosted brain microglial activity and glucose metabolism.ConclusionThus, ATV:TREM2 represents a promising approach to improve microglial function and treat brain hypometabolism found in patients with AD.
Characterising the covariance pattern between lifestyle factors and structural brain measures: a multivariable study of two cohorts of older adults
Authors: Demnitz Naiara , Hulme Oliver J , Siebner Hartwig R , Kjaer Michael , Ebmeier Klaus P , Boraxbekk Carl‐Johan , Gillan Claire 
Published: December 2023

AbstractBackgroundModifiable risk factors have been shown to promote healthy brain ageing. However, most studies to date have focused on the relationship between a single risk factor and brain health. Given that risk factors do not occur in isolation, multivariable analyses may provide a more realistic model of the effects of modifiable lifestyle factors on brain ageing.MethodHere, the relationship between 9 modifiable lifestyle factors and 7 indices of brain structure were examined using canonical correlation analyses to identify a covariance pattern between lifestyle factors associated with dementia risk and MRI‐derived measures of brain structure. Analyses were first conducted on a Danish cohort of older adults (n = 251) and then cross‐validated in an independent cohort of older adults from the United Kingdom (n = 668).ResultsIn a 5‐fold cross‐validation analysis of the test dataset, a canonical correlation of 0.14 was observed between the lifestyle and brain variates. In the cross‐study validation, the lifestyle‐brain correlation was r = .10. In the Danish cohort, feelings of loneliness, BMI, depressive symptoms, and years of smoking were the primary contributors to the lifestyle variate (rs ≥ 0.3). In the British cohort, a different pattern of lifestyle factors was found to relate to brain structure the most (rs ≥ 0.3: physical activity, education, alcohol consumption, blood pressure and BMI).ConclusionIn both cohorts, we found that a latent of lifestyle factors was positively associated with age‐related measures of brain structure and this relationship was validated across cohorts of older adults. However, the covariance pattern between lifestyle and brain outcomes differed between datasets. Taken together, these findings highlight how future lifestyle interventions should be tailored to suit their target populations.
Abnormality of the pulvinar in posterior cortical atrophy: A multimodal MRI study
Authors: Chu Min , Liu Li , Yang Caishui , Wu Liyong 
Published: December 2023

AbstractBackgroundAlthough the pulvinar is known for its extensive connections with both ventral and dorsal visual streams, details of pulvinar functional connectivity in the setting of posterior cortical atrophy (PCA) remain unclearTo study pulvinar functional connectivity and relevant associations with higher visual dysfunction in PCA.MethodA total of 29 patients with PCA and 30 normal controls were recruited. Each participant underwent comprehensive neuropsychological assessment and both structural and resting‐state functional MRI scanning. Voxel‐based morphometry (VBM) and seed‐based functional connectivity analyses were conducted to assess pulvinar gray matter volume as well as connectivity between the pulvinar and whole brain regions. A partial correlation analysis was performed to analyze neuropsychological test and pulvinar imaging data.ResultCognitive and visual functions including visuospatial processing, visual perception, episodic memory, and naming were impaired among PCA patients. Marked pulvinar atrophy was noted in PCA patients. Furthermore, functional connectivity between the pulvinar and precuneus was significantly decreased in PCA patients as compared to normal controls (FWE corrected; P<0.001). Left pulvinar gray matter volume was found to associate with object agnosia (r = 0.42, P<0.05) and right–left disorientation (r = 0.29, P<0.05) among PCA patients. The bilateral pulvinar region was found to associate with Boston Naming Test (left, r = 0.51, P = 0.015; right, r = 0.46, P = 0.03) and Activities of Daily Living (left, r = ‐0.46, P = 0.019; right, r = ‐0.53, P = 0.006) scores. Correlation analyses did not reveal significant findings concerning functional connectivity.ConclusionOur findings confirm pulvinar degeneration and its contributions in the setting of PCA.
Cognitive dynamics in healthy aging and mild cognitive impairment
Authors: Aschenbrenner Andrew J. , Jackson Joshua J. 
Published: December 2023

AbstractBackgroundIn observational and clinical intervention studies of Alzheimer disease (AD), cognition is typically assessed in an extended, “single‐shot” testing session to measure mean‐level changes in performance over time. However, this strategy ignores day‐to‐day fluctuations in cognition that may occur due to mood, stress or fatigue. It is possible that the overall magnitude of daily variability in cognition is a more sensitive endpoint than traditional metrics of cognitive change. Previous research has suggested that attention and personality traits are important predictors of AD, yet it is unknown how scores on these outcomes fluctuate over short intervals. The aim of this project was to evaluate the extent to which scores on attention, personality and mood and fatigue vary across 3 weeks of daily testing and whether cognitive variability increases in early‐stage AD.MethodA total of 66 younger adults (YAs), 52 cognitively healthy older adults (OAs), and 37 individuals with cognitive impairment (CIs) completed 21 daily assessments of attention, personality, and mood. Cognitive impairment was determined as a rating of 0.5 on the Clinical Dementia Rating scale or a score of less than 11 on the mini Montreal Cognitive Assessment. Group differences in mean performance and variability were assessed using Bayesian mixed effects location scale models.ResultAdherence was high with an average of 20.1, 19.7 and 19.2 daily sessions (out of 21 possible) completed for YAs, OAs and CIs, respectively. YAs reported overall lower mood compared to the OAs. No other mean comparisons were significant. In terms of daily variability, YAs had greater fluctuations in reported fatigue, conscientiousness and neuroticism compared to healthy OAs. Finally, both YAs and CIs had greater variability in attention relative to OAs. These differences persisted after accounting for global cognition.ConclusionHealthy aging (OAs compared to YAs) results in greater stability in personality ratings. In contrast, pathological aging (CIs compared to OAs) results in greater variability in attention scores with no detectable changes on mean performance. We argue that cognitive variability provides unique insight to cognitive changes that occur in healthy aging and early‐stage AD and should continue to be explored as primary outcomes.