bluuebunny/crossref_metadata_2025_split huggingface dataset:
Multifactor mid‐life risk for Alzheimer’s disease associated with alterations in navigation but not episodic memory: the PREVENT‐Dementia study
Authors: Newton Coco , Pope Marianna , Dounavi Maria‐Eleni , Carter Stephen F , Muniz‐Terrera Graciela , Henson Richard N , Ritchie Karen , Ritchie Craig W. , O'Brien John T , Su Li , Chan Dennis 
Published: December 2022

AbstractBackgroundThe entorhinal cortex (EC) is the first cortical brain region to exhibit neurodegeneration in Alzheimer’s disease (AD). Given that the EC contains unique grid cells underpinning path integration, tests probing this aspect of navigation may have added value in detecting AD in its earliest preclinical stages. Building on our past work showing that a VR path integration task was highly sensitive and specific for prodromal AD (Howett et al., 2019 Brain), we tested the hypothesis that path integration may be affected in asymptomatic middle‐aged individuals at increased risk of AD.Method100 cognitively healthy adults (aged 43–66) from the PREVENT Dementia cohort performed an immersive VR path integration task in a simulated environment with distal boundary cues to generate allocentric spatial representations. We manipulated EC‐dependence by pseudo‐randomly removing supportive spatial cues from the virtual environment (Figure 1). Participants additionally performed a battery of cognitive tasks including the ACE‐R and COGNITO episodic memory. Linear mixed effects models and Tukey‐corrected post‐hoc contrasts were used to explore the contributions to task performance of parental family history, APOE‐e4 status, global amyloid PET uptake value (N = 46) and CAIDE lifestyle dementia risk score, adjusted for age, sex and education.ResultIndividuals with a positive family history, APOE‐e4 allele or higher CAIDE dementia risk score showed a selective impairment in path integration only when supportive boundary cues were removed. Significant sex interactions indicated that the family history effect (t = 2.31, pTukey = 0.022, Figure 2) and APOE‐e4 effect (t = 3.18, pTukey = 0.023) was specific to males. The effect of CAIDE risk score was specific to individuals with a family history (t = 2.45, pTukey = 0.038) (Figure 3). Conversely, these AD risk factors showed no effect on performance for the other cognitive tasks. Global amyloid PET uptake values showed no association to any task performance.ConclusionThese results suggest that navigation tests based on EC grid cell function may identify the earliest cognitive changes in individuals at greater risk of AD. The additional moderation by sex indicates a future need to consider male/female differences when using family history or APOE status to inform detection of initial stages of AD.
Two progression patterns in Alzheimer's disease identified from structural MRI in a memory clinic‐based cohort
Authors: Baumeister Hannah , Ziegler Gabriel , Wolfsgruber Steffen , Ramirez Alfredo , Peters Oliver , Priller Josef , Schneider Anja , Wiltfang Jens , Fliessbach Klaus , Bürger Katharina , Perneczky Robert , Teipel Stefan , Laske Christoph , Spottke Annika , Heneka Michael T. , Wagner Michael , Duzel Emrah , Jessen Frank , Berron David 
Published: December 2022

AbstractBackgroundAlzheimer’s disease (AD) is known to be heterogeneous in pathobiology and clinical manifestation. Most previous studies demarcating AD subtypes rely on data‐driven clustering methods that are likely confounded by interindividual differences in disease progression within samples. Addressing this problem, we aim to identify and characterize distinct AD atrophy progression patterns in a memory clinic‐based cohort.Method
N = 914 subjects (296 cognitively unimpaired, 366 with subjective cognitive impairment, 153 with mild cognitive impairment, and 99 with AD dementia) from the multicenter observational DZNE Longitudinal Cognitive Impairment and Dementia Study (DELCODE) were included. The Subtype and Stage Inference algorithm (Young et al., 2018, Nat. Commun.) was applied to ROI‐based cortical thickness and gray matter volume data obtained from T1w and T2w 3T‐MRI using FreeSurfer. Subtypes were characterized in demographics, ApoE genotype, various fluid biomarkers, and cognition.ResultTwo atrophy subtypes were identified. A limbic‐predominant subtype exhibited initial volume loss in the amygdala and hippocampus, followed by cortical thinning in the medial temporal, temporal, frontal, parietal, and occipital lobes. Contrary, in a hippocampal‐sparing subtype, cortical thinning first occured in the frontal, parietal, and occipital lobes before the temporal and medial temporal lobes, hippocampus, and amygdala were affected. Compared to the hippocampal‐sparing subtype, the limbic‐predominant subtype included subjects who were older, reported fewer years of education, and tended to have more ApoE e4 alleles, higher risk of vascular pathology, and higher plasma neurofilament light levels. The subtypes differed in their CSF biomarker profiles indicating higher β‐amyloid and tau burden in the limbic‐predominant subtype. In the limbic‐predominant subtype, cognitive impairment was accentuated in the learning and memory as well as language domains. Belonging to the hippocampal‐sparing subtype was associated with an impairment in executive functions and processing speed, visuospatial functions, and working memory.ConclusionWe provide evidence on atrophy heterogeneity that is largely in line with previous theoretical and empirical contributions while overcoming key limitations that are commonly faced in earlier studies. Heterogeneity may have substantial impact even in cohort studies designed to primarily include “typical” amnestic AD which highlights the need for optimized and subtype‐specific measures of early detection and disease progression.
APOE genotype modifies microglial immunometabolism
Authors: Devanney Nicholas A. , Lee Sangderk , Williams Holden C. , Allenger Elizabeth J. , Smith Cathryn T , Segovia Gabriella Morillo , Walsh Adeline E. , Friday Cassi , Morganti Josh M. , Johnson Lance A 
Published: December 2022

AbstractBackgroundMetabolic dysfunction and neuroinflammation characterize Alzheimer’s disease (AD), but it is unclear if these two facets of the disease are linked. The E4 allele of Apolipoprotein E (APOE) is the strongest genetic risk factor for late‐onset AD and is associated with increased neuroinflammation. Recent data from our lab and others show that E4 is also associated with increased aerobic glycolysis. These two findings may be intrinsically linked through the concept of ‘immunometabolism’ ‐ an emerging paradigm that implicates increased glycolysis as a core requirement during pro‐inflammatory activation, whereas increased oxidative phosphorylation is required for anti‐inflammatory responses.MethodPrimary microglia were isolated from targeted replacement mice expressing human APOE isoforms and stimulated with pro‐inflammatory (lipopolysaccharide (LPS); IFNγ + TNFα) or anti‐inflammatory (IL‐10; IL‐4 + IL‐13) cytokines. Metabolic responses were measured using the Agilent Seahorse platform and targeted metabolomics. We also performed single‐cell RNA sequencing on brains from APOE targeted replacement mice at 3‐, 10‐, and 18 months of age +/‐ LPS.ResultSeahorse revealed increased glycolysis and decreased mitochondrial respiration in E4 microglia. Targeted metabolomics revealed increased lactate and succinate in E4 microglia, metabolites known to accumulate in pro‐inflammatory macrophages. Aged E4 brains were uniquely found to harbor a metabolically distinct subcluster of microglia that expressed a signature similar to the established ‘disease associated microglia’ phenotype, even in the absence of neuropathology. SCENIC regulon analysis linked this cluster to the transcription network of HIF1a, and increased expression of HIF1a was validated in E4 microglia. In LPS‐treated animals, two distinct microglia subclusters emerged in E4 brains that were defined by altered expression of genes relating to oxidative phosphorylation and mitochondrial function.ConclusionOur findings reveal that age and LPS treatment induce a distinct metabolic response in E4 microglia. The accumulation of lactate and succinate and increased glycolysis in E4 microglia indicate altered metabolic preference conducive to pro‐inflammatory activation, whereas the decreased mitochondrial respiration may preclude effective anti‐inflammatory responses. We propose that this altered metabolism skews E4 microglia towards a phenotype that favors chronic neuroinflammation and neurodegeneration. Thus, reprogramming metabolism in E4 microglia may provide a novel therapeutic avenue for the treatment of AD.
An Unsupervised Data‐Driven Approach to Profiling Distinct Tau Progression Patterns
Authors: Tosun Duygu , Rajaram Ramya , Spottiswoode Bruce , Fahmi Rachid 
Published: December 2022

AbstractBackgroundGiven the central role that accumulation of tau pathology plays in the clinical progression of Alzheimer’s disease, the ability to quantify and predict the spread of tau is of great interest. Due to observed heterogeneity in patterns of tau deposition, though, stratification of individuals into homogenous phenotypes is critical to better understanding the natural course of this pathology progression, and ultimately the clinical disease progression. We propose an unsupervised data‐driven whole‐brain pattern analysis approach leveraging the spatially rich information provided by longitudinal tau‐PET, first to identify distinct tau accumulation profiles from longitudinal observation data and then to build baseline models predictive of tau accumulation type.MethodLongitudinal ADNI flortaucipir‐PET images (N=530) were normalized to cerebellar‐uptake and corrected for partial‐volume‐effects to estimate flortaucipir‐burden for Braak regions I, III, IV, V, and VI. Braak II region was excluded due to spill‐in from choroid‐plexus. A mixture of multivariate generalized linear mixed models was used as an unsupervised data‐driven longitudinal clustering approach to identify distinct flortaucipir‐progression profiles with random‐intercept to analyze flortaucipir‐burden from all Braak regions and all time‐points simultaneously (i.e., multivariate longitudinal feature‐space) while accounting for inter‐regional dependence and irregular time sampling. Multiclass random‐forest classification (MRFC) was employed to predict the identified flortaucipir‐progression profiles using baseline variables.ResultThree distinct flortaucipir‐progression profiles were identified: 1) “stable” with minimal flortaucipir‐accumulation across all Braak regions; 2) “moderate‐accumulator” with slow (1.01‐2.35 %SUVR/year) flortaucipir‐accumulation rates within Braak I, III, IV, and V; and 3) “fast‐accumulator” with accelerated (1.07‐4.03 %SUVR/year) flortaucipir‐accumulation rates in Braak IV, V, and VI. Prevalence of moderate to fast flortaucipir‐progression profiles increased with Aβ‐positivity, cognitive impairment, age and APOE‐ϵ4. Majority of Aβ‐negative cognitively unimpaired individuals fell within the "stable” category while Aβ‐positive individuals with dementia presented with moderate to fast flortaucipir‐progression profiles. MRFC trained on baseline demographic/clinical characteristics and baseline Braak flortaucipir burdens (60%/40% train/test) differentiated the three flortaucipir‐progression groups with a balanced accuracy of 93% (sensitivity=92%; specificity=95%).ConclusionWe derived data‐driven distinct longitudinal tau‐PET patterns that characterize the flortaucipir‐progression differences in ADNI. The ability to detect flortaucipir‐progression with baseline imaging and non‐imaging markers could have potential to screen high‐risk individuals for accelerated pathology progression.
Assessing Risk of Incident Cognitive Impairment Using Stages of Objective Memory Impairment (SOMI) and Cerebrospinal Fluid
Authors: Petersen Kellen K. , Grober Ellen , Lipton Richard B. , Nallapu Bhargav Teja , Ezzati Ali 
Published: December 2022

AbstractBackgroundThe asymptomatic period for persons with preclinical Alzheimer’s disease (AD) lasts for several years despite the presence of AD biomarkers. These biomarkers are critical for disease detection and monitoring, but collection is burdensome and costly. Sensitive cognitive measures such as Stages of Objective Memory Impairment (SOMI) may be a low‐cost alternative or adjunctive marker of disease‐progression risk. Here, we used longitudinal data from the Knight Alzheimer’s Disease Research Center to investigate the odds of disease progression associated with baseline SOMI stage and cerebrospinal fluid (CSF) biomarkers of Aβ42/Aβ40 ratio, p‐tau181, and t‐tau.MethodsWe used data from 617 cognitively unimpaired participants with baseline Clinical Dementia Rating (CDR) of 0, CSF measures, and longitudinal Free and Cued Selective Reminding Test (FCSRT) scores used to classify participants into different SOMI stages (Table 1). We examined the association between SOMI stage, CSF biomarkers, and incident cognitive impairment based on time to conversion from CDR of 0 to CDR>0 (incident cognitive impairment) using Cox Models.ResultsParticipants, at enrollment (Table 2), were on average 67.2 (SD = 9.4) years old, 56.6% were female, and had average 7.5 years of follow‐up (range 1‐18). At baseline, 325 (52.7%) were SOMI‐0, 206 (33.4%) were SOMI‐1, 64 (10.4%) were SOMI‐2, and 22 (3.6%) were SOMI‐3 or ‐4 (merged groups). A total of 127 (20.6%) individuals converted to CDR>0. The Cox proportional hazards regression models indicated that in comparison with individuals in SOMI‐0 stage, those in SOMI‐3/4 stage were more than twice as likely to show disease progression (HR=2.43 (95% CI, 1.21‐4.89, p=0.013)) (Table 3). Adding individual CSF biomarkers to the models did not affect the association of SOMI‐3/4 with incident cognitive impairment (p<0.05 for all). In models that included SOMI stages and all CSF biomarkers, SOMI‐3/4 (HR=2.13, 95% CI 1.07‐4.12, p=0.033) Aβ42/Aβ40 (HR=9.76e‐6, 95% CI=2.70e‐10 ‐ 0.35, p=0.031) and t‐tau (HR=1.001, 95% CI=1.000‐1.002, p=0.018), but not p‐tau (p=0.645), showed significant association with incident cognitive impairment.ConclusionsSOMI‐3/4 predicts incident cognitive impairment (change in CDR) independently from CSF AD biomarkers. These results support the utility of SOMI stage as an early marker of incident cognitive impairment.
Is Poor Sleep Quality Associated with Lower Levels of and Faster Declines in Cognitive Function? Results from the Kaiser Healthy Aging and Diverse Life Experiences (KHANDLE) Study
Authors: Chen Ruijia , Calmasini Camilla , George Kristen M. , Gilsanz Paola , Whitmer Rachel A. , Glymour M. Maria 
Published: December 2022

AbstractBackgroundPoor sleep quality has been linked to worse cognitive function, but most research has been conducted in predominantly White samples. We investigated whether poorer sleep quality is associated with lower levels of and faster declines in cognition and whether these associations differ by race/ethnicity.MethodWe used data from KHANDLE (N = 1,438; mean age: 75.7 years), a multi‐ethnic cohort of Kaiser Permanente Northern California members. We created a global sleep score by summing scores on six sleep components assessed by a modified Pittsburgh Sleep Quality Index: subjective sleep quality, latency, duration, disturbances, sleep medication use, and daytime dysfunction. Executive function (EF) and verbal memory (VM) were assessed by the Spanish and English Neuropsychological Assessment Scale (3 waves each separated by 18 months). Linear regression models assessed the associations between sleep quality and baseline cognition. To understand associations with cognitive decline, we fit linear mixed‐effect models with random intercepts accounting for practice effects and interview mode. Covariates included baseline age, gender, income, education, depression, physical activity, and central adiposity. We included interactions between time (years since baseline) and sleep and time and covariates to determine associations between sleep and cognitive decline. To assess racial/ethnic differences, we included interactions (race*sleep in linear regression models and time*sleep*race in mixed‐effect models for each racial/ethnic category) and performed likelihood ratio tests to determine the presence of interactions.ResultAfter adjusting for covariates, sleep quality was not associated with baseline EF or VM and the associations did not differ by race/ethnicity (Figure 1). Overall, poorer sleep quality was associated with faster declines in EF (β
time*sleep = ‐0.02, 95% CI ‐0.03, ‐0.004: Figure 2). The associations between sleep and declines in EF were modified by race/ethnicity (β
time*sleep*Black = ‐0.06, 95% CI ‐0.09, ‐0.03), such that poorer sleep quality was associated with faster declines in EF among Black adults only (β
time*sleep = ‐0.06, 95% CI ‐0.08, ‐0.04; Figure 3).ConclusionPoorer sleep quality was associated with faster cognitive decline, and the association was particularly strong among Black older adults. Further research is needed to elucidate the mechanisms through which sleep influences cognitive decline among Black populations.
Differences in Alzheimer’s disease and cerebrovascular disease neuropathology between latent class groups of cardiovascular risk factors
Authors: Ruthirakuhan Myuri , Cogo‐Moreira Hugo , Swardfager Walter , Herrmann Nathan , Lanctôt Krista L. , Keith Julia , Black Sandra E. 
Published: December 2022

AbstractBackgroundIndividual cardiovascular risk factors (CVRFs) have been associated with neurodegeneration. However, CVRFs are often comorbid with one another, and little is known regarding how groups of co‐occurring CVRFs are associated with Alzheimer’s disease (AD)‐ and cerebrovascular disease (CVD)‐related neuropathologies. We identify distinct groups of CVRFs in cognitively normal (CN) individuals with post‐mortem data.MethodIndividuals from the National Alzheimer’s Coordinating Center dataset who were CN one year prior to death were analyzed. To identify CVRF classes, a latent class analysis (LCA) was conducted with seven CVRFs (hypertension, hypercholesterolemia, heart condition, stroke, and smoking history, diabetes, and obesity). Differences in the presence of 1) mixed AD neuropathology (ADNP) and CVD neuropathology (CVNP), and 2) CVNP only, were compared between CVRF groups. Age, sex, years of education, Mini‐Mental State Examination (MMSE) score, and presence of APOE E4 allele were included as covariates. The presence of pure ADNP was not investigated as this was only present in two individuals.ResultThis study included 415 CN individuals (age of death: 86.2+/‐9.6, MMSE: 28.3+/‐1.8, education: 15.8+/‐2.8 years, male = 53%, APOE E4 allele: 21%). The LCA identified three groups of CVRFs (Figure 1). One group had low probabilities of CVRFs (N = 89). The second group had higher probabilities of hypertension and hypercholesterolemia (N = 255) (vascular‐dominant group). The third group had higher probabilities of hypertension, hypercholesterolemia, smoking history, diabetes, and obesity (vascular‐metabolic group) (N = 71). The vascular‐dominant group had significantly more individuals with mixed ADNP/CVNP than the vascular‐metabolic group (24% vs. 9%, p = .014). However, the vascular‐metabolic group had significantly more individuals with CVNP only compared to the vascular‐dominant group (61% vs. 37%, p = .002).ConclusionThese findings suggest that those in the vascular‐dominant group have an increased odds of having mixed ADNP/CVNP, while those in the vascular‐metabolic group have an increased odds of having increased CVNP only. Future studies targeting ADNP/CVNP in the vascular‐dominant group, and CVNP in the vascular‐metabolic group should be investigated to determine their modifying effects on cognitive‐related outcomes.
GM‐CSF reduces amylin amyloid and prevents pancreatic cell death in the hIAPP mouse model of Type 2 diabetes mellitus, a known risk factor for Alzheimer’s disease
Authors: Wang Athena Ching‐Jung , Boyd Timothy D. , Markham Neil , Adame Vanesa , Potter Huntington 
Published: December 2022

AbstractBackgroundPeople with Type II diabetes mellitus (T2D) are at higher risk for developing Alzheimer’s disease (AD). T2D is characterized histopathologically by the accumulation of fibrillary amyloid deposits in the pancreas, which are comprised primarily of human islet amyloid polypeptide (hIAPP), also known as amylin. Amylin, which self‐aggregates in a manner similar to amyloid beta, has been implicated as a source of pathogenesis in both T2D and AD. In T2D patients, pancreatic amyloid deposition occurs before and induces islet β‐cell apoptosis.Granulocyte‐macrophage colony‐stimulating factor (GM‐CSF) has demonstrated anti‐apoptotic, neuroprotective, neurotrophic, immunomodulatory, and regenerative effects in several neuronal injury models. We discovered that GM‐CSF treatment rapidly reduced cerebral amyloidosis and reversed cognitive impairment in transgenic AD models (Boyd et al, 2010), which led to the initiation and successful completion of a Phase 2 clinical trial (NCT01409915) using sargramostim (rhuGM‐CSF) in mild‐to‐moderate AD participants (Potter et al., 2021). Thus, we hypothesized the GM‐CSF might also reduce amyloid and prevent cell death in the pancreas of the hIAPP mouse model of T2D.MethodWe investigated GM‐CSF treatment effects in 12‐week‐old male hemizygous hIAPP mice (Jackson strain Tg(Ins2‐IAPP)RHFSoel), which accumulate amylin amyloid in pancreatic islets. Mice received daily subcutaneous injections (5 days/week for 23 total injections) of either recombinant murine GM‐CSF (5 µg/day or ∼167 µg/kg; n=9) or sterile saline (n=7), and the animals were then euthanized, perfused according to CU Anschutz OLAR regulations, and pancreatic tissues were obtained and processed for histopathology. Whole blood samples were obtained before perfusion, and blood chemistry analyses were performed for T2D biomarker levels (BUN, amylase, LDH, glucose, ALT). Unpaired t‐tests were used to determine significant differences (p<0.05) between treatment groups.ResultThioflavin‐S staining revealed significantly less pancreatic amyloid (p=0.00114, saline n=3, GM‐CSF n=7) and Caspase‐3 immunohistochemistry showed significantly less apoptosis (p=0.0057, Saline n=7, GM‐CSF n=9) in pancreatic tissue from the GM‐CSF‐treated group. There were no significant differences observed for the blood chemistry biomarkers, but trends were observed for lower levels of BUN and higher levels of amylase in the GM‐CSF‐treated group.ConclusionThese preliminary data suggest a therapeutic potential for GM‐CSF to prevent or treat T2D, and thereby reduce AD risk.