bluuebunny/crossref_metadata_2025_split huggingface dataset:
APOE and gender influence cerebrospinal fluid lipids
Authors: Hanson Angela J , Farris Kristen M , Miglani Jasroop K , Djukovic Danijel , Raftery Daniel 
Published: January 2025

AbstractBackgroundHigh fat diets are a risk factor for Alzheimer Dementia (AD) but little is known about the effect of acute high fat feeding on brain lipid metabolism. Previous studies suggest that diet results may differ by APOE genotype and sex. Here we examined cerebrospinal fluid (CSF) lipidomic profiles after high and low fat feeding in a group of older adults to ascertain how APOE and sex influenced post‐prandial lipids.MethodAs part of the Meal and Memory study (CT# NCT03070535), 78 healthy older adults (50% E4+, each E4 group 56% women) ingested high fat meal (HFM) and low fat meal (LFM) breakfasts 3‐5 weeks apart after overnight fast. Plasma triglycerides (TG) were measured at 7 time points, and lumbar puncture was performed 4 hours post‐meal. Lipidomics were performed on 250 ul of CSF on a Lipidyzer platform consisting of an AB Sciex 5500 MS/MS QTraps system equipped with a SelexION for differential mobility spectrometry (DMS). Multiple reaction monitoring was used to target 1,530 lipid species (across 20 lipid classes/subclasses) in positive and negative ionization modes with and without DMS, respectively. Lipids were analyzed using MetaboAnalyst 6.0 and SAS OnDemand (2021).ResultHFM expectedly increased plasma triglycerides (TG) (LFM peak TG 134±69 mg/dL, HFM peak TG 149±80, F 8.85, p = 0.004), results unaffected by E4 status or sex. No differences were found between the two meals for the 20 lipid classes or for individual lipid species in CSF. When examined by sex*APOE group, important baseline differences were noted in 10 of the 20 lipid classes. Furthermore, there were meal*group effects for phosphoserines (ANOVA F statistic 3.57, p = 0.024), with all groups except for E4+ men showing decreases in these lipids after HFM compared to LFM.ConclusionMeals that produced predictable changes in plasma lipids did not change overall CSF lipids; however, changes were noted when analyzed by APOE*sex and further differed depending on whether the meal was high in fat. These findings suggest that diet or treatments that rely on brain lipid metabolism may need to be further stratified by APOE genotype and sex.
CSF Phosphoproteomics Biomarker Analysis from the Phase 2 Clinical Trial SHINE to Elucidate the Role of CT1812 in Alzheimer’s Disease
Authors: Cho Eunah , Caldwell Jill , Pandey Kiran , Duong Duc M , Seyfried Nicholas T , Caggiano Anthony O , Caro Valentina Di , Hamby Mary E. 
Published: January 2025

AbstractBackgroundThe sigma‐2 receptor (S2R) modulator CT1812 is a first‐in‐class investigational therapeutic, currently in Phase 2 clinical trials for Alzheimer’s disease (AD). Preclinical and clinical studies have shown that CT1812 displaces Aβ oligomers from synapses and clears them from the brain into the cerebrospinal fluid, restoring cognitive performance in a transgenic mouse model of AD. To investigate the mechanism of action of CT1812 and enable biomarker discovery, a phosphoproteomic analysis of CSF samples from SHINE‐A was performed.MethodSHINE is a Phase 2 randomized, double‐blind, placebo‐controlled trial to assess the safety and tolerability of two doses of CT1812 for 6‐months in mild to moderate AD patients (NCT03507790), and an interim analysis was performed on the first 24 patients enrolled (SHINE‐A). Tandem‐mass tag mass spectrometry (TMT‐MS) proteomics and phosphoproteomics were performed on baseline and end‐of‐study CSF samples from SHINE‐A (n = 18) and differential abundance (CT1812 vs placebo; p≤0.05) was assessed. STRING pathway analyses (v 12.0) and comparative analyses between differentially abundant proteins and phosphoproteins were conducted (p≤0.05, p≤0.1). Pearson correlation analyses with altered phosphopeptides and CSF Aβ42 and ADAS‐Cog‐11 were performed. An independent cohort from the SPARC trial assessing the effect of CT1812 in AD patients (NCT03493282) was used for clinical validation of findings.ResultAltered phosphoproteins identified in SHINE‐A CSF samples included AD‐related proteins, APOE (p≤0.05), CHGB, SPARCL1, and SPP1 (p≤0.1). STRING pathway analysis underlined the role of CT1812 in altering key pathways: “vesicle trafficking”, “regulation of neurofibrillary tangle assembly”, “amyloid fibril formation”, and “low‐density lipoprotein particle receptor catabolic process”, these findings replicated in the SPARC independent cohort. Comparative analyses with proteomic data indicated that 2 phosphoproteins were differentially abundant at the protein level: APOE and MEPE (p≤0.1). Correlation analyses between the phosphoproteome and CSF Aβ42 and ADAS‐Cog‐11 identified highly correlated proteins, APOL1, CHGB, SERPINA10, and TALDO1 (p≤0.05).ConclusionThe altered phosphorylated proteins and pathways affected by CT1812 highlight a potential impact of CT1812 in modulating amyloid, trafficking, and LDL biology, all pathways dysregulated in AD. Overall, findings support proof of mechanisms of action of CT1812 and the continued clinical development of CT1812.
Polygenic score‐wide association study of comorbidities to incident dementia
Authors: Jung Sang‐Hyuk , Woerner Jakob , Lee Dong‐gi , Nam Yonghyun , Shen Li , Won Hong‐Hee , Kim Dokyoon 
Published: January 2025

AbstractBackgroundPrevious studies have reported various prodromal symptoms and comorbidities that precede the development of dementia. In this study, we comprehensively investigate the impact of genetic predispositions to multiple comorbidities on the risk of incident dementia.MethodsOur study included 377,653 participants of European descent from the UK Biobank, comprising 370,183 controls and 7,470 cases of incident dementia. We utilized large‐scale genome‐wide association study (GWAS) data from the FinnGen Consortium to generate the polygenic score (PGS) for quantifying genetic predispositions. From 2,405 GWASs, we selected those with a heritability greater than 1% using LD Score regression. We then analyzed pairwise genetic correlations, retaining the more heritable factor in cases where the collinearity (genetic correlation) exceeded 0.9. Consequently, we included 331 eligible PGSs in the Cox proportional hazard model‐based polygenic score‐wide association study (PolyWAS) for incident dementia.ResultsWe identified 53 significant comorbidity‐PGSs (Bonferroni corrected p‐value = 0.05/331) through PolyWAS analysis, adjusted for the covariates age, sex, ApoE ε4 status, and dementia PGS. Notably, cardiometabolic‐related diseases categorized under the ICD‐10 code blocks ‘I’ (diseases of the circulatory system) and ‘E’ (endocrine, nutritional and metabolic diseases) showed the most significant associations with the risk of incident dementia. Depression and mood disorders under category ‘F’ (mental, behavioral and neurodevelopmental disorders) were risk factors in Alzheimer’s disease (AD) but not in Vascular dementia (VD). In addition, the genetic predisposition to Medical abortion under the category ‘O’ emerged as a risk factor for all‐cause dementia and its subtypes, including AD and VD. All significant PGSs were positively associated with incident dementia.ConclusionOur study implemented a novel association test approach using comorbidity‐PGSs to investigate the genetic predispositions associated with numerous comorbidities and their impact on incident dementia and its subtypes. The proposed PolyWAS approach can better advance our knowledge of disease mechanisms and enhance our understanding of the shared genetics of comorbidities.
Early basal ganglia imaging abnormalities in pre‐symptomatic and early symptomatic novel APP duplication carriers
Authors: Paz Rotem , Bergmann Eyal , Eran Ayelet , Rozen Yael , Golan Sapir , Merhav Goni , Hoffmann Chen , Domachevsky Liran , Beeri Michal S , Kalfon Limor , Falik‐Zaccai Tzipora , Aharon‐Peretz Judith , Kahn Itamar , Lesman‐Segev Orit H. , Ravona‐Springer Ramit 
Published: January 2025

AbstractBackgroundWe aim to describe the imaging findings in pre‐symptomatic and early‐symptomatic individuals carrying a recently described novel APP duplication rearrangement causing early‐onset AD (EOAD).MethodWe studied individuals from one pedigree that carry APP duplication and CH 5 mutation gain that had structural and resting state functional (rs‐f) brain MRI. Non‐carrier family members were assessed as controls. Volumetric analysis was performed using Freesurfer and normalized to total intracranial volume. Fazekas scores for white matter hyperintensities (WMH) and microbleed count were performed visually by two neuroradiologists. rs‐fMRI seed to whole brain analysis was used to create functional connectivity maps of the default mode network (DMN). F18‐Flutemetamol amyloid‐PET was available for two of the mutation carriers. Amyloid deposition was quantified using SUVR with the pons as reference region and compared to SUVR of young adults and amyloid‐positive older adults (Ab+OA).ResultFourteen mutation carriers (mean age 29.8[19‐39], 8 (57%) F, median education 12Y[11‐14Y], mean MMSE 28[23‐30]), and nine non‐carrier family members were included (36.8Y[19‐56Y], 5 (55%)F, 12Y[12‐19], 29[27‐30]). Volumetric analysis revealed an increase in amygdala volume (log) (estimate = 0.01, p = 0.03) and a (non‐statistically significant) trend toward decrease in the putamen, globus pallidus, and pons volume with age in mutation carriers (Figure 1A). WMHs and microbleeds were found in some mutation carriers from the age of 28Y (Figure 1B). rs‐fMRI showed a trend toward a disconnection between the anterior and the posterior component of the DMN in the APP‐dup carriers >30Y (n = 6) compared with non‐carrier (n = 8; U = 10, p = 0.08). Moreover, increased connectivity was found between the anterior component of the DMN and the striatum compared to carriers <30Y (n = 8, U = 9, p = 0.06) and to non‐carriers (U = 9, p = 0.06) (Figure 2). Cortical amyloid deposition was high but within the range of Ab+OA, and extremely high, above the level of deposition in Ab+OA in the putamen, caudate, and thalamus (Figure 3).ConclusionWe found early basal ganglia abnormalities in presymptomatic and early symptomatic novel APP duplication mutation carriers, including high amyloid deposition, DMN disconnection, increased connectivity between anterior DMN and striatum, and volumetric alterations. These findings point to the basal ganglia as a region of early pathology that requires further research.
Mapping the spatial immunometabolic responses of microglia in response to Alzheimer’s pathology
Authors: Saito Kai , Goulding Danielle S. , Dimas Sophia H , Patel Ela , Snipes Andy , Nelson Peter T , Macauley Shannon L , Morganti Josh M. 
Published: January 2025

AbstractBackgroundSingle cell RNA sequencing has defined multiple transcription states of microglia in the context of AD neuropathology. Growing appreciating for several of these disease‐associated phenotypes are linked with acquisition of altered metabolism, conceptually known as immunometabolism. Despite increasing knowledge in microglial heterogeneity, relatively little is known regarding the spatial distribution of these phenotypes in the context of pathology proximity.MethodUsing 10X Genomics Xenium system, we developed a fully custom 400+ gene panel consisting of probes for deep phenotyping of microglial heterogeneity, in tandem with canonical and rate‐limiting genes associated with multiple cellular metabolic pathways, as well as genes that canonically define neuronal subsets, astrocytes, endothelia, oligodendrocytes, pericytes, and infiltrating immune classes, etc. This panel was employed across three AD‐recapitulating mouse models (n = 2/3 per genotype): PS19 (12 months old), APP/PS1 (12 months old), and 5xFAD (22 months old), and their age‐matched ‘WT’ littermate controls. In parallel, we performed the identical experiments using custom Xenium probe set in age and sex matched human autopsy tissue from the dorsolateral PFC gray matter from cases (n = 2/bin) with low (Braak I/II), middle (Braak III/IV) and high (Braak V/VI) pathological burden.ResultWe demonstrate unique intrinsic relationships of microglial heterogeneity as a function of AD‐associated pathological burden in our mouse models. ‘DAM’‐like microglia displace anatomically‐restricted homeostatic‐associated heterogeneity in as a function of pathology accumulation. In the PS19 model, we demonstrate significant susceptibility of the hippocampal formation to acquire DAM‐like and Interferon‐assocatied microglial phenotypes, whereas in both the APP/PS1 and 5xFAD broader anatomical accumulation was apparent in cortical, hippocampal, and thalamic regions. Using machine learning, we demonstrate that proximity to ThioS+ pathology drives distinctive metabolic shifts in microglial populations, with preferential signatures enriching upon both glycolytic as well as cholesterol metabolism alterations. Further, several of the indices observed in our mouse models were conserved in the human tissue.ConclusionMicroglial heterogeneity is governed by anatomical locale as well as a function of proximity to AD‐related pathology, highlighting areas of susceptibility, which is correlated with shifts in transcriptional profiles linked with both glycolytic and cholesterol metabolism.
Integration of GWAS and cerebrospinal fluid proteogenomics identifies proteins for AD and shared dysregulated mechanisms in other neurological traits
Authors: Western Daniel , Yang Chengran , Timsina Jigyasha , Gorijala Priyanka , Liu Menghan , Ruiz Agustin , Marquié Marta , Boada Mercè , de Rojas Itziar , Rutledge Jarod , Oh Hamilton Se‐Hwee , Wilson Edward N. , Guen Yann Le , Greicius Michael D , Wyss‐Coray Tony , Alvarez Ignacio , Aguilar Miquel , Pastor Pau , Robins Chloe , Pulford David J. , Sung Yun Ju , Cruchaga Carlos 
Published: January 2025

AbstractBackgroundCerebrospinal fluid (CSF) is a valuable resource for the study and diagnosis of neurological diseases, but few studies have comprehensively characterized the genetic determinants of CSF protein levels that may contribute to the development of disease. These quantitative trait loci (QTL) have proven vital to identifying candidate genes for disease treatment and monitoring. Here, we utilize our largest‐to‐date CSF protein QTL atlas to prioritize potentially causal proteins for 14 neurological traits and examine the unique and overlapping disease mechanisms observed using CSF proteins.MethodWe generated the largest CSF proteogenomic dataset (3,506 samples, 6,361 proteins) to date. We performed proteome‐wide association study (PWAS), colocalization, and Mendelian Randomization (MR) to identify potentially causal proteins for 14 neurodegenerative and psychiatric diseases or disorders. We then performed pathway analysis to identify dysregulated mechanisms underlying disease and used RHOGE to assess the overlap of proteogenomic profiles between diseases. We are repeating these analyses using blood plasma to assess overlap with a more accessible tissue.ResultAcross the 14 diseases, we identified 171 protein‐disease associations in CSF through at least two of PWAS, COLOC, and MR. For Alzheimer’s disease (AD), we identified 38 proteins enriched in immune‐relevant pathways (TREM2, CD33, IL34) and lysosomal function (GRN, CLN5, TMEM106B). Many proteins were found for schizophrenia (38), multiple sclerosis (27), and bipolar disorder (22), among others. We identified negative genetic correlations between PD and neuroticism and between anorexia nervosa and most other psychiatric traits. We observed limited overlap between CSF and plasma pQTLs (1,225/4,767 colocalize; 25.7%) with a moderate correlation in pQTL effect size (R = 0.576). Disease‐specific analyses in plasma are ongoing.ConclusionWe have identified numerous novel associations for neurological diseases that may represent therapeutic or biomarker targets in disease. We highlighted substantial differences in proteogenomic regulation between CSF and plasma, demonstrating the importance of investigating novel tissues in genetic studies. Through the integration of analyses from both tissues (ongoing), we will uncover disease‐relevant changes specific to neurological tissues or shared between tissues that may allow for diagnosis or prioritization of individuals for treatment based solely on proteomics generated from accessible tissues.
GRK2 activity promotes Aβ generation by altering GPR3 signaling and intracellular trafficking
Authors: Lu William , Guimaraes Thais Rafael , Huang Yunhong , Todd Nicholas , Thathiah Amantha 
Published: January 2025

AbstractBackgroundG protein‐coupled receptors (GPCRs) are associated with multiple stages of the pathophysiology of Alzheimer’s disease (AD). Biased GPCR signaling preferentially activates G protein‐ or β‐arrestin‐mediated signaling pathways and presents opportunities to develop more selective and safer therapeutics but remains largely unexplored in AD. Recently, we developed a G protein‐biased GPR3 AD mouse model, which does not recruit β‐arrestin 2, that displays reduced amyloid‐β (Aβ) pathology without adverse cognitive effects associated with elimination of both G protein and β‐arrestin signaling.MethodWe investigated how G protein‐biased GPR3 signaling ameliorates Aβ accumulation in HEK293 cells stably expressing the full‐length amyloid precursor protein (HEK‐APP) using biochemical and immunocytochemical methods. To investigate the involvement of GPCR kinases (GRKs) in GPR3‐ mediated Aβ generation, we employed a CRISPR/Cas9 genome editing strategy to generate Grk2‐deficient HEK293 cells along with complementary pharmacological inhibition of GRK2 in HEK‐APP and human neurons.ResultWe first validated that biased GPR3 signaling reduces Aβ generation in HEK‐APP cells. To gain mechanistic insight into how biased GPR3 affects Aβ generation, we determined that biased GPR3 displays reduced binding to APP relative to wild‐type GPR3. We then determined that Grk2 deficiency leads to reduced β‐arrestin 2 recruitment to GPR3 and decreased Aβ generation in HEK‐APP cells. Similar to the effect of Grk2 deficiency, pharmacological inhibition of GRK2 activity with CMPD101 also leads to a reduction in Aβ generation in both HEK‐APP cells and familial AD neurons. Further studies indicate that GRK2 modulates the localization of GPR3 and APP to the Golgi apparatus, early endosomes and endoplasmic reticulum. Interestingly, GRK2 inhibition also leads to increased levels of APP phosphorylation at threonine 668.ConclusionThese results suggest a role for GRK2 in regulating the intracellular trafficking and localization of G protein‐biased GPR3 and APP, which may directly affect Aβ generation. Future studies will further elucidate how GRK2 activity impacts GPR3‐mediated Aβ generation and could illuminate novel targets for the development of AD therapies.
Clinical Use of Lecanemab at an Academic Medical Center
Authors: Honig Lawrence S. , Kim Jee Min , Gonzalez Wendy P. , DiMuro Vanessa , Jagannathan Radhika , Marder Karen , Noble James M. , Bell Karen L. , Mayeux Richard 
Published: January 2025

AbstractFor Alzheimer’s disease (AD), there are currently two FDA‐approved agents developed as disease‐modifying treatments. Approval of lecanemab (Leqembi®) in 2023, via accelerated approval mechanism, followed by traditional approval accompanied by medical coverage decision by the Center for Medicare Services, has resulted in increasing use of this anti‐amyloid monoclonal antibody, demonstrated in 18‐month long clinical trials to slow Alzheimer’s disease. Despite a broad package insert (with only contraindication product severe hypersensitivity), nationwide prescriptions have been reportedly affected by concerns regarding drug eligibility, monitoring, and whether real‐world experience would mirror clinical trial data. In our practice, prescription of the medication has been contingent upon: (a) diagnosis of AD, (b) early stage of AD, (c) amyloid confirmation by CSF or PET, (d) acceptable ARIA‐H at baseline MRI, and (e) non‐mandatory apolipoprotein‐E genotyping. Here we present data on the first 85 patients prescribed lecanemab at our center. Patient age is 73±8 yr (51‐88) and sex 51% women, with 82% accepting apolipoprotein‐E4 testing (42% non‐carriers, 44% heterozygotes, and 14% homozygotes). Barriers associated with our above eligibility criteria (a) through (e) have been minimal. Similarly, barriers have generally not been large for MRI monitoring and infusion center availability; but during this first year of drug availability there have been challenges in coverage by insurers/payors other than standard original Medicare. Patients/families have had strong interest in this drug, with apparent good understanding and acceptance of risks of ARIA‐E and ARIA‐H. Patients deemed not eligible by their treating practitioners have been declined for the following reasons in descending order of frequency: disease too severe, non‐Alzheimer’s dementia (no amyloid confirmation), logistical (travel/time) considerations, disease too mild (presymptomatic), and excessive ARIA‐H on baseline MRI. Overall, with up to 21 infusions per patient, adverse event rates have been similar to those in clinical trials with 7% ARIA–E (all asymptomatic), and low rates of infusion reactions. Suspension or discontinuation of therapy has occurred in 9% (7% due to ARIA, 1% due to persistent infusion reactions, 2% due to disinterest). Overall findings at our center suggest that experience in clinical use may not be dissimilar to that in the clinical trials.
Brainstem and midbrain structures involved in memory encoding in healthy aging and mild cognitive impairment, a 3T task‐fMRI study
Authors: Penalba‐Sánchez Lucía , Yi Yeo‐Jin , Kurt Elif , Femminella Grazia Daniela , Loane Clare , Duckett Millie , Callaghan Martina F , Weiskopf Nikolaus , Dolan Ray , Howard Robert J , Düzel Emrah , Hämmerer Dorothea 
Published: January 2025

AbstractBackgroundMemory decline, which is especially prevalent in Alzheimer’s disease (AD), has been studied via fMRI, primarily focusing on the prefrontal cortex and hippocampus. However, emerging evidence suggests that the brainstem, alongside various midbrain regions, is an initial target for pathological processes like hyperphosphorylated TAU protein accumulation. Among these, the locus coeruleus, a noradrenergic nucleus in the pons, projects to critical midbrain areas supporting memory encoding. Hence, our study aimed to investigate BOLD task activations in AD relevant to memory, while focusing on differences in responses to emotional versus neutral stimuli in the brainstem and midbrain.MethodUsing event‐related fMRI, 53 subjects (28 healthy older adults, 25 with mild cognitive impairment (MCI)) (see table 1) underwent an incidental recognition memory task involving emotional and neutral images. Memory tests followed immediately, and 4 hours after encoding. Group differences in brain activations for remembered versus not remembered images using the study template were examined.ResultResults revealed a trend for greater activation in the left caudate nucleus in older adults, compared to those with MCI, when subsequently remembered items were compared with not remembered ones (small volume correction (SVC), cluster level pFWE‐corr = 0.08). Similarly, a significant increased activation was observed in the locus coeruleus (SVC, cluster level pFWE‐corr = 0.018). However, after adjusting for group and individual differences in LC integrity and global grey matter volume (GMV), no significant differences persisted, suggesting that structural changes contribute significantly to differences in LC activation between healthy controls and MCI participants (see Figures 1 and 2).ConclusionIn conclusion, our findings underscore the caudate nucleus’s role in memory encoding for healthy older adults versus those with MCI. A decline in LC function in MCI appears related to a decline in LC integrity. These insights contribute to understanding memory mechanisms in healthy aging versus MCI. Future studies are needed to explore potential neural memory compensatory processes in MCI.