bluuebunny/crossref_metadata_2025_split huggingface dataset:
APOE genotype vs Local ancestry: what contributes the most to Alzheimer’s disease risk?
Authors: Moura Sofia , Celis Katrina , Muniz Maria , Rajabli Farid , Rivero Joe , Hamilton‐Nelson Kara L. , Whitehead Patrice , Gearing Marla , Bennett David A. A , Flanagan Margaret E , Weintraub Sandra , Geula Changiz , Scott William K. , Schuck Theresa , Jin Fulai , Dykxhoorn Derek M. , Pericak‐Vance Margaret A. , Griswold Anthony J. , Young Juan I. , Vance Jeffery M. 
Published: December 2023

AbstractBackgroundThe APOEε4 confers the highest genetic risk factor for Alzheimer’s disease (AD). Specifically, Non‐Hispanic Whites (NHW) are more susceptible to developing AD than African American (AA) individuals (OR∼15 vs 8, respectively). Local ancestry (LA) surrounding the APOE region has been implicated in this risk difference, with APOEε4 carriers of European LA (ELA) having increased chromatin accessibility and higher APOEε4 expression than individuals of African LA (ALA). In contrast, carriers of APOEε3, the most common allele, are not predisposed to AD. We here sought to investigate whether this differential accessibility and gene expression are solely due to APOE LA or whether the APOE genotype also contributes to the different disease risk.MethodWe screened 94 brains from individuals self‐identified as either AA or NHW of which we identified a total of 22 AD autopsy samples (18 with ELA and 4 with ALA) by GSA, all homozygous for LA and APOEε3. We performed single nuclei ATAC‐seq and single nuclei RNA sequencing (snRNA‐seq) using frozen frontal cortex using the 10x Genomics.ResultTo date, we have performed snRNA‐seq in a total of 16,099 nuclei for four brains (2 ELA and 2 ALA). We identified 27 distinct cell clusters at a resolution of 0.6. The proportion of cells per cluster between ELA and ALA samples was similar for all clusters, except for 8 clusters (primarily neurons) which had a greater than 2‐fold difference in ELA. Preliminary results show that APOEε3 carriers with ELA have a significantly higher APOE expression in astrocytes (cluster 11) than those of ALA similar to previous reports in APOEε4 carriers (Griswold, A. et al, (2021)). Interestingly, we also observed an increase in APOE expression in ALA for one oligodendrocyte cluster and four neuronal clusters (inhibitory and excitatory neurons) independent of those mentioned above.ConclusionWe report novel insights on the effect of APOE LA and genotype and its contributions to Alzheimer’s disease risk. Specifically, as APOEε3 allele expression follows a similar pattern of overexpression in ELA vs ALA as observed for APOEε4 carriers, our data support that LA and not allele status contribute to the differential APOE expression observed among different ancestral populations.
Examining practice effects within the GENFI pre‐symptomatic FTD cohort
Authors: Adams‐Carr Kerala L , Convery Rhian S , Bouzigues Arabella , Goldsmith Sophie E , Rohrer Jonathan D. , Russell Lucy L. 
Published: December 2023

AbstractBackgroundPractice effects can be observed on repeated cognitive testing and are often viewed as potential sources of bias. However, there is mounting evidence that their absence or reduction can indicate early changes in cognition, with decreased ‘learning over repeated exposure’ seen in those with mild cognitive impairment. A recent GENFI study demonstrated practice effects are diminished in C9orf72 and GRN mutation carriers proximal to disease onset compared to controls at testing intervals of one year. The aim of this study is to explore how practice effects differ in the GENFI cohort at shorter time intervals using Ignite, an iPad‐based set of cognitive tests, with the aim of exploiting this understanding to detect subtle cognitive impairment within clinical trials.Method36 individuals from the UCL GENFI cohort took part, 26 of whom were presymptomatic mutation carriers and 10 were non‐carrier controls. They completed Ignite at baseline and at 3 months. Change scores were calculated for each task, and linear regressions were performed comparing mutation carriers with non‐carriers, controlling for significant co‐variates of age, education, and sex.ResultThere was a trend towards improvement on repeat testing in both the carrier and non‐carrier groups, but a difference emerged on the Think Back Level 1 task, a test of working memory analogous to the ‘N‐back’ task, where the non‐carriers improved on a speed‐accuracy trade‐off score to a greater degree than mutation carriers (mean improvement 16.4 vs 5.2 respectively, p = 0.026). There was also a trend towards a difference on the Path Finder Level 1 and 2 tasks, adaptations of the Trail Making Tests Parts A and B, where the non‐carriers improved more than the mutation carriers.ConclusionPractice effects were observed across the majority of tasks in both the carrier and non‐carrier groups, except for a working memory task, where a difference was observed between the groups. This was a small pilot study, and a larger scale study of ‘burst testing’ within the GENFI cohort is underway to examine practice effects in greater detail, at shorter time intervals. Subanalyses to stratify by genetic subtype and proximity to disease onset are required.
Modulation of inflammatory regulation by plasma exchange with albumin replacement revealed by deep plasma and CSF proteomic profiling of the AMBAR study
Authors: Feng Chunmiao , Gonzalo Ricardo , Minguet Carla , Ortiz Ana Maria , Bravo Isabel , Lohr Scott , Boada Mercè , Lopez Oscar L. , Páez Antonio , Braithwaite Steven P , Costa Montserrat , Lehallier Benoit 
Published: December 2023

AbstractBackgroundAMBAR trial (phase 2b/3 clinical trial) evaluates plasma exchange efficacy with albumin replacement (PE‐Alb) in mild‐to‐moderate Alzheimer’s Disease (AD) patients. It includes an intensive period (IP) comprising 6‐weeks of conventional therapeutic PE‐Alb (TPE; 1 TPE/week) followed by 12‐month maintenance period of low volume PE‐Alb (LVPE; 1 LVPE/month). Our previous study reporting deep plasma and CSF proteomics profiling identified multiple AD‐associated pathways modulated by PE‐Alb (Feng et al. CTAD2022). Here we dissected immune pathways changes over time and reported their crosstalk between plasma and CSF to further understand molecular mechanisms of PE‐Alb.Method7288 proteins were measured by SomaScan technology in 671 plasma samples (148 patients, 5 visits) and 422 CSF samples (144 patients, 3 visits). Acute effects (post‐TPE/LVPE versus pre‐TPE/LVPE samples) for plasma, and lasting effects (baseline to either end of IP or end of study (EOS)) for both matrices were calculated through a mixed model approach comparing PE‐Alb‐treated patients versus placebo. Network features of the top identified proteoforms were explored in STRING and OmniPath databases. Relationships between enriched pathways were analyzed by pathway crosstalk based on Jaccard coefficient and correlations between plasma and CSF proteomes at each visit were calculated by spearman correlation.ResultPlasma samples showed that 90 proteoforms from acute TPE, 16 from acute LVPE, and 14 at the end of IP were significantly decreased and enriched in immune and inflammation‐related pathways. Three proteins involved in immunoglobulin‐mediated immune pathways were in the core of the interactome network and were consistently decreasing over time, one of them also significantly decreased in the CSF proteome. Finally, 113 proteins with spearman correlations >0.5 at least at one of the 3 visits were detected and were significantly enriched in immune system functions (adjusted‐pvalue<0.05).ConclusionThis analysis demonstrates acute and lasting PE‐Alb effects on immune and inflammatory pathways. We identified 3 potential players and a crosstalk between plasma and CSF immune proteomes, suggesting the importance of the modulation of peripheral inflammation in AD treatment. This study further helps understand the molecular basis of AMBAR therapeutic approach that may contribute to slowing down AD progression.
The impact of subjective cognitive decline on aging effects in the brain as measured by diffusion tensor imaging
Authors: Flaherty Ryn , Sui Yu Veronica , Masurkar Arjun V. , Rusinek Henry , Lazar Mariana 
Published: December 2023

AbstractBackgroundDiffusion tensor imaging (DTI) can separate subjective cognitive decline (SCD) participants who progress to mild cognitive impairment and those who do not 1. We explored the effect age and memory performance has on DTI measures in SCD and controls in the hippocampal cingulum bundle, which is typically affected early in the course of Alzheimer’s disease2.Method325 participants Cam‐CAN 3 (127 SCD) older than 55 were included in the analysis. Diffusion imaging data was collected on a 3T Siemens TIM Trio scanner with a 32‐channel head coil for 0, 1000 and 2000 s/mm2 b‐values and 30 gradient directions. Preprocessing and calculation of the DTI metrics fractional anisotropy (FA, mean diffusivity (MD), radial diffusivity (RD) and axial diffusivity (AxD) were completed using MRTrix3, FSL and MATLAB. The hippocampal cingulum bundle regions of interest (ROIs) were extracted from the ICBM‐DTI‐81 atlas. Memory was assessed using the delayed story recall (DSR) task from WMS‐III. Linear regression models were completed in R. Gender was included as a nuisance variable.ResultThere were no differences in gender or age distribution between cohorts, however participants with SCD had a 14% lower DSR score (Table 1). There was a significant interaction effect between age and cohort in MD, AxD, and RD (Figure 1), as well as between memory and age in AxD (Figure 2). In post‐hoc analyses, compared to controls, the SCD group showed a stronger correlation with age in MD, AxD, and RD (Figure 1) while participants with worse memory showed a stronger correlation with age in MD (Figure 2), indicating an accelerated aging effect.ConclusionParticipants with SCD and worse memory present with an accelerated aging effect, showing steeper variations in diffusion microstructure with age. Since SCD is likely to be a preclinical stage of Alzheimer’s disease, future work will analyze this effect with more advanced diffusion microstructure models to further elucidate the underlying pathophysiology.1. Selnes P, Aarsland D, Bjornerud A, et al. J Alzheimers Dis. 2013;33(3):723‐36.2. Jack Jr CR, Knopman DS, Jagust WJ, et al. The Lancet Neurology. 2013;12(2):207‐16.3. Shafto MA, Tyler LK, Dixon M, et al. BMC neurology. 2014;14(1):1‐25.
Nutrient intake in relation to longitudinal change of blood‐based biomarkers of Alzheimer’s disease
Authors: Hoost Serena S. , Honig Lawrence S. , Kang Min Suk , Sanchez Danurys , Reyes‐Dumeyer Dolly , Lantigua Rafael A. , Dage Jeff L. , Brickman Adam M. , Manly Jennifer J. , Mayeux Richard , Gu Yian 
Published: December 2023

AbstractBackgroundIntake of key nutrients is associated with improved cognitive performance and reduced risk of Alzheimer’s dementia (AD). We examined whether omega‐3 polyunsaturated fatty acid (O‐3 PUFA), omega‐6 (O‐6) PUFA, and monounsaturated fat (MUFA) from foods are associated with plasma biomarkers for AD.MethodWe selected 695 participants in a community‐based cohort study who were dementia‐free at baseline, completed the 61‐item semi‐quantitative food frequency questionnaire and had at least three plasma samples collected at different time points. We used linear regression to examine the cross‐sectional relationship between nutrients and AD biomarkers, including phosphorylated Tau‐181 (pTau181), amyloid‐beta (AB) 42/40 ratio, glial fibrillary acidic protein (GFAP) and Neurofilament light chain (NfL). We also examined whether baseline nutrient intake was associated with the longitudinal change of plasma biomarkers using generalized estimating equations. All analyses were adjusted for age, sex, race/ethnicity, total calorie intake, APOEe4 status, years of education, sample storage time and Mediterranean diet score as the overall measure of diet quality.ResultParticipants’ mean age was 74 years, and 69% were women. Participants were non‐Hispanic White (25.2%), non‐Hispanic Black (24.5%), and Hispanic (48.6%). Participants with the highest tertile of O‐3 PUFA intake had low GFAP at baseline (p = 0.023), had a slower increase of P‐tau 181 (p = 0.004) and NfL (p = 0.022) and had a slower decrease of AB 42/40 ratio (p = 0.010), compared to those with the lowest tertile. Those with high O‐6 PUFA intake had a higher baseline AB 42/40 ratio (p = 0.005) and a slower increase in GFAP (p = 0.001) compared to the low O‐6 PUFA intake group. Those with moderate and high O‐6 PUFA intake both had slower increase of pTau181 (p = 0.018 and p = 0.001, respectively), compared to the low O‐6 intake group.ConclusionHigher intake of O‐3 and O‐6 PUFAs from foods was associated with lower levels of plasma AD biomarkers cross‐sectionally, and a slower change in biomarker concentrations over time. This suggests that intake of key dietary nutrients may prevent or slow the progression of AD pathophysiology.
Evaluating the Causal Association Between Genetically Proxied Psychiatric Disorders and SuperAging
Authors: Nassan Malik , Piras Ignazio , Geula Changiz , Mesulam Marsel , Huentelman Matthew J , Rogalski Emily J 
Published: December 2023

AbstractBackgroundSuperAgers are individuals aged 80+ who have episodic memory capacity that would be considered at least average for those 2‐3 decades younger. The causal factors for SuperAging are not known. Observational studies have linked psychiatric disorders with the risk for late life cognitive decline. It is not known if psychiatric disorders or their genetic liability have a causal effect on SuperAging. We sought to assess the causal relationship between genetically proxied psychiatric disorders (major depression (MD), bipolar disorder (BD), and schizophrenia (SCZ)) and SuperAging using a 2‐sample Mendelian randomization (MR). For comparison, we performed secondary analyses for the association of the same exposures with Alzheimer’s dementia (AD), Lewy Body dementia (LBD), and Frontotemporal dementia (FTD).MethodGenome‐wide significant single nucleotide polymorphisms (SNPs) associated with MD (102 SNPs, 246,363 cases, 561,190 controls), BD (64 SNPs, 41,917 cases, 371,549 controls) and SCZ (287 SNPs, 76,755 cases, 243,649 control), were used as genetic proxies for the exposures. Summary statistics of the genome wide association study (GWAS) for SuperAging was included as the primary outcome (69 SuperAgers, 3,479 controls). Summary statistics were obtained for the largest GWAS studies of neurodegenerative disorders: AD (111,326 cases, 677,663 controls), LBD (2,591 cases, 4,027 controls) and FTD (2,154 cases, 4,308 controls). Inverse variance weighted MR was performed as the main analysis for testing the relationship between the exposures and outcomes.ResultMR analyses showed a significant association between higher genetic liability to SCZ and lower likelihood of SuperAging (OR = 0.98, P = 0.02), but no significant association between MD or BD with SuperAging (P>0.05). Secondary analyses showed that genetic liability to BD was associated with an increased risk for AD (OR = 1.1, P = 0.003), while genetic liability to SCZ was associated with an increased risk for FTD (OR = 1.16, P = 0.04).ConclusionThis is the first study to investigate the potentially causal factors for SuperAging. We found that genetic liability to SCZ is causally associated with lower likelihood of SuperAging. We also found that the genetic liability to BP and SCZ are associated with an increased risk for AD and FTD, respectively. Further exploration of causal factors to SuperAging is warranted.
Brazilian Subjective Cognitive Decline (BRASCODE) Cohort: protocol and preliminary results
Authors: Giordani Manuella Edler Zandoná , Souza Victória Tizeli , da Mota Simone Sieben , De Marchi Bruno De Oliveira , Formoso Carolina Rodrigues , Rivas Gabriela Raquel Paz , Carvalho Guilherme Da Silva , De Souza Haniel Bispo , Beltrami Lucas Bastos , Santos Rhaná Carolina , Suwa Samuel Masao , Slaviero Wesley , de Albuquerque Ana Letícia Amorim , Strelow Matheus Zschornack , Borelli Wyllians Vendramini , Carello‐Collar Giovanna , Chaves Marcia L. , Zimmer Eduardo R , Castilhos Raphael Machado 
Published: December 2023

AbstractBackgroundSubjective Cognitive Decline (SCD) is a condition characterized by consistent cognitive complaints in cognitively unimpaired (CU) individuals and is associated with progressive cognitive impairment, especially in the context of Alzheimer’s disease (AD). We aimed to show the study protocol and the preliminary results of the Brazilian Subjective Cognitive Decline (BRASCODE) Cohort.MethodCU individuals with > 65 years old and cognitive complaints were recruited. Exclusion criteria were previous diagnosis of dementia, uncontrolled neuropsychiatric/clinical illness, or cerebrovascular disease. The assessment was performed exclusively by phone calls. It consisted of a brief cognitive (Modified Telephone Interview for Cognitive Status ‐ TICS‐M) and anxiety/depression screenings, in addition to the SCD‐scale (Figure 1).ResultBetween March and November 2022, 52 SCD patients were included, 73.1% (n = 38) women. Their median interquartile range (IQR) age was 70 (68‐73) years old, with 16 (9.25‐19) years of formal education and median score of 28.5 (IQR 26,30) on Mini Mental State Examination (MMSE) (Table 1). Percentage of agreement on the presence of cognitive complaints between informants and patients was 38.5%. The main SCD‐plus criteria were the age at onset of SCD ≥ 60 years old (84.6%, n = 44) and concerns associated with SCD (78.8%, n = 41). The key findings of the neuropsychological assessment are reported in Table 2. Deficits were observed mainly in memory and executive functioning domains. Explorative analysis showed that Cognitive Reserve Scale scores correlated positively with MMSE (rho = 0.311; p = 0.02) and with formal education (rho = 0.541; p<0.001) and negatively with CDR‐sum of boxes (rho = ‐0.307; p = 0.03). The prevalence of APOE ε4 carriers was 29.8% (n = 14) and a dementia family history was more frequent in APOE ε4 carriers ‐ 12 (85.7%) ‐ than non‐carries, 12 (36.4%).ConclusionThe increase in the sample size, especially with individuals with low education, associated with AD biomarkers analysis and long‐term follow‐up may bring valuable information about the progression of SCD to cognitive decline in Brazil. We estimate that a total of 150 individuals will be included by the end of 2023.
Predictors of hospital mortality in older adults with and without dementia: a necessary step towards personalized prognostication
Authors: Avelino‐Silva Thiago J , Campora Flavia , Curiati Jose A E , Jacob‐Filho Wilson 
Published: December 2023

AbstractBackgroundDementia has been associated with increased risk of hospital mortality (1). However, predictors of hospital mortality for patients with dementia have not been widely addressed. We aimed to investigate predictors of hospital mortality according to preexisting clinical dementia in older adults.MethodsWe analyzed data from a prospective cohort study in Sao Paulo, Brazil. We included acutely ill patients aged ≥60 years admitted to a tertiary university hospital between 2009 and 2020. Candidates underwent comprehensive geriatric assessments in the first 24 hours of hospitalization. Preexisting clinical dementia (after this, referred to as dementia) was determined by a Clinical Dementia Rating (CDR) ≥1 (2). We investigated independent predictors of hospital mortality according to dementia using multivariable Poisson regressions. We further analyzed our multivariable models' accuracy in predicting hospital mortality using area under the ROC curves (AUC).ResultsWe included 3,863 participants (mean age = 80; female = 62%). Overall, 1,761 participants (46%) had dementia. Mortality was 11% in participants without dementia and 21% in those with dementia (p<0.001). In participants without dementia, mortality was independently predicted by age, multimorbidity, functional status, delirium, nutritional status, and serum albumin (Table 1). However, in participants with dementia, mortality was also predicted by illness acuity and creatinine. Finally, we observed that our multivariable model had an AUC = 0.88 (95%CI = 0.86‐0.90) in participants without dementia and 0.80 (0.78‐0.83) in those with dementia (Figure 1).ConclusionOlder adults with dementia were twice as likely to die in the hospital than those without dementia. Moreover, independent predictors of hospital mortality were not necessarily shared between patients with and without dementia. Given the importance of prognostic assessments for decision‐making processes, researchers should consider exploring new algorithms that differ according to baseline cognition.
References:1. Bouza C, Martínez‐Alés G, López‐Cuadrado T. The impact of dementia on hospital outcomes for elderly patients with sepsis: A population‐based study. PLoS One. 2019;14(2):e0212196. Published 2019 Feb 19. https://doi.org/10.1371/journal.pone.0212196
2. Hughes CP, Berg L, Danziger WL, Coben LA, Martin RL. A new clinical scale for the staging of dementia.Br J Psychiatry. 1982;140:566‐572. https://doi.org/10.1192/bjp.140.6.566
Analysis of apoE levels in Alzheimer’s disease patients and control subjects of APOE ε4 variant carriers and non‐carriers
Authors: Hurla Mikolaj , Banaszek Natalia , Florczak‐Wyspianska Jolanta , Zasada Aleksandra , Szymanowicz Oliwia , Kozubski Wojciech , Dorszewska Jolanta 
Published: December 2023

AbstractBackgroundAlzheimer’s disease (AD) is the most common progressive dementia disease in people over 60 years of age. The pathogenesis of AD is thought to be complex and depends on environmental and genetic factors. The most important genetic factors responsible for AD include variants of the APOE gene, which encodes the protein apolipoprotein E (apoE). There are 2 polymorphisms in the APOE, which presence of three alleles: protective ‐ ε2, neutral ‐ ε3, and pathogenic ‐ ε4. On the other hand, the presence of the ε4 allele is associated with an approximately four times higher risk of developing AD in people with a heterozygous system and a twelve times higher risk in ε4/4ε. Disorders of epigenetic mechanisms affecting the concentration of apoE may participate in the development of AD. Disturbed levels of apoE may impair clearance of Aβ from the brain and exacerbate disease progression. It is not known what level of apoE ensures the removal of Aβ and whether genetic and familial predispositions can regulate the efficiency of protective mechanisms. So far, there is little information on the level of apoE in AD patients and controls who are and are not APOE ε4 carriers.The aim was to analyze genetic variants of the APOE gene and apoE protein concentration in AD patients, control subjects related to AD cases (CR), and controls subjects without a family history of AD (CU), carriers and non‐carriers of the APOE ε4 variant.MethodThe studies were conducted on 156 individuals (AD and controls). The APOE genotype was determined by real‐time PCR. The apoE concentration was determined by the ELISA method.ResultThe highest concentration of apoE was found in CR compared to AD and CU (p<0.001). In both APOE ε4 carriers (p<0.05) and non‐carriers (p<0.001), the highest levels of apoE were found in CR. At the same time, in all tested subjects, carriers of APOE ε4, the level of apoE was lower compared to non‐carriers of this pathogenic variant.ConclusionIt seems that the ε4 pathogenic variant of the APOE gene may lead to the development of AD by regulating the level of apoE.