bluuebunny/crossref_metadata_2025_split huggingface dataset:
Detecting Protective Rare Variants for Alzheimer’s Disease from Whole‐Genome Sequencing in the Amish
Authors: Song Yeunjoo E. , Wang Weihuan , Miskimen Kristy L. , Laux Renee A. , Fuzzell M. Denise , Fuzzell Sarada L. , Hochstetler Sherri D. , Main Leighanne R. , Osterman Michael D. , Lynn Audrey , Prough Michael B. , Slifer Susan H. , Adams Larry D. , Caywood Laura J. , Clouse Jason E. , Herington Sharlene D. , Dorfsman Daniel A. , Vance Jeffery M. , Cuccaro Michael L. , Ogrocki Paula K. , Lerner Alan J. , Scott William K. , Pericak‐Vance Margaret A. , Haines Jonathan L. 
Published: December 2023

AbstractBackgroundA shift in focus from risk to resilience for Alzheimer’s disease (AD) encourages efforts to uncover novel AD biological mechanisms. Rare variants identified through whole genome sequencing (WGS) may represent an important and understudied component of complex trait genetics. While population‐based studies are powered to discover associations with common genetic variants, founder populations are better powered for discovery of previously unknown rare alleles that have risen to higher frequency due to genetic drift.MethodWe examined WGS data from the Mid‐Western Amish population in a genome‐wide search for rare coding variants shared only among cognitively‐unimpaired (CU) individuals. The cognitive status of each individual was assigned via consensus review of medical history and neuropsychological testing. Allele frequencies were calculated across all samples and for CU and cognitively‐impaired (CI) groups separately. We defined rare variants as having an allele frequency <0.05 across all samples. Variants with a minor allele count (MAC)>10 in the CU group, and 0 in the CI group were annotated to determine likely loss of function.ResultAfter extensive QC, 1,048 samples were available to estimate overall allele frequency. Allele frequencies of rare variants (n = 11,854,817) within 634 CU (mean age = 81.53±6.10, 60% female) and within 184 CI (mean age = 84.77±6.60, 62% female) individuals were compared and 51,616 variants with MAC >10 were found only in CU. There were 316 unique coding variants (288 missense, 4 inframe_insertion, 6 inframe_deletion, 11 frameshift, 4 stop_gained, 3 splice_donor) and 180 synonymous variants located within 425 unique genes. Among them, 7 missense variants and 7 synonymous variants had MAC >20 and the remaining variants had MAC of 11‐20. The mean allele frequency of the 7 missense variants was 0.0038 in TOPMed compared to 0.0154 in our data. Two synonymous variants were located within proposed AD genes (NYAP1 and ZNF423). Additionally, several untranslated region or nonsense‐mediated decay transcript variants existed within 26 known AD gene regions, among which 8 of them are reported to harbor protective variants for AD.ConclusionNumerous rare variants potentially impacting gene function were found only in CU individuals, providing a rich resource for further investigation of genes that may provide protection from cognitive impairment.
Anterior and posterior default mode network functional connectivity and segregation in aging
Authors: Taylor Lisa M. , Adams Jenna N. , Kim Soyun , Harris Alyssa L. , McMillan Liv , Keator David B. , Yassa Michael A. 
Published: December 2023

AbstractBackgroundThe default mode network (DMN) supports memory performance and has been shown to be vulnerable to the effects of aging. The posterior DMN (pDMN) is an early region of amyloid‐β (Aβ) accumulation, which may lead to disrupted communication within/between subnetworks of the DMN. Using resting state functional connectivity (FC), we tested whether communication within and between the pDMN and anterior DMN (aDMN) were altered by aging and Aβ pathology and related to memory performance. We also tested segregation FC between the aDMN and pDMN.MethodData from 27 cognitively normal adults (69.6 years, 59% females) with resting state fMRI (rsfMRI), 18F‐florbetapir (FBP) PET to measure Aβ, and the Rey Auditory Verbal LearningTest (RAVLT) delayed recall to assess memory were analyzed. The rsfMRI data were preprocessed using CONN toolbox. ROI‐to‐ROI FC matrices were constructed for regions included in the aDMN and pDMN. We calculated: (1) the average FC within each network (Zw), (2) average FC between the aDMN and pDMN (Zb), and (3) network segregation [(Zw‐Zb)/Zw] for each DMN network. Global FBP SUVR was calculated as the mean across association cortical regions, and a cutoff of 1.11 was used to determine Aβ positivity. Analyses included the FC variables and their associations with age, Aβ, and memory.ResultOlder age was associated with reduced network segregation of the pDMN (r = ‐0.53, p = 0.004), and a trend level association for reduced within‐pDMN FC (r = ‐0.37, p = 0.057). Global FBP SUVR was not associated with FC or network segregation, and there was no significant difference in FC between Aβ groups (controlling for age). There was a trend‐level association between better memory performance and stronger FC between aDMN and pDMN (r = 0.37, p = 0.066; controlling for age and education).ConclusionResults demonstrated that aging is associated with specific FC disruptions of pDMN, leading to reduced specialization of processing as indexed by network segregation. Moreover, increased communication between DMN subnetworks may support memory in aging. Future analyses in a larger sample will further test the association between Alzheimer’s pathology and functional changes to DMN subnetworks.
Semantic cognition as an early cognitive marker of Alzheimer’s disease: importance of executive processes mediation
Authors: Guinea Sara Fernández , Rivera‐Fernandez Claudia , Soto‐Añari Marcio F. , Marqués Javier González 
Published: December 2023

AbstractBackgroundImpaired semantic memory is one of the earliest characteristic features of Alzheimer’s disease. Its assessment is crucial to accurately predict conversion to Alzheimer disease related disorders (ADRD). Recent evidence supports the necessity to differentiate between subprocesses of semantic cognition: a) activation in the semantic representation system; b) executive processes to control or select relevant aspects of semantic knowledge. In this study we compare semantic memory tests that differ in these subprocesses to find out which of them are the best predictors of conversion of MCI to ACD in two years. We also want to identify which semantic memory tests have more sensitivity and specificity at the baseline in the differentiation MCI‐no converters and MCI converters after two yearsMethodWe assessed 130 amnestic MCI patients. Semantic memory tests more based on integrity of semantic knowledge (Similarities, ACE‐language) and more executive determined (verbal fluency – phonemic and categories, Boston Naming Test) were administered at baseline and at 2‐years follow‐up, together with cognitive screening tools and IADL measures. A binary regression model was used to examine which semantic memory tests predict MCI progression to Alzheimer’s Clinical Syndrome (ACS) in two years. ROC curves were used to study early clinical diagnosis differentiating MCI converters and MCI non convertersResultOnly semantic category fluency test significantly explained the conversion to ACS (p<.01). Baseline score semantic categories fluency were significantly lower in MCI patients who develop ACS after two years (p<.001). ROC curves showed that semantic categories fluency and Boston Naming tests were the best tests to differentiate at baseline between MCI converter and non‐converter (AUC = 0.768, p<0,0001 and AUC = 0.712, p<0,01, respectively)ConclusionSemantic category fluency test was the best predictor from MCI to ACS conversion in two years. Semantic category fluency and Boston Naming tests clearly identify people with high risk to develop ACS in two years. Semantic memory tests including executive contributions could detect and characterize prodromal Alzheimer’s disease
Bilingualism and APOE4 alelle as a risk‐protective factor in dementia among Peruvian Andean aging population
Authors: Soto‐Añari Marcio F. , Rivera‐Fernandez Claudia , Ramos‐Vargas Luis , Custodio Nilton , Montesinos Rosa , Chambergo‐Michilot Diego , Ore‐Gomez Maria Fernanda , Carreño‐Galvez Jose , Reyes‐Dumeyer Dolly , Tosto Giuseppe 
Published: December 2023

AbstractBackgroundBilingualism has been considered as a protective factor against dementia. But the evidence in Native American populations is spare and to our knowledge, there are no studies analyzing risk factors, as the APOE4 genotype and environmental protective factors as the bilingualism and education. Our objective was to analyze the risk/protective association between bilingualism and APOE4 status (carrier/non‐Carrier) on Alzheimer Dementia Related Disorders (ADRD). In addition, we analyzed the impact of the bilingual/monolingual condition on cognition.MethodWe used the data of the ongoing study “Genetics of Alzheimer’s disease in Peruvian Populations study” (GAPP). 275 older adults (mean age = 71.57, SD = 8.3) were recruited from 3 Peruvian cities: Lima, Arequipa and Puno. These last located in the southern of Peru where Quechua and Aymara ethnics are the most important population. Bilingual condition was evaluated as a dichotomous condition (yes/no). A clinical and neuropsychological protocol was applied which included brief cognitive test, functional status measures and clinical dementia scales (CDR). Cognitive measures included attention, memory, abstract reasoning, language and visuoconstruction. Genotyping was conducted on The Infinium Global Screening Array‐24 BeadChip, which combines multi‐ethnic genome‐wide content. Binary logistic regression was performed taking the CDR 1 score as the dependent variable and gender, education, being bilingual/monolingual, and APOE4 Carrier/non‐Carrier status as predictors. Finally, we use mean comparison test in cognition measures according the bilingual/monolingual condition.ResultWe observed that bilingualism (OR = 0.23, p<.001), APOE non‐carrier status (OR = 0.26, p<.001) and more years of schooling (OR = 0.92, p<.01) are associated with a lower risk of dementia. We also see that bilinguals have better scores than monolinguals in orientation tasks (t = 2.65, p<.01), memory total recall (t = 2.02, p<.05), semantic fluency‐animals (t = 2.71, p<. 01) and visuoconstructional abilities (t = 6.62, p<.001). Likewise, only in perception recognition tasks, monolinguals scored higher than bilinguals (t = 3.17, p<.01).ConclusionEnvironmental factors seem to have a significant protective effect along with biological known risk factor in dementia and have a significant effect on cognition.
Mediterranean Diet Foods are Associated with Plasma Biomarkers of Alzheimer’s Disease and Related Dementias
Authors: Dempsey Desarae A , Deardorff Rachael , Apostolova Liana G. , Brosch Jared R. , Clark David G. , Farlow Martin R. , Mathew Sunu , Unverzagt Fredrick , Dage Jeff L. , Russ Kristen A. , Blennow Kaj , Zetterberg Henrik , Gao Sujuan , Clark Daniel , Saykin Andrew J. , Risacher Shannon L 
Published: December 2023

AbstractBackgroundThe Mediterranean diet (MeDi) has been reported as preventative against cognitive decline and AD (Berti et al. 2018, Neurology) and associated with decreased brain atrophy (Staubo et al. 2016, Alz&Dem). Here, we examined associations between specific foods in the MeDi and plasma biomarkers of ADRD in the Indiana ADRC (IADRC) sample.MethodPlasma ptau181 and neurofilament light (NfL) from 177 individuals (57 CN/53 SCD/40 MCI/27 AD), and amyloid beta (Aβ) 42 and 40, total tau, and glial fibrillary acidic protein 2 (GFAP) from 161 individuals (49 CN/51 SCD/35 MCI/26 AD) were generated using SIMOA assays at IU or Gothenburg, Sweden. Participants completed a self‐report diet questionnaire at the IADRC, which was coded into high, medium, or low intake groups for each food. We performed linear regressions to test the association of the food groups and total MeDi score to ADRD plasma biomarkers, covaried for age, sex, diagnosis, and SIMOA batch.ResultHigher intake of red meat (p = 0.014), grains (p = 0.029), and beans (p = 0.009) significantly correlated with higher plasma NfL. Fast food also followed this trend (p = 0.053). Higher intake of olive oil showed a trend toward lower pTau181 (p = 0.055). Higher intake of grains was associated with higher Aβ42 (p = 0.038), while higher intake of sweets was associated with lower levels of Aβ40 (p = 0.016). There were no significant associations with specific foods and the Aβ42/40 ratio after covarying.ConclusionAs expected, olive oil was associated with decreased pTau181, while higher intake of red meat and fast foods were associated with increased levels of NfL. Contrary to the MeDi hypothesis, beans and grains contributed to higher NfL. While grains and sweets influenced individual levels of Aβ42 and Aβ40 respectively, these individual levels are less understood than the ratio and require further investigation. Previous studies have shown correlation of high carbohydrate and sugar intake with smaller entorhinal cortex thickness, and legumes with larger cortical thickness. A limitation is that specific types of beans and grains consumed were not collected. Further studies will investigate diagnostic group, ethnoracial, socioeconomic, and BMI effects, as well as the role of the gut microbiome.
Association of urine dicarboxylic acid levels with intracranial volume–normalized brain regions and with white matter hypo‐intensities
Authors: Fonteh Alfred N. , Maldonado Salvador , Buennagel David P , Aguda Shelly , Butler Ryan , Kang Jimmy , Macias thomas , Sin Caleb , Spezzaferri Mitchell , Rising Shant , Nolty Anne , Chui Helena C , Minazad Yafa , Kloner Robert A , Arakaki Xianghong 
Published: December 2023

AbstractBackgroundNon‐invasive molecules related to AD imaging biomarkers can reveal disease mechanisms and may help in the mass screening of an aging population. Our study aims to determine if urine dicarboxylic acids (DCA) that changed in AD are coupled with brain volume changes.MethodStudy participants (> 65 years) were recruited in an ongoing HMRI Brain aging study, and MRI data were acquired and analyzed using NeuroQuant. The data were normalized to the intracranial volume (icv). DCAs were quantified using gas chromatography/mass spectrometry. We compared DCA and icv‐normalized brain region volumes in two ways: first, we used descriptive statistics to obtain the median (Q2) for short‐chain DCAs (C4+C5), medium‐chain DCAs (C7+C8+C9) and the ratio of short to medium chain DCAs ((C4+C5)/(C7+C8+C9)). Brain regions were then sorted to correspond to less than (<Q2) or greater than the DCA medians (>Q2). Differences were determined using two‐sample t‐tests and Wilcoxon rank‐sum tests with adjustment for multiple comparisons using FDR. Secondly, icv‐normalized brain regions and T1 hypo‐intensity were compared with DCA levels using a two‐tailed student’s t‐test.ResultThere was no significant difference in the DCA levels of participants with low (icv<Q2) or high icv (icv>Q2) (Fig.1A). In contrast, C4+C5 levels were higher, while C7+C8+C9 were lower in participants with higher whole brain volumes (WBV) (Fig. 1B). In addition, hippocampal volumes were greater when participants had a higher urine C4+C5 and lower C7+C8+C9. We identified 19 other icv‐normalized brain regions that were bigger when urine C4+C5 levels were high. In addition, participants with higher white matter hypo‐intensities had lower urine C4+C5 and a higher C7+C8+C9 DCA levels (Table 1).ConclusionThese data suggest that urine lipid composition is linked to icv‐normalized brain volumes. Higher mitochondrial‐associated lipids reflected larger brain volumes, while oxidized lipids indicated lower brain volumes. Thus, urine lipid levels can be used as surrogate biomarkers in clinical trials targeting brain volume changes. We will use a bigger sample size normalized for ApoE genotype, age, and sex to further examine lipids and brain volumes in participants with different cognitive states.
Recruitment and Retention of Underrepresented Minorities in Interventional Alzheimer’s Disease Clinical Trials
Authors: Soto Elizabeth , Anziska Yaacov 
Published: December 2023

AbstractBackgroundAlzheimer’s disease is a progressive neurodegenerative disorder that affects thinking, and behavior and is the most common cause of dementia. In Alzheimer’s disease (AD) clinical trials, there is a severe lack of underrepresented and marginalized populations. Despite overwhelming evidence that these groups are more likely to develop AD, various recruitment barriers impair them from being accepted into current AD clinical studies, which threatens these findings' overall generalizability and scientific impact. As a result, there is less understanding of overall needs, no mechanism for identifying and comparing disease variations, and a limited range of available interventions. In this study, we aim to analyze the recruitment, reporting, and retention strategies of Hispanic/Latinx and Black individuals in AD Clinical Trials for the last 35 years to create a novel model system to increase the diversity and inclusion of minoritized groups in Alzheimer’s Clinical Trials.MethodWe extracted the data from the clinicaltrials.gov database and applied the inclusion criteria: Year: 1999‐Present, Population: Older Adults (65>), Alzheimer’s Diagnosed, and Healthy. Intervention: Pharmaceutical/drug. Funding: NIH, Industry. Status: Completed. For our outcome variables, we included the following: Reported and non‐reported recruitment demographic, the inclusion of white, Hispanic/Latin, Black/African American, Asian, and Unknown. For our analyses, we performed a Linear regression on cohort demographic makeup in five‐year intervals, reported vs. non‐reported demographic, and the percentage of ethnicity recruited.ResultOur search yielded n = 117 clinical trials. 28% of NIH‐sponsored drug‐based clinical trials have reported cohort demographic makeup. 61% of Industry‐sponsored drug‐based reported cohort demographic make‐up.ConclusionWe found that despite the increasing research focusing on the importance of the inclusion of underrepresented individuals in clinical trials. The number of underrepresented minorities in AD clinical trials continues to be significantly and alarmingly low, hindering the scientific process of developing therapeutic methods for Alzheimer’s Disease. Moreover, several laws and policies have been released to enforce the reporting of ethnicity/race of clinical trials cohort have not been adequately enforced and followed, raising concerns for policy efficacy.
Potentially Cognitive Stimulating Activities and cognitive performance in middle‐age and older adults
Authors: de Araujo Camila Farias , Ferri Cleusa P , Bertola Laiss 
Published: December 2023

AbstractBackgroundLow education attainment is rampant in low‐ and middle‐income countries (LMICs). Considering that education is a protective factor against dementia, engagement in activities promoting learning might be an alternative to the impact of classical schooling. Therefore, we aim to verify if potentially cognitive stimulating activities (PCSAs) could be an alternative to enhance and maintain cognitive performance in middle‐aged and older adults with diverse educational attainment.MethodWe analyzed baseline data from 7,568 participants of the Brazilian Longitudinal Study of Aging (ELSI‐Brazil). We evaluated engagement in PCSAs through questions about currently attending the Open University for older adults program or attending free courses (foreign language, data processing or computer sciences, sewing/tailoring, cooking, or arts). A global cognition regression‐based norms z‐score was computed using episodic memory and fluency tests scores. We performed three linear regression models to verify the association between engagement in PCSAs with cognition. The first unadjusted model with only the PCSAs as a predictor of cognitive performance. The second model was adjusted for sociodemographic characteristics (age, sex/gender, education, and race), and the third model was additionally adjusted for variables related to memory self‐ratings (current performance and perceived decline for the past two years), general health perception, depressive symptoms, and chronic diseases.ResultParticipants had a mean age of 61.5 (±8.98) years, a mean of 6.3 (±4.73) years of schooling, 53.5% of females and 54.9% of Black/Brown (Table 1). Engagement in PCSAs was a predictor of better cognitive performance in model 1 (β = 0.10, CI 95% 0.01;0.18), model 2 (β = 0.10, CI 95% 0.02;0.19) and model 3 (β = 0.10, CI 95% 0.03;0.21) (Table 2).ConclusionOur results suggest that better global cognition might be associated with some socially common and cheaper activities. Despite the study limitations, in a scenario where structured continuing education might not be readily available, these results indicate that PCSAs should be a target of future studies as a potential source of cognitive reserve.
Associations of APOE4 and Alzheimer’s disease biomarkers with cortical reinstatement and episodic memory in clinically unimpaired older adults
Authors: Trelle Alexandra N , Wilson Edward N. , Romero America , Kasireddy Nandita , Deutsch Gayle K. , Sha Sharon , Greicius Michael D , Andreasson Katrin I. , Carr Valerie A , Kerchner Geoffrey A. , Mormino Elizabeth C. , Wagner Anthony D 
Published: December 2023

AbstractBackgroundCortical reinstatement is a key neural correlate of episodic remembering across the lifespan and explains significant variability in memory performance among older adults. We assessed whether Alzheimer’s disease (AD) risk factors – cerebrospinal fluid (CSF) Aβ42/Aβ40, CSF pTau181, plasma pTau181, and APOE genotype – impact cortical reinstatement in clinically unimpaired older adults.MethodParticipants were 150 clinically unimpaired older adults enrolled in the Stanford Aging and Memory Study (SAMS). APOE genotype was determined from whole‐genome sequencing and participants were classified as ε4 carriers (N = 38) or non‐carriers (N = 112). CSF Aβ42/Aβ40 and pTau181 and plasma pTau181 were quantified using the automated Lumipulse G system. Cortical reinstatement was quantified during successful retrieval of word‐picture associations using fMRI multivoxel pattern analysis (MVPA) in five regions of interest, including parahippocampal gyrus (PHG), ventral temporal cortex (VTC), middle temporal gyrus (MTG), angular gyrus (ANG), and posterior medial cortex (PMC). Regression analyses examined cross‐sectional relationships between regional cortical reinstatement and a) APOE genotype (N = 150), b) CSF Aβ42/Aβ40 and pTau181 (N = 113), and (c) plasma pTau181 (N = 140), as well as associations of these variables with associative memory discrimination (d’). All models included age, sex, and regional MVPA classifier accuracy during memory encoding.ResultAPOE ε4 genotype was negatively associated with reinstatement strength in VTC (β = ‐0.54, p < .005), MTG (β = ‐0.32, p < .05), and ANG (β = ‐0.32, p < .05) and CSF Aβ42/Aβ40 burden was linked to weaker reinstatement in ANG (β = 0.16, p < .05). In VTC, the effect of APOE ε4 on reinstatement remained significant after controlling for CSF Aβ42/Aβ40 (β = ‐0.47, p < .05); a similar pattern was observed in MTG and ANG. Although CSF pTau181 was unrelated to reinstatement strength, both pTau181 and cortical reinstatement explained unique variance in memory performance (pTau181: β = ‐0.26, p < .005, reinstVTC: β = 0.39, p < .001). Analogous findings were observed with plasma pTau181.ConclusionThese results suggest that APOE ε4 impacts cortical reinstatement, and that this effect may be independent of amyloid burden. These effects of APOE ε4 may be distinct from tau‐mediated effects on episodic memory in human aging.