bluuebunny/crossref_metadata_2025_split huggingface dataset:
Sex‐specific CSF proteomic profiling of amyloid/tau positivity identifies distinctive sex‐specific alternation of multiple proteins involved in Alzheimer’s disease
Authors: Do Anh , Ali Muhammad , Timsina Jigyasha , Wang Lihua , Ruiz Agustin , Pastor Pau , Cruchaga Carlos , Sung Yun Ju 
Published: December 2023

AbstractBackgroundSporadic Alzheimer’s disease (AD) is a highly heterogeneous multifactorial disease in which females have a higher risk. Among 5.3 million senior Americans diagnosed with AD, over 60% are female. Despite the well‐established sex differences, sex‐specific molecular findings in AD are still limited. We therefore examined the role of sex in the proteomic alterations due to AD to elucidate potential protein markers of AD heterogeneity.MethodIn the discovery cohort, 599 preclinical AD and 435 controls underwent lumbar puncture. Over 7,000 proteins in cerebrospinal fluid (CSF) were measured using SomaLogic assay. Amyloid/tau positivity (AT classification) was determined using ELISA Aβ42 and pTau181 levels in CSF. Proteins with sex‐specific effects were identified through linear models focusing on the interaction term between AT classification and sex. Results were tested in the independent cohort (N = 732) using the identical approaches. We analyzed brain proteomics and transcriptomics data to validate the replicated sex‐specific proteins. We performed pathway enrichment, interaction network using ConsensusPathDB and drug‐target prediction.ResultWe identified 594 proteins with sex‐specific effects in discovery (P<0.05 and permutation FDR <0.05). Among them, 36 were validated in replication (P<0.05 and consistent direction). These proteins were found to be involved in neurologic disorders and highly enriched in axon regeneration (fold enrichment = 9.38 and FDR = 2.8×10−4). Among the 36 proteins identified, 13 were classified as female‐specific and 23 as male‐specific. These 36 proteins strongly predicted amyloid/tau positivity (AUC = 0.926) for all individuals as well as 13 female‐specific proteins for females (AUC = 0.929). The interaction network identified CCN2 as a hub and contained 10 additional proteins including JAG1 and DLL4 of Notch signaling pathway and CTSB, an amyloid precursor protein secretase, among others. The results of 36 proteins in brain proteomics and transcriptomics confirmed the sex‐specific effect of CCN2 and others on AD in different tissues. Drug target prediction suggests minocycline and etoposide as potential treatments for females as well amitriptyline and verteporfin for males.ConclusionWe robustly identified 36 proteins that showed significant sex‐specific alterations by preclinical AD. Several proteins involved in AD and neurodegeneration were highlighted. Our findings facilitate mechanistic understanding of sex differences for AD risk and progression.
Plasma ALZpath p‐tau217 for the identification of amyloid and tau positivity
Authors: Ashton Nicholas J. , Molfetta Guglielmo Di , Brum Wagner Scheeren , Benedet Andrea Lessa , Arslan Burak , Jonaitis Erin M. , Langhough Rebecca E , Cody Karly Alex , Betthauser Tobey J , Hogan Kirk J. , Christian Bradley T. , Rahmouni Nesrine , Stevenson Jenna , Montoliu‐Gaya Laia , Rodriguez Juan Lantero , Triana‐Baltzer Gallen , Kolb Hartmuth C. , Vanbrabant Jeroen , Stoops Erik , Jeromin Andreas , Rosa‐Neto Pedro , Johnson Sterling C , Blennow Kaj , Zetterberg Henrik 
Published: December 2023

AbstractBackgroundIn the last 5 years, immunoassays for the quantification of phosphorylated tau (p‐tau) in blood have proven to accurately identify Alzheimer’s disease (AD) pathology with important implications for primary care management and therapeutic trials. Comparisons of p‐tau epitopes (p‐tau181, p‐tau217, p‐tau231) show small differences in diagnostic accuracy, however, often p‐tau217 is preferred, citing its larger fold‐change in symptomatic patients and lower rate of false positives in amyloid‐negative individuals. This study describes the performance of a novel Single molecule array (Simoa) for p‐tau217 (p‐tau217ALZpath)MethodWe included 355 participants from Translational Biomarkers in Aging and Dementia (TRIAD) participants, which was representative of the AD continuum. Further, 425 cognitively unimpaired individuals, with longitudinal plasma measures (≤8 years), were included from Wisconsin Registry for Alzheimer’s Prevention (WRAP). All plasma samples were measured for ALZpath p‐tau217ALZpath, a validated Simoa assay at the University of Gothenburg, Sweden. In TRIAD, amyloid positivity (A+) was defined as [18F]AZD‐4694 SUVR >1.5 or CSF Aβ42/40 <0.068. In WRAP, A+ was defined by [11C]PiB >1.16. 18F‐MK‐6240 determined tau status (T+) both cohorts (TRIAD, >1.24 SUVR; WRAP, >1.3).ResultIn TRIAD, p‐tau217ALZpath determined A+ (AUC = 0.957, 0.935‐978) and T+ (AUC = 0.952, 0.929–0.976) individuals with high accuracy. A sensitivity analysis, including only participants with imaging (amyloid and tau) and CSF biomarkers (p‐tau181, p‐tau205, p‐tau217, Aβ42/40), p‐tau217ALZpath demonstrated equivalent accuracies in determining A+ (Figure 1A) and T+ (Figure 1B) than these high‐performing modalities. In addition, plasma p‐tau217AlzPATH demonstrated a good accuracy to identify T+ from all A+ participants (AUC = 0.839, 0.767‐910). Concentration cut‐points derived in WRAP to identify A+ (>0.676 pg/mL; PPV = 87.2%) and A– (<0.235 pg/mL; NPV = 98.2%) were directly tested in TRIAD with high accuracy (>0.676 pg/mL, PPV = 98.8%; <0.235 pg/mL, NPV = 95.1%. In WRAP, longitudinal analysis (Figure 2) demonstrated that over 8‐years, p‐tau217AlzPATH increased only in A+ individuals and more steeply in A+T+ participants (βestimate = 0.1 pg/mL per year; P<0.0001) compared to A+T‐ (βestimate = 0.022 pg/mL per year, P = 0.0008).ConclusionThe novel p‐tau217ALZpath immunoassay demonstrates high accuracy to determine amyloid and tau pathology across all stages of AD continuum. Clinical cut‐points to identify A+ or A– with high PPV and NPV are directly transferable across cohorts.
Associations among plasma, MRI and amyloid PET biomarkers of dementia and the impact of health‐related comorbidities
Authors: Rudolph Marc D. , Sutphen Courtney L. , Register Thomas C. , Whitlow Christopher T. , Sai Kiran K. Solingapuram , Hughes Timothy M. , Bateman James R. , Dage Jeff L. , Russ Kristen A. , Mielke Michelle M. , Craft Suzanne , Lockhart Samuel N. 
Published: December 2023

AbstractBackgroundKnowledge regarding associations between plasma and neuroimaging biomarkers indexing neurodegeneration and neuropathology observed in dementia is limited. Further, it is uncertain how comorbid health complications (e.g., kidney function) may alter plasma levels and impact associations with neuroimaging biomarkers.MethodWe examined associations between plasma and neuroimaging biomarkers in cognitively normal participants (NC; N = 300) and individuals with consensus diagnosis (Dx) of mild cognitive impairment (MCI; N = 192) or dementia (DEM; N = 64) enrolled in the Wake Forest ADRC (Table 1). We examined plasma biomarkers (Quanterix SIMOA HD‐X: Aβ42/40, GFAP, NfL, p‐tau181) and neuroimaging measures of amyloid deposition (global PiB PET SUVr; Aβ‐PET), total brain volume (BVOL), global white matter hyperintensity volume (WMH), diffusion‐weighted fractional anisotropy (FA) and NODDI freewater (FW; white matter). Linear models adjusted for APOE‐ε4 carrier status, demographics (age, sex, race, education), and cardiometabolic factors (estimated glomerular filtration rate (eGFR); BMI).ResultsPlasma biomarkers were moderately correlated with each other (absolute r = .22‐.64; all p<.001) and significantly elevated (Aβ42/40 lower) in DEM and MCI (Figure 1) versus NC, and Aβ‐PET‐positive (SUVr >1.21) versus negative individuals (all p<.001). Plasma and neuroimaging markers were significantly associated in both unadjusted models and models including eGFR and BMI (all p<.05; attenuation effect <10% with and without Dx; Figure 2a & 2b). In fully adjusted models (Figure 2b: Dx and all covariates), age, sex, and race differentially impacted associations of Aβ42/40, p‐tau181, and NfL with neuroimaging biomarkers (coefficients p <.05). APOE‐ε4 status exclusively impacted associations with Aβ‐PET SUVr/status. GFAP remained significantly associated with all neuroimaging biomarkers after covariate adjustment; no Aβ42/40 associations survived adjustment. P‐tau181 remained significantly associated with Aβ‐PET and BVOL, while associations with NfL were reduced in models stratified by Dx.ConclusionAmong aging community‐dwelling participants, plasma biomarkers significantly differed between diagnostic groups (DEM>MCI>NC), were elevated in Aβ‐PET positive individuals, and associated with poorer brain health. Except for GFAP, and to an extent p‐tau181, associations between plasma and neuroimaging biomarkers were differentially impacted by inclusion of comorbidities and covariates when stratified by diagnosis. Future work will examine high‐dimensional interactions among comorbidities, demographic information, and plasma and neuroimaging biomarkers in individuals with or at‐risk of dementia.
Genetically Regulated Telomere Length Relates to Brain Amyloidosis
Authors: Libby Julia B. , Roshani Rashedeh , Seto Mabel , Wang Ting‐Chen , Nudelman Kelly N. H. , Buckley Rachel F. , Saykin Andrew J. , Mormino Elizabeth C. , Sperling Reisa A. , Mayeux Richard , Dumitrescu Logan C , Hohman Timothy J. 
Published: December 2023

AbstractBackgroundIt is well‐established that telomeres shrink over the course of aging and that this process is genetically regulated. Work from our group and others has highlighted the complex interplay between measured leukocyte telomere length and Alzheimer’s Disease (AD) biomarkers over the course of AD. We expand on this work to explore whether a polygenic score predicting telomere length relates to PET measures of brain amyloidosis in the preclinical stages of disease.MethodA Polygenic Risk Score (PRS) of telomere length was built from a published GWAS on telomere length from UK Biobank (N = 472,174). We leveraged genetic data from non‐Hispanic White participants from the Alzheimer’s Disease Neuroimaging Initiative (ADNI; N = 1,414) and the Anti‐Amyloid Treatment in Asymptomatic Alzheimer’s study (A4; N = 3,002). The relation of the score to measured telomere length was validated using leukocyte telomere length data from ADNI. A linear regression model was used to evaluate whether the PRS relates to a PET measure of brain amyloidosis in a harmonized dataset including ADNI and A4, with a total sample size of 3,940 after restricting to individuals with both genetic data and amyloid measurements. Covariates included age, sex, and diagnostic status.ResultAs expected, telomere PRS related to measured telomeres in ADNI when covarying for age, sex, and baseline diagnosis (Figure 1, p = 0.045). Interestingly, we also observed a counter intuitive association between genetically predicted telomere length and amyloidosis whereby longer predicted telomere length was associated with higher amyloid burden (Figure 2, β = 1305, p = 0.006).ConclusionA PRS for telomere length modestly relates to measured telomere length in older adults and relates to higher amyloid burden. Previous work from our group has highlighted the interaction between measured telomere length and amyloid status such that the association is counter intuitive among those who are biomarker positive. The present results highlight the exciting possibility that telomere length may relate directly to AD biomarkers and open the opportunity for future work further probing the complex interplay between telomere length and AD biomarkers leveraging this powerful genetic tool.
Optimization of voice biomarkers to predict Alzheimer’s disease
Authors: Ko Hyunwoong , Kwon Sukbong 
Published: December 2023

AbstractBackgroundEmerging evidence indicates the feasibility of utilizing a surrogate biomarker to detect Alzheimer’s disease. One of the noninvasive markers, the vocal biomarker, may be used to screen for dementia without the use of language markers. Regarding model performance based on vocal biomarker, speech activity detection algorithm (SAD) that eliminates the non‐speaking portion of demented speech may improve the outcome. The aim of the study was to determine whether the SAD algorithm can achieve superior performance.MethodFor this experiment, the ADReSSo Challenge dataset from DementiaBank was used. The participants consisted of 87 AD and 74 CN. 18 silence‐related features (e.g., silence count rate), 2 MFCCs, 2 Spectrograms, MelSpectrogram, 2 Spectral centroids, 4 pitchs, loudness, 5 jitters, 5 shimmers, and harmonics‐to‐noise ratio comprised the vocal biomarker features. SincNet was used to develop the SAD method, which is based on a deep convolution neural network. To compare the SAD’s quality, naive bayes, the most basic machine learning algorithm, was utilized.ResultWith SAD, the F1 score was 0.750 (0.083). Without the SAD, the F1 score was 0.59 (0.075).ConclusionThe performance of the prediction of AD based only on speech may be improved by including essential SAD algorithm characteristics. In practice, even eliminating irrelevant speech parts may result in improved performance.
Elucidating APOE4‐dependent cholesterol dysregulation in endolysosomes related to Alzheimer’s disease biology
Authors: Leeuw Sherida M , Putter Julian , van der Kant Rik , Nuriel Tal 
Published: December 2023

AbstractBackgroundAberrant cholesterol processing may be the missing link in the biology of AD, and in our understanding of AD etiology. APOE4 is a major genetic risk factor for AD, and a key player in cholesterol metabolism in the brain. Previous research from our group has shown that APOE4 is related to increased lysosomal cholesterol accumulation in human iPSC‐astrocytes, and altered endolysosomal morphology has been observed in the entorhinal cortex (EC) of aged APOE4 mice. However, it is unclear how endolysosomal cholesterol mistrafficking changes with age.MethodTherefore, we studied endolysosomal cholesterol accumulation in middle (15‐16month) and old age (25‐26month) old mice, enabling us to study these processes already in mid‐life. We used brain sections of humanized APOE mice, looking at different brain regions to study regional vulnerability and temporal progression. Cholesterol was labeled using the novel and highly specific D4H probe, enabling its quantification within the endolysosomal system using immunohistochemistry. Cholesterol and endolysosomal markers were quantified and colocalized using Cellprofiler.ResultOlder APOE4 mice showed an increase of total cholesterol in their brain, and specifically an increase of lysosomal cholesterol. Middle aged mice did not show a difference in total cholesterol, however, there was a specific decrease in early endosomal (EE) and late endosomal (LE) cholesterol only in the entorhinal cortex (EC) of female APOE3 mice, while lysosomal cholesterol was increased in this group (APOE4 and APOE2 showed similar levels). The EE and LE cholesterol differences were specific to neurons, but not the lysosomal cholesterol increase, indicating that non‐neuronal cells play a role. Another striking finding was the increase of neuronal EE cholesterol in the EC of middle aged APOE3 male vs female mice, whereas the reverse was seen in APOE4 brain tissue.ConclusionAltogether these results indicate that endolysosomal cholesterol is a dynamic process throughout aging, which may play and active role in AD biology. There is a noticeable shift from EE and EL cholesterol changes in midlife, to lysosomal cholesterol accumulation in older age, which are APOE‐genotype dependent. Notably, the EC specifically of female mice show the most variable endolysosomal cholesterol levels, and may be involved in increased vulnerability to pathology.
Role of Discrimination and Physiological Dysregulation in Racial Disparities in Cognitive Function: The Multi‐Ethnic Study of Atherosclerosis (MESA)
Authors: Forrester Sarah N , Gallo Joseph J , Leoutsakos Jeannie‐Marie S , Thorpe Roland J. , Rapp Stephen R. , Hayden Kathleen M. , Luchsinger Jose A , Seeman Teresa E. 
Published: December 2023

AbstractBackgroundBlack‐White disparities in cognitive test scores are well documented. Studies suggest that structural racism‐related factors like quality of education and cumulative stress exposure may contribute to disparities in inflammation and cardiometabolic health that undergird racial disparities in Alzheimer’s disease and cognitive health.MethodWe used MESA data from (N = 1,839) participants that self‐report being racialized as Black or White. We used path analyses to examine the association between racialized group and age‐ and education‐adjusted cognitive scores from the Cognitive Ability Screening Test (CASI) at Exam 5 (2010‐12) and Exam 6 (2016‐18). We examined the relationship between discrimination using the Everyday Discrimination Scale at Exam 1 (2000‐02) and physiological dysregulation at Exam 5 (using a cardiometabolic index = waist‐to‐hip ratio, triglycerides, low‐density lipoprotein cholesterol, high‐density lipoprotein cholesterol, glucose, systolic blood pressure, resting heart rate, and pulse pressure). All models were adjusted for Exam 5 age, sex, site, depression, general stress, socioeconomic stress, and APOE‐e4.ResultMean age was 69.6 years (SD = 9.3) at Exam 5. Participants racialized as Black had significantly lower CASI scores at Exam 5 (b = ‐0.26) and Exam 6 (b = ‐0.29) than counterparts. Physiological dysregulation was directly associated with lower CASI scores at both exams (Table 1). Discrimination and physiological dysregulation had a significant indirect association with racialized group‐cognition at both exams (Figure 1). Physiological dysfunction was associated with lower CASI scores for participants racialized as Black compared to White at Exam 5 (b = ‐0.004, 95% CI: ‐0.010, ‐0.001) and Exam 6 (b = ‐0.005, 95% CI: ‐0.011, ‐0.002). Higher discrimination was associated with higher CASI scores for participants racialized as Black compared to White at Exam 5 (b = 0.013, 95% CI: 0.001, 0.024) and Exam 6 (b = 0.012, 95% CI: 0.001, 0.024). There was no racialized difference in decline from Exam 5 to Exam 6.ConclusionPhysiological dysregulation may be a mechanism to partially explain the Black‐White disparity in cognitive test scores among middle‐aged and older adults. Endorsing more everyday discrimination was associated with a significantly higher cognitive test scores, though further research is needed to determine if this is due to coping‐related resilience.
Religious Attendance, Childhood Trauma, and Later Life Depressive Symptoms
Authors: Britt Katherine C , Dong Fanghong 
Published: December 2023

AbstractBackgroundOlder adults who experienced childhood trauma are at higher risk of developing depression. Depression is linked with structural changes in the brain and alterations in neurotransmitters and inflammation, placing individuals with depression at 2 times as likely to develop dementia than individuals without depression. A growing body of literature supports religion and spirituality as protective factors for mental health, yet few studies have examined the mediating role of religious attendance on the association between childhood trauma and depressive symptoms in later life. Identifying modifiable protective factors to decrease depression and, potentially, dementia is needed to decrease the growing dementia burden.MethodWe analyzed data from the Health and Retirement Study in 2006‐2012 to examine the mediating role of religious attendance (in 2010) on the association of childhood trauma (in 2008) with later‐life depressive symptoms (in 2012) among older adults in the U.S. (N = 3,240) aged 60 years and older. A mediation analysis was conducted while controlling for covariates: sex, race, education, age, marital status, body mass index (BMI), and cognition.ResultAged 60‐104 years, participants had a mean age of 72.7 (8.45) years, were 57.9% female, and were 82.9% White. A significant association was found for childhood trauma using 4 self‐report items and self‐reported depressive symptoms using the Center for Epidemiological Studies‐Depression scale (CES‐D) (β = 0.2124, 95% CI [0.31, 0.1201], p<.001). There was a partial mediating effect of self‐reported religious attendance (high vs. low) between childhood trauma and depressive symptoms (β = 0.017, 95% CI [0.03, 0.003], p<.05) adjusting for sex, race, education, age, marital status, BMI, and cognition.ConclusionReligious attendance plays a partial mediating role in the relationship between childhood trauma and later‐life depressive symptoms in older adults. Clinical trials are needed to further examine the effect of religious attendance on depressive symptoms in older adults with a history of childhood trauma, with the potential to decrease the risk of dementia.
Association of Dietary Fat and the ApoE4 Allele with Cognitive Decline in a Biracial Population Sample
Authors: Liu Xiaoran , Beck Todd , Evans Denis A , Rajan Kumar B 
Published: December 2023

AbstractBackgroundIntake of dietary fat has been linked with cognition. Apolipoprotein E plays a critical role in lipid metabolism; however, the potential interaction between ApoE ε4 carrier and dietary fat on cognition is not fully understood. We aim to examine the association of types of dietary fat and their relation to cognitive decline among those with and without the ApoE ε4 allele.MethodThe study included 3,528 participants from the Chicago Health and Aging Project (62% African Americans, 63% female). Global cognition was assessed using a composite score of episodic memory, perceptual speed, MMSE; and diet using a 139‐item food frequency questionnaire. ApoE genotype was assessed by hME Sequenom mass‐array platform. Longitudinal mixed effect regression models were used to examine the association of dietary fat and the ApoE ε4 allele with cognitive decline, adjusting for age, sex, education, smoking status, and calorie intake.ResultAmong varying types of dietary fat, including saturated fat (SFA), monounsaturated fat, and polyunsaturated fat, we found that a higher intake of SFA was associated with faster cognitive decline (p for trend 0.0274). Per 5% increase in calorie from SFA was associated with a 15% faster cognitive decline (β = ‐0.0064, p = 0.04). Participants in the highest quintile of intakes of SFA had a 34% faster cognitive decline than those in the lowest quintile (β = ‐0.0125, p = 0.0095).In those with ApoE ε4 allele, per 5% increase in calorie from SFA was association with a 21% faster decline (β = ‐0.0197, p = 0.0038). Among participants with ApoE ε4 allele, individuals in the highest quintile of intakes of SFA had a 45% faster cognitive decline compared to those in the lowest quintile of intake (β = ‐0.0372, p = 0.0003). Higher SFA was not associated with cognitive decline among those without the ApoE ε4 allele nor other types of dietary fat.ConclusionOur study found a significant association of saturated fat with faster cognitive decline among those with the ApoE4 allele. Higher intake of saturated fat among the ApoE4 carriers might lead to significantly higher risk of cognitive decline in old age.