bluuebunny/crossref_metadata_2025_split huggingface dataset:
Comparison of plasma ALZpath p‐Tau217 with Lilly p‐Tau217 and p‐Tau181
Authors: Bali Divya , Janelidze Shorena , Salvadó Gemma , Serrano Geidy E , Beach Thomas G. , Jeromin Andreas , Hansson Oskar 
Published: January 2025

AbstractBackgroundThere is an urgent need for accurate and validated methods to measure plasma phosphorylated tau (p‐Tau) biomarkers in Alzheimer´s disease (AD). Here we compared the performance of newly developed plasma ALZpath p‐Tau217 assay to other established p‐Tau assays such as Lilly p‐Tau217 and Lilly p‐Tau181.MethodWe included 72 participants from the Arizona Study of Aging and Neurodegenerative Disorders cohort, where we analysed antemortem collected plasma samples with ALZpath p‐Tau217 as well as Lilly p‐Tau217 and p‐Tau181. The plasma biomarkers were compared with relevant post‐mortem neuropathological measures.ResultWe found that ALZpath p‐Tau217 correlated significantly with Lilly p‐Tau217 and Lilly p‐Tau181. ALZpath p‐Tau217, Lilly p‐Tau217 and Lilly p‐Tau181 were found to be significantly associated with plaque (ρ=0.58, ρ=0.78, ρ=0.65; p<0.001) and tangle (ρ=0.26, ρ=0.51, ρ=0.37; p<0.05) load, when adjusting for age, sex and time of interval between blood sampling and death (Table 1). All the three biomarkers were also found to be significantly associated with plaque load (r=0.53, r=0.73 and 0.59; p<0.001), when adjusting for tangle load. However, only Lilly p‐Tau217 was significantly associated with tau tangle load (r=0.32, p=0.007), when adjusting for plaques. The correlations of ALZpath p‐Tau217 and Lilly p‐Tau181 with plaque load were comparable but Lilly p‐Tau217 exhibited significantly higher correlations with plaques (ρdiff =0.20; p=0.015) and tangles (ρdiff =0.29; p=0.003) than ALZpath p‐Tau217. ALZpath p‐Tau217 and Lilly p‐Tau181 predicted the elevated levels of ADNC, tangle, and amyloid pathology with similar accuracy (AUCrange, 0.74‐0.79) but the AUC´s of Lilly p‐Tau217 were significantly higher in comparison to ALZpath p‐Tau217 (ADNC, AUCdiff=0.12, pdiff=0.021; Braak, AUCdiff=0.08, pdiff=0.021; CERAD, AUCdiff=0.11, pdiff=0.024) (Figure 1). When looking at the changes in biomarker levels for non‐AD pathologies, we found that only Lilly p‐Tau217 was significantly higher in participants with both AD and cerebral amyloid angiopathy (CAA) pathology in comparison to those with only AD and CAA pathology (Figure 2).ConclusionALZpath p‐Tau217 exhibited similar performance as Lilly p‐Tau181, but in this cohort associations between ALZpath p‐Tau217 and the core measures of AD pathology were significantly lower in comparison with Lilly p‐tau217. These findings will need to be replicated in larger independent cohorts.
BDNF Val66Met influences the mediation of sex differences in VLM scores by plasma BDNF in a cohort enriched with risk for Alzheimer‘s disease
Authors: Edmunds Kyle J , Mamlouk Gabriella M , Lose Sarah R , Asthana Sanjay , Sager Mark A. , Stremlau Matthew , Johnson Sterling C. , van Praag Henriette , Okonkwo Ozioma C 
Published: January 2025

AbstractBackgroundBrain‐derived neurotrophic factor (BDNF)—a key neurotrophin involved in synaptic plasticity, neurogenesis, and neuroprotection—has been shown to mediate sex differences in verbal learning and memory (VLM) ability, but it remains unclear whether this relationship is conditionally dependent upon carriage of the Val66Met polymorphism in the BDNF gene. This study investigates how BDNFVal66Met carriage influences the mediation of sex differences in VLM scores by plasma BDNF levels in a cohort enriched for AD risk.MethodCognitively unimpaired participants in the Wisconsin Registry for Alzheimer’s Prevention (WRAP; n=198, age 63.8±6y, 66% women, 66% family history of AD, 38% apolipoprotein E4 (APOE‐ε4) carriers, 31% BDNFVal66Met carriers) underwent the Rey Auditory Verbal Learning Test (RAVLT). Scores from learning trials 3‐5 and the delayed recall test were aggregated as a VLM performance index. Plasma BDNF levels were measured using a Human BDNF Quantikine Immunoassay (R&D Systems). Striatified mediation analysis and bootstrapping were performed to test the conditional dependence of BDNF mediation on BDNFVal66Met carriage, and model covariates included age, APOE‐ε4 carriage, parental history of AD, education, hippocampal volume, and date difference between VLM and plasma data acquisition.ResultStratified mediation models showed a significant association between sex and VLM scores in BDNFVal66Met carriers [β=‐0.61; p=0.04], but no significant association between sex and BDNF levels [β=0.06; p=0.85]. By comparison, in BDNFVal66Val homozygotes, women had significantly higher BDNF levels [β=‐0.62; p<0.01] and VLM scores [β=‐0.77; p<0.01], and bootstrapping showed BDNF to be a significant partial mediator of the effect of sex on VLM [β=‐0.14; 95% CI: ‐.292, ‐.021].ConclusionThis study indicates that BDNFVal66Met carriage may attenuate the mediating role of plasma BDNF expression on the relationship between sex and VLM scores.
Genetic characteristics of PUMCH dementia cohort
Authors: Dong Liling , Shang Li , Qiu Yuyue , Bao Jialu , Mao Chenhui , Chu Shanshan , Jin Wei , Peng Bin , Cui Liying , Gao Jing 
Published: January 2025

AbstractBackgroundDementia is prevalent over the world with unclear mechanism. Gene is supposed to play a vital role in the pathogenesis of dementia. However, the genetic basis of the majority of dementia patients is unknown.MethodAll the participants were from the dementia cohort of Peking Union Medical College Hospital (PUMCH). They all received history inquiry, cognitive evaluation, biochemical test, brain imaging and gene testing. According to the standards of American College of Medical Genetics and Genomics (ACMG), the pathogenic/likely pathogenic variants (PLPV) related to dementia were screened.Result2593 subjects were enrolled, including 1144 males and 1447 females. The average age was 66.8±12.1 years old. 56.3% (1461/2593) cases were early‐onset (age of onset < 65 years old), while 43.7% (1132/2593) cases were late onset. 66.4% (1722/2593) cases were APOE‐ε4 non‐carriers, and 33.6% (871/2593) cases were APOE‐ε4 carriers. 6.2% (162/2593) subjects carried the PLPV related to dementia. The NOTCH3 had the greatest mutation frequency (n=32, 1.2%), followed by the PSEN1 (n=21, 0.8%) and the CSF1R (n=13, 0.5%).ConclusionThere is genetic diversity among the PUMCH dementia cohort, with a high mutation frequency of the NOTCH3.
Unraveling the Link Between SGLT2 Inhibition, Circulating Metabolites, and Alzheimer’s Dementia: A Mendelian Randomization Study
Authors: Yang Hao , Ning Yuye , Chen Meilin , Jia Jianping 
Published: January 2025

AbstractBackgroundIndividuals with type 2 diabetes mellitus (T2DM) face an increased risk of dementia. Recent discoveries indicate that SGLT2 inhibitors, a newer class of anti‐diabetic medication, exhibit beneficial metabolic effects beyond glucose control, offering a potential avenue for mitigating the risk of Alzheimer’s disease (AD). However, limited evidence exists regarding whether the use of SGLT2 inhibitors effectively reduces the risk of AD. Previous cohort studies encountered challenges related to potential reverse causality. Hence, our study aims to explore the impact of circulating metabolites mediating SGLT2 inhibition on AD through Mendelian randomization (MR).MethodIn this study, a two‐sample Mendelian randomization (MR) approach was employed to investigate the association between SGLT2 inhibition and AD. Genetic instruments for SGLT2 inhibition were identified based on variants associated with the expression of the SLC5A2 gene and glycated hemoglobin level (HbA1c). Positive control analysis for T2DM validated the chosen genetic instruments. Furthermore, we explored the relationships between SGLT2 inhibition and different forms of AD (late‐onset and early‐onset AD). Two‐step MR was utilized to examine the mediation effects of circulating metabolites linking SGLT2 inhibition with AD.ResultGenetically predicted SGLT2 inhibition (per 1 SD decrement in HbA1c) was associated with a reduced risk of both T2DM (odds ratio [OR] = 0.36 [95% CI 0.31, 0.41], p < 0.001) and AD (0.48 [0.36, 0.63], p < 0.001). The causal relationship between SGLT2 and late‐onset and early‐onset AD was consistent (OR = 0.29 [0.14‐0.60], p = 0.001; 0.29 [0.09‐0.89], p = 0.03). Among the 123 circulating metabolites examined, citrate demonstrated significant associations with both SGLT2 inhibition and AD (0.81 [0.79, 0.83, p < 0.001]).ConclusionThis study provides robust evidence supporting the association between SGLT2 inhibition and a reduced risk of AD. Notably, citrate levels may mediate this association, emphasizing the imperative for further investigation through randomized controlled trials.
Diagnostic Performance and Clinical Applications of a Commercial Alpha‐Synuclein Seed Amplification Assay in a Tertiary Care Memory Clinic
Authors: Porter Amanda , Lachner Christian , Tipton Philip W , Graff‐Radford Neill R , Day Gregory S 
Published: January 2025

AbstractBackgroundSAAs represent a promising biomarker of Lewy Body disease (LBD), with high sensitivity (87.3%, 95%CI: 0.755‐0.947) and specificity (97.2%, 95%CI: 0.922‐0.994) for detection of patients in the Parkinson’s Progression Markers Initiative repository with positive DaT SPECT; and reasonable sensitivity (78.7%, 95%CI: 0.66‐0.88) and specificity (89.5%, 95%CI: 0.78‐0.96 referencing clinical diagnoses in participants included within national research repositories. However, test performance in heterogeneous clinical cohorts is unknown.MethodPatients with typical (n=122) and rapid progressive dementia (n=76) consented to banking of CSF at the time of clinically‐indicated diagnostic lumbar puncture. Clinical data were deidentified and uploaded to a secure research database and clinical (etiologic) diagnoses established by two neurologists following independent review of available records. SAA (SYNTap™) were run on stored CSF by Amprion Diagnostics (San Diego, CA).ResultMedian participant age was 69.1 years (18.4‐86.1); 56.3% were female. CSF was sampled median 1.4 years (0‐10.3) after symptom onset. Pathological alpha‐synuclein was detected in 28/122 patients with typically progressive dementia (including 6/18 patients with presumed LBD; sensitivity 33%, specificity 79%) and 11/76 patients with rapid progressive dementia (including 3/9 patients with presumed LBD; sensitivity 33%, specificity 88%). “Positive” SAA was associated with tremor (OR=3.2, 95%CI: 1.3‐7.8), visual hallucinations (OR=6.14, 95%CI 1.6‐23.6), and REM behavior disorder (OR=3.7, 95%CI: 1.4‐9.5) in patients with typical but not rapid progressive dementia. Brain autopsies were completed in 17 patients: Lewy bodies were detected in 2/3 patients with positive SAA and no patients with negative SAA.Conclusion“Positive” SAA demonstrated reasonable specificity but low sensitivity for the diagnosis of LBD. Additional studies in heterogeneous cohorts with neuropathologic data are needed to optimize clinical applications of SAA.
Model‐based analysis of episodic memory retrieval in healthy aging and mild cognitive impairment
Authors: Hill Paul F , Garren Joshua D , Markham Donette C , Ekstrom Arne 
Published: January 2025

AbstractBackgroundEpisodic memory declines during healthy aging and is often reported as an early symptom of Alzheimer’s disease (AD). However, standardized assessments of memory performance are limited in their accuracy to predict progression of early‐stage AD pathology. The ‘all‐or‐none’ approach commonly used in neuropsychological assessment for quantifying memory performance might miss out on subtle variation in the fidelity or quality mnemonic representations retrieved from memory.MethodsThirty‐five cognitively healthy older adults and nine older adults with MCI completed five study‐test cycles of a continuous report item‐location memory task. A subsample of 21 healthy older adults performed the task while undergoing high‐resolution fMRI. During the study phase, participants viewed trial‐unique objects located around the perimeter of an invisible circle. During the test phase, old and new objects were presented in the center of the screen and participants were instructed to recall the original location of each object using a continuous analogue response dial to indicate their response. Trial‐wise distance error between the remembered and true location of each object were fit with a probabilistic mixture model to estimate two distinct memory processes that are often conflated by categorical response memory paradigms: the ability to accurately retrieve prior details from memory (i.e., retrieval success), and the fidelity of details successfully retrieved from memory (i.e., memory precision).ResultsBehavioral measures of retrieval accuracy and memory precision were significantly reduced in the MCI cohort relative to healthy older adults. Critically, we observed substantial individual differences in memory precision that were independent of retrieval success and performance on standardized assessments of verbal and visuospatial memory. Encoding‐related brain activity predictive of subsequent memory precision was evident in the left hippocampus along with robust bilateral effects in dorsomedial frontal and occipitotemporal cortices. Precision effects at retrieval were modest by comparison, yielding a single cluster in the left intraparietal sulcus.ConclusionsPrecision‐based measures of episodic memory appear to capture subtle changes in cognitive function during early stages of AD progression that cannot be readily accounted for by standardized assessments of verbal and visuospatial memory.
Temporal dynamic effects of cortical resilience proteins on trajectories of cognitive aging
Authors: Zammit Andrea R , Wang Tianhao , Yu Lei , Oveisgharan Shahram , Jager Philip L. De , Petyuk Vladislav A , Bennett David A. , Buchman Aron S 
Published: January 2025

AbstractBackgroundIn prior work we identified cortical resilience proteins associated with the linear trajectories of cognitive decline independent of the effects of neuropathology. Some of these proteins were associated with slower and some with faster cognitive decline. We tested the hypothesis that the temporal onset and duration of effects of cortical resilience proteins associated with cognitive trajectories may vary in aging adults.MethodWe used data from 1,088 older participants (31% males, mean age at death =89.7, SD = 6.4; mean education = 16.3 years, SD = 3.6) from two clinical‐pathologic studies. Participants completed a battery of 19 cognitive tests annually, underwent neuropathologic examination, and had targeted proteomic analysis performed in the dorsal lateral prefrontal cortex. To identify cortical resilience proteins, we first ran linear mixed effects models with cognitive decline as outcome, and the proteins as predictors, controlling for the effects of neuropathologic indices. To estimate the temporal effect of the identified resilience proteins on cognitive decline, we then ran functional mixed effects models, which allow i) individuals to have heterogeneous (linear and nonlinear) patterns of cognitive decline, and ii) the influence of predictors to vary flexibly over time.ResultWe identified 40 cortical resilience proteins which linear and nonlinear effects on cognitive decline spanned the entire studied trajectory of up to 25 years of follow‐up. We found that the effects of 17 proteins were significantly nonlinear: while 10 were associated with higher resilience, 7 were associated with lower resilience. The onset of effects of these proteins showed that i) the effects of higher resilience (slower rate of decline) proteins start up to 23 years before death, while the effects of the lower resilience (faster rate of decline) proteins are restricted within the last 7 years of life.ConclusionMultiple cortical proteins may underlie the resilience afforded by varied lifestyles and behaviors. Yet, the temporal window during which different proteins may provide cognitive resilience may vary. Different analytic techniques may be needed to elucidate the molecular mechanisms underlying cognitive resilience and their critical temporal window during later life.
Cognitive reserve is associated with the recruitment of compensatory brain networks in individuals at risk for Alzheimer’s disease
Authors: Lizarraga Aldana , Kassinopoulos Michalis , González‐de‐Echávarri José María , Huguet Jordi , Sánchez‐Benavides Gonzalo , Brugulat‐Serrat Anna , Suarez‐Calvet Marc , Milà‐Alomà Marta , Blennow Kaj , Zetterberg Henrik , Kollmorgen Gwendlyn , Quijano‐Rubio Clara , Molinuevo Jose Luis , Gispert Juan Domingo , Cacciaglia Raffaele ,   ALFA study
Published: January 2025

AbstractBackgroundCognitive Reserve (CR) refers to the brain's ability to maintain optimal cognitive function despite damage or pathology. The neural implementation of CR is a major research focus, and resting‐state functional connectivity (RSFC) has emerged as a promising imaging correlate of CR. We assessed RSFC as a function of two different proxy measures of CR and further assessed the impact of these brain networks on longitudinal cognitive performance in a sample of cognitively unimpaired (CU) individuals at risk of Alzheimer's disease (AD).MethodAnalyses were conducted in 328 CU individuals from the ALFA cohort (mean age=60.8, SD=4.74) with available CSF Aβ, p‐tau, resting‐state fMRI and longitudinal cognitive assessment (average follow‐up time=3.35 years, SD=0.53). CSF Aβ42 and Aβ40 were assessed with the exploratory NeuroToolKit, while p‐tau181 was measured with the Elecsys® Phospho‐Tau (181P) CSF immunoassay (both Roche Diagnostics International Ltd). We examined the impact of years of education (YOE) and global score of the Cognitive Reserve Questionnaire (CRQ) on the RSFC amongst 246 brain regions of the Brainnetome atlas using the CONN toolbox, selecting a cluster threshold of p<0.005, and adjusting or the effects of age, sex, and APOE status.ResultOf the entire sample, 38.4% had positive CSF Aβ42/40 markers. YOE was related to an increased RSFC between regions of the salience network and the anterior default‐mode network (DMN). Increased negative RSFC was found as a function of YOE between primary visual areas and regions of the executive control as well as dorsal attention (Figure 1). In models adjusted by CSF biomarkers, the increased RSFC between the anterior DMN and salience regions predicted better PACC score over time and further modulated the association between CSF Aβ42/40 and longitudinal PACC (Figure 2). CRQ score was associated with a decreased RSFC between the posterior DMN and inferior temporal areas. These patterns of reduced RSFC significantly mediated the impact of CSF Aβ42/40 on longitudinal memory performance (Figure 3).ConclusionRSFC may provide insights into the mechanisms relating CR and cognitive resilience in preclinical AD. Further, the expression of RSFC patterns may serve as an outcome in intervention studies aiming to boost CR.
Brain metabolic alterations associated with cognitive resilience
Authors: Li Jun , Capuano Ana W. , Bennett David A. , Liang Liming , Arvanitakis Zoe , Grodstein Francine 
Published: January 2025

AbstractBackgroundCognitive resilience (CR) refers to the continuum from worse to better‐than‐expected cognition, given the degree of neuropathology. Understanding mechanisms underlying CR could inform discovery of novel targets for dementia prevention; however, specific metabolic pathways underlying CR are yet to be elucidated.MethodsOur study included 484 deceased participants (mean age at death =91 years, 70.2% women) from the Religious Orders Study and Rush Memory and Aging Project. Metabolomics profiling was conducted at Metabolon Inc. by a chromatography–mass spectrometry in postmortem dorsolateral prefrontal cortex tissue, yielding 600 known metabolites quantified for analysis. Antemortem cognitive function was assessed annually by 17 neuropsychologic tests through death, and neuropathologies were evaluated in postmortem brain. CR was defined as the residual slope of cognitive decline after controlling for age at death, sex, education, and nine Alzheimer’s disease, other neurodegenerative, and cerebrovascular neuropathologies. We analyzed the associations between individual brain metabolites and CR score using linear regressions. We also constructed co‐regulatory networks for metabolites significantly related to CR, and identified key metabolites for CR within each network using recursive conditional analysis.ResultsWe identified 72 metabolites whose levels in the prefrontal cortex were associated with CR (FDR<0.05), encompassing diverse biochemical categories including 33 amino acids and peptides, 21 lipids, 7 cofactors and vitamins, 6 carbohydrates/energy metabolites, and 5 others. Based on partial correlations, the 72 CR‐related metabolites were constructed into 6 co‐regulatory networks, each linked to specific biological functions including oxidative stress (key metabolites driving the associations were N‐acetylmethionine sulfoxide, ergothioneine, and carotene diol), synaptic function (led by myo‐inositol, glycerate, and docosahexaenoyl ethanolamide), neuroinflammation (led by 7‐hydroxycholesterol), cell signaling (led by inositol 1‐phosphate and gamma‐glutamylthreonine), phospholipid metabolism (led by glycerophosphorylcholine), and energy/glucose metabolism (led by UDP‐glucose and adenosine monophosphate). The eigenvectors of all 6 co‐functional networks were significantly associated with CR (FDR<0.05).ConclusionWe identified brain metabolites implicated in oxidative stress and necroinflammation, synaptic function and cell signaling, and lipid/energy metabolism, associated with rates of cognitive decline after controlling for neuropathologies. These CR‐related metabolites may inform the discovery of novel targets for improving cognitive resilience to neuropathology.