bluuebunny/crossref_metadata_2025_split huggingface dataset:
Novel quantitative method for characterization of hippocampal sclerosis and its association with other neuropathologies and cognitive deficits
Authors: Sordo Lorena , Qian Tianchen , Nguyen Katelynn M. , Bukhari Syed A. , Woodworth Davis C. , Montine Thomas J. , Head Elizabeth , Corrada María M. M. , Kawas Claudia H. , Sajjadi S. Ahmad 
Published: December 2023

AbstractBackgroundHippocampal sclerosis of aging (HS) is characterized by neuronal loss and astrogliosis in subiculum and/or CA1 subfield of hippocampus. Using a novel quantitative approach, we studied the prevalence and localization of HS pathology in a well‐characterized oldest‐old cohort and examined its association with other neuropathologic changes and cognitive impairment.MethodsWe studied 409 consecutive autopsied participants of The 90+ Study with longitudinal assessments. In those with HS by traditional method (presence/absence), we used digitized hematoxylin and eosin and luxol fast blue hippocampal slides for further quantitative analysis. Using QuPath, we measured the length of each hippocampal subfield partitioned into three subregions (Figure1). We then calculated the proportion affected by HS for each subregion. Both traditional (presence/absence) and quantitative (subfield‐specific proportions) measures were used to study the relationship between HS and other neuropathologic changes and cognitive outcomes using regression models adjusted for sex, age at death, and education with all neuropathologic changes as covariates.ResultsHS was present in 11% of participants and was always focal, mostly affecting CA1 (89%), followed by subiculum (27%). Overlapping CA1/subiculum pathology was seen in 16% (Figure2). Left‐sided HS was more frequent (75%) than right‐sided (18%). Bilateral cases were the least frequent (7%). HS presence (traditional measure) was only associated with Limbic‐predominant age‐related TDP‐43 encephalopathy (LATE) (OR = 3.45, p<0.001). Quantitative measures revealed that HS proportion in subiculum and CA1 was associated with arteriolosclerosis (t36 = 4.11, p = 0.001) and LATE (t35 = 2.98, p = 0.005). HS proportion in subiculum alone was inversely associated with microvascular lesions (t41 = ‐3.16, p = 0.003) (Table1). HS proportion in subiculum and CA1 was associated with dementia at death and impairment of memory, language, calculation, and orientation. HS proportion in subiculum was additionally associated with impaired executive function. HS traditional measure was only associated with impaired orientation (Table1).ConclusionBased on our novel quantitative analysis, HS pathology was always focal, mostly unilateral, and associated with dementia and impairment in major cognitive domains. We found associations between HS and vascular pathologies that were not detected using traditional measure. The associations of HS with dementia and impaired memory, language, and calculation, identified with our quantitative method, were not detected using traditional measure.
Sex‐specific effects of genetically predicted BMI and education on risk of AD
Authors: Andrews Shea J , Chao Michael J , Fulton‐Howard Brian , Pa Judy , Yaffe Kristine , Goate Alison 
Published: December 2023

AbstractBackgroundExamining sex differences on the impact of modifiable risk factors in Alzheimer’s disease (AD) risk can help us better understand the mechanisms underlying sex differences in the prevalence and incidence of AD. Here, we used polygenic risk scores (PRS) and Mendelian randomization (MR) to investigate sex‐specific effects of sleep duration, insomnia, blood pressure, diabetes, alcohol intake, smoking, body mass index, high cholesterol, and education on AD risk.MethodWe obtained combined and sex‐stratified genome‐wide association study (GWAS) summary statistics for each risk factor from the UK Biobank and used them as the base dataset for constructing PRS and exposure datasets in the MR analysis. Linkage disequilibrium clumping was performed to identify independent genome‐wide significant single nucleotide polymorphisms (SNPs) across the sex‐combined, male‐specific, and female‐specific GWAS. The combined lead SNPs were then weighted by their strata‐specific effect sizes in the stratified PRS and MR analyses. PRS were constructed for each risk factor in participants from the Alzheimer’s Disease Genetics Consortium. Linear regression was used to investigate the association of each PRS with AD risk, adjusting for age, principal components, and cohort. MR was used to estimate sex‐stratified causal effects of each risk factor on AD. Sex differences in PRS associations and MR causal estimates were determined using Fisher’s Z score method.ResultsAssociation testing of the PRS with AD risk in sex stratified cohorts revealed that the BMI PRS was associated with differential effects in men and women (OR [95%CI]: males: 1.05 [1.00, 1.10] vs females: 0.96 [0.93, 0.99], p = 0.003). Furthermore, the university completion PRS was non‐significant in men but was associated with reduced risk in women (OR [95%CI]: males: 0.96 [0.92, 1.01] vs females: 0.92 [0.89, 0.96], p = 0.12). In the follow‐up MR analysis, university completion was also causally associated with reduced risk in women only (OR [95%CI]: males: 1.09 [0.77, 1.53] vs females: 0.55 [0.42, 0.72], p = 0.002) (Figure 1). No other risk factors showed evidence of sex‐differences.ConclusionOur study found sex‐specific effects of genetically predicted BMI and educational attainment on AD risk. These findings suggest the need for sex‐specific approaches to AD prevention and management.
TMS‐based measures of cortical excitability are related to distributed atrophy in early Alzheimer’s disease
Authors: Buss Stephanie S. , Zeng Victor , Manning Daniel , Touroutoglou Alexandra , Dickerson Brad C. , Press Daniel Z. , Shafi Mouhsin , Pascual‐Leone Alvaro , Fried Peter J. 
Published: December 2023

AbstractBackgroundAlzheimer’s disease (AD) is associated with increased cortical excitability, including an elevated risk of seizures. Transcranial magnetic stimulation with electromyography (TMS‐EMG‐EEG) can be used to index intracortical excitability. Prior work has shown that TMS‐based excitability measures are altered in AD and are related to disease severity. However, it is not yet known how TMS‐EMG measures are related to neurodegeneration within brain regions affected by AD.MethodTMS‐EMG was applied to left motor cortex (M1) in 22 participants with biomarker‐confirmed mild cognitive impairment due to AD (early AD, aged 70.5±8.4, 11 females). Single pulse TMS was preformed to measure resting motor threshold (RMT) and motor evoked potential amplitude (MEP Amplitude). Paired‐pulse TMS was preformed to measure short interval intracortical inhibition (SICI, GABA‐ergic) and intracortical facilitation (ICF, glutamatergic). In 5 participants, TMS‐evoked responses on EEG were also obtained during single‐pulse stimulation to M1 and the inferior parietal lobe (IPL), and the local mean field amplitude (LMFA) was computed from 15 to 40 msec after the TMS pulse. Structural MRI scans for each participant were processed using Freesurfer to obtain cortical thickness measurements within the distributed Alzheimer‐signature brain regions (AD‐signature atrophy). The primary analyses tested the relationship between each TMS measure and AD‐signature atrophy using separate linear models, controlling for age. For TMS‐EEG analysis, effect sizes were reported in lieu of p‐values given the small sample sizes.ResultIn early AD, SICI was related to AD‐signature atrophy (R2
adj = 0.40, B = ‐0.13, p = 0.018; Fig1), with less intracortical inhibition related to greater atrophy. RMT, MEP Amplitude, and ICF were not related to AD‐signature atrophy (p‐values>0.105). There was a large effect size of IPL LMFA on AD‐signature atrophy (R2
adj = 0.70), while the effect size of M1 was small (R2
adj = ‐0.19).ConclusionDecreased intracortical inhibition is related to increased AD‐signature atrophy in early AD. Decreased function of GABA‐A circuitry related to cortical atrophy may play a role in the development of cortical hyperexcitability in AD. Our preliminary results further suggests that TEPs from stimulation of IPL, a node of the default mode network and an area commonly showing AD pathology, may also be related to AD‐signature atrophy.
Sex‐specific associations of gene expression in brain with Alzheimer’s disease pathology and cognitive performance
Authors: Clifton Michelle , Seto Mabel , Buckley Rachel F. , Gifford Katherine A. , Jefferson Angela L. , De Jager Philip L , Bennett David A. A , Barnes Lisa L. , Wang Yanling , Schneider Julie A , Hohman Timothy J. , Dumitrescu Logan C 
Published: December 2023

AbstractBackgroundAlzheimer’s disease (AD) disproportionately affects women, who make up two‐thirds of all clinical cases of AD. While sex differences in AD neuropathology, the response to pathology, and the genetic predictors of clinical AD have been well described, sex differences in the brain transcriptomic signatures of AD endophenotypes have not been fully characterized.MethodsWe leveraged bulk RNA‐sequencing data from three brain regions (dorsolateral prefrontal cortex (DLPFC), posterior cingulate cortex, and caudate nucleus from the Religious Orders Study and Rush Memory and Aging Project (ROS/MAP). Propensity scoring was used to match male to female participants due to disproportionate sample size. As a result, there were 791 participants (50% male; mean age at death = 87.6 years). Sex‐stratified and sex‐interaction (int) regression models assessed sex‐specific transcript associations with amyloid and tau burden, along with longitudinal global cognition. Age at death, latency to death, and post‐mortem interval were included as covariates. Sex‐specific genes were defined as related to a trait in one sex (FDR‐corrected P<0.05) but not in the other sex and that showed evidence of a sex‐modifying effect (Pint<0.05).ResultsOf the more than 20,000 significant autosomal gene expression associations with the three AD endophenotypes, 11% were sex‐specific with DLPFC having largest number of sex‐specific genes (7%). Despite equivalent percentages of males and females, we observed more female‐specific effects (10%) than male‐specific effects (1%) (Figure 1). Several genes showed particularly strong effects among females, including LRIG3 with amyloid (Pmen = 0.20, Pwomen = 3.34×10−06, Pint = 0.017) and tau tangles (Pmen = 0.34, Pwomen = 0.008, Pint = 0.008), and SLC22A17 with amyloid (Pmen = 0.8, Pwomen = 1.63×10−04, Pint = 0.02) and tau tangles (Pmen = 0.18, Pwomen = 4.81×10−05, Pint = 0.04). There were 16 genes with male‐specific associations with at least two traits including FAIM2 (Pmen = 9.9×10−4, Pwomen = 0.49, Pint = 0.004), ATP13A2 (Pmen = 8.3×10−5, Pwomen = 0.68, Pint = 0.002), and PRSS35 (Pmen = 7.5×10−5, Pwomen = 0.64, Pint = 0.02) (Figure 2).ConclusionOur results highlight sex‐specific transcriptomic associations with AD endophenotypes, including genes for protein misfolding and neurotrophic signaling among females and for neuron apoptotic involvement among males. Similar sex‐specific patterns with AD were observed in independent AMP‐AD cohorts for LRIG3, SLC22A17, and FAIM2 (https://agora.adknowledgeportal.org/).These findings highlight the exciting potential of precision medicine approaches that consider sex‐specific biological pathways to select new targets for mechanistic evaluation.
Sex differences in plasma p‐tau181 accumulation is associated with subsequent tau‐PET signal
Authors: Hsieh Stephanie , Townsend Diana , Coughlan Gillian T , Boyle Rory , Klinger Hannah M , Seto Mabel , Hanseeuw Bernard J , Yang Hyun‐Sik , Amariglio Rebecca E. , Hassenstab Jason J. , Hohman Timothy J. , James Bryan D , Risacher Shannon L , Properzi Michael J , Schultz Aaron P. , Baker Suzanne L. , Sperling Reisa A. , Buckley Rachel F. 
Published: December 2023

AbstractBackgroundPET and post‐mortem studies show that women consistently exhibit higher medial‐temporal and neocortical tau compared to men, independent of age or diagnostic status. What remains unclear is whether such sex differences are also observed in the plasma biomarkers and related to future tau‐PET deposition. We examined baseline and longitudinal phosphorylated‐tau (plasma p‐tau181‐UGOT), which was derived prior to a tau‐PET scan, in order to determine whether changes in p‐tau181 are associated with higher regional tau‐PET in women relative to men.MethodWe selected 313 participants (clinically normal, n = 169; MCI/dementia, n = 144) from ADNI (Female% = 146(46%); AgeMean = 71(±7)years; APOEe4 = 105(34%); Ab+ = 162(52%)) with at least two timepoints of plasma p‐tau181‐UGOT measured in ADNI1/2/GO (time‐pointsMean = 3.7(±1)). Cross‐sectional Ab‐PET and tau‐PET (Flortaucipir) scan were collected in ADNI3 ((time‐difference from baseline plasmaMean = 7.1y(±1.9)). Two a priori tau‐PET partial volume corrected (PVC) regions were selected: entorhinal (EC) and inferior temporal (IT). We used linear regression to examine the influence of baseline p‐tau181 and sex on subsequent tau‐PET, adjusting for time gap between plasma‐PET and tau‐PET. Linear mixed‐effects models probed how retrospective change in plasma tau were associated with regional tau‐PET and sex, covarying for neocortical Ab‐PET, diagnosis, APOEe4 and age. We also examined interactions between sex and variables of interest.ResultBaseline p‐tau181 was strongly associated (b = 0.86 and b = 0.53) with subsequent tau‐PET, although sex did not display main effects in the model, nor did sex moderate the plasma‐PET association. Longitudinal p‐tau181 was not associated with subsequent tau‐PET. Women with accumulating p‐tau181 exhibited higher subsequent tau‐PET burden in EC and IT regions than men (p = 0.04 and p = 0.03, respectively; Figure 1). Higher‐order interactions between sex and tau‐PET with APOEe4, diagnosis or Ab‐PET were not significant, although, women diagnosed with MCI/dementia and elevated Ab seemed to drive the interaction (Figure 2).ConclusionElevated tau‐PET burden in women may be more strongly associated with prior increases in plasma p‐tau181 relative to men. Given the pre‐established association between p‐tau181 and Ab, this could be initial evidence that early events related to the deposition of Ab predict later cortical tau deposition in a sex‐specific manner. Given the novelty of examining longitudinal plasma measures, further investigation is necessitated beyond this preliminary evidence.
Synergistic effects of age at menopause and vascular risk on cognitive decline in postmenopausal women
Authors: Wood Madeline 
Published: December 2023

AbstractBackgroundMenopause‐related estrogen depletion is linked to greater vascular risk, Alzheimer’s disease (AD) pathology, and dementia risk in women. Age‐at‐menopause and vascular risk may together influence the likelihood of developing AD in women. We investigated whether earlier menopause and elevated vascular risk independently or synergistically contribute to cognitive decline in postmenopausal women compared to men.MethodWe used data from the Canadian Longitudinal Study on Aging. We included 7,678 postmenopausal women (mean age = 64.6±8.49 years, mean age‐at‐menopause = 50.1±5.02 years) and 7,678 age‐matched men (mean age = 64.6±8.49 years). Sex was operationalized using self‐reported sex at birth. Vascular risk was calculated using a summary score tallying the presence/absence of hypertension, diabetes, smoking, obesity, cardiovascular disease, and stroke. Participants completed cognitive assessments at baseline and 3‐year follow‐up. Self‐reported age‐at‐menopause was categorized into tertiles: early (<49), average (49‐52), and late (>52). Linear models tested independent and interactive effects of age‐at‐menopause and vascular risk on 3‐year cognition, adjusting for baseline cognition, baseline age, education, APOE4, and test language (English/French).ResultIn women, vascular risk and age‐at‐menopause were independently associated with cognitive decline (vascular risk: β = ‐0.107, p<.001). Relative to average age‐at‐menopause, early menopause was associated with greater cognitive decline (β = ‐0.026, p = .03), whereas late menopause was associated with less decline (β = 0.025, p = .04). In men, vascular risk was also associated with greater cognitive decline (β = ‐0.112, p<.001). Next, we examined synergistic effects of age‐at‐menopause and vascular risk in postmenopausal women. Early (vs. average) menopause and elevated vascular risk interacted to accelerate cognitive decline (β = ‐0.224, p = .002). There was no interaction between late (vs. average) menopause and vascular risk (β = ‐0.073, p = .3). In a model comparing sexes (Figure 1), vascular risk was more strongly associated with cognitive decline in women with early menopause compared to men (β = ‐0.127, p = .03). In women with average or late menopause, associations of vascular risk with cognitive decline did not significantly differ from men (average: β = ‐0.010, p = .07; late: β = ‐0.024, p = .7). Sensitivity analyses additionally adjusting for physical activity, race/ethnicity, depression, alcohol, and hormone therapy yielded similar results.ConclusionEarly menopause and vascular processes may synergistically contribute to increased AD risk in women. These findings have implications for sex‐specific dementia prevention strategies.
Cortical microinfarcts along the Alzheimer’s disease continuum in adults with Down syndrome ‐ an update
Authors: Aranha Mateus Rozalem , van den Brink Hilde , Bejanin Alexandre , Montal Victor , Pegueroles Jordi , Carmona‐Iragui Maria , Videla Laura , Benejam Bessy , Valldeneu Sílvia , Barroeta Isabel , Altuna Miren , Fernandez Susana , Garzón Diana , Padilla Concepcion , Iulita M. Florencia , Alcolea Daniel , González‐Ortiz Sofía , Blesa Rafael , Sánchez‐Valle Raquel , Biessels Geert Jan , Lleó Alberto , Fortea Juan 
Published: December 2023

AbstractBackgroundCortical microinfarcts (CMI) are emerging biomarkers of vascular damage associated with cognitive decline and are frequent in sporadic AD (sAD) patients. However, no study assessed CMI in Down syndrome (DS), a genetically determined form of AD. Therefore, we aimed to assess CMI’s frequency in adults with DS, sAD, and cognitively unimpaired euploid controls and its relationship with age, sex, clinical status, and APOE ε4 carriership.MethodCross‐sectional study. We included 175 participants with 3T‐MRI: 64 with DS (39 asymptomatic [aDS], 11 prodromal AD [pDS], and 14 AD‐dementia [dDS]), 62 with sAD (41 prodromal AD, 21 AD dementia), and 49 controls. A neuroradiologist blind to participants’ data visually analyzed the 3T‐MRI images following a validated protocol to detect CMI (Figure 1). We compared CMI’s prevalence in the different clinical groups along the AD continuum in DS and sAD, in APOE ε4 carriers vs. non‐carriers, and males vs. females using Chi‐square, Mann‐Whitney, or Kruskal‐Wallis tests when appropriate.ResultCMI’s prevalence was 7.8% in DS (5.1% in aDS, 21.4% in pDS, and 0% in dDS [p = 0.085]), 17.7% in sAD (22.0% in prodromal AD and 9.5% in AD dementia [p = 0.389]), and 10.2% in controls (p = 0.207). CMI frequency increased with age in DS, sAD, and controls (Table 1). Regarding sex, CMI’s frequency was 10% in men and 5.9% in women with DS (p = 0.884), and 27.3% in men and 12.5% in women with sAD (p = 0.267). In controls, CMIs’ frequency was 10% in men and 10.3% in women (p = 1.000). Regarding APOEε4 carriership, CMI’s prevalence was 21.4% in APOEε4 carriers and 9.1% in non‐carriers in sAD (p = 0.428), 8.7% in carriers and 6.0% in non‐carriers in DS (p = 1.000), and 8.3% in carriers and 8.6% in non‐carriers controls (p = 1.000) (Table 2).ConclusionCMI’s prevalence increased with age, but was not different in DS, sporadic AD, and controls. Also, sex and APOEε4 carriership did not impact the prevalence of CMI in the three study groups.
Fibrillar tau induces blood brain barrier permeability, endothelial cell activation and bioenergetic alterations
Authors: Guzman‐Hernandez Roberto A , Fossati Silvia 
Published: December 2023

AbstractBackgroundAlzheimer’s Disease, the most common form of dementia, is characterized by the accumulation of amyloid‐beta plaques and neurofibrillary tangles formed by hyperphosphorylated tau in the brain, leading to neuronal loss and cognitive decline. The neurovascular unit, a complex system of several cell types surrounding brain vessels, is extremely important for blood flow regulation, amyloid and tau clearance, and proper brain function. Tau aggregates produced by neurons and glial cells reach endothelial cells (EC) at vessel walls by tau spreading. Currently, the mechanisms responsible for the effects of tau on ECs remain to be understood. We hypothesize that aggregated tau fibrils mediate alterations in bioenergetics in these cells, associated to pro‐inflammatory EC activation, BBB permeability and eventually EC death.MethodImmortalized human brain microvascular endothelial cells (D3) and primary human cerebral endothelial cells (hCECs) were challenged with aggregated 1N4R tau fibrils (5nM‐25nM) for 3‐72h. Trans‐endothelial electrical resistance (TEER) was measured by the ECIS Zθ system as an in vitro model of the BBB. Cytokine production and release was assessed using a V‐Plex Neuroinflammatory Panel 1 (MSD). We performed immunocytochemical analysis of junction protein expression and western blotting for EC activation markers. EC bioenergetics were measured by Seahorse Extracellular Flux Analyzer and EC death was determined by Cell Death Elisa and LDH Release (Roche).ResultTEER was reduced following incubation with fibrillar 1N4R tau. VCAM‐1 expression significantly increased with 25nM tau (24h) and 5nM (48h), and ICAM‐1 followed similar trends. Junction protein (ZO‐1, VE‐Cadherin) expression was decreased. Aggregated tau (25nM) caused an increase in glycolysis at 24‐hours, which reverted at further timepoints, whereas mitochondrial ATP production increased (48h) and then decreased (72h). After 72h treatment, 25nM tau induced a significant increase in apoptotic cell death and LDH release, yet no significant changes in cell death were observed at previous timepoints.ConclusionOur results suggest that tau fibrils mediate a stress response with a metabolic shift in ECs, in association with pro‐inflammatory EC activation. These molecular changes can contribute to BBB permeability and eventually cell death, further exacerbating cerebrovascular dysfunction.