bluuebunny/crossref_metadata_2025_split huggingface dataset:
The impact of late‐onset epilepsy as a co‐occurring condition of Alzheimer’s disease on tau levels in older adults with Down syndrome
Authors: Queder Nazek , McMillan Liv , Sathishkumar Mithra , Taylor Lisa M. , Keator David B. , Doran Eric , Hom Christy L. , Krinsky‐McHale Sharon J. , Petersen Melissa , O'Bryant Sid E. , Brickman Adam M. , Head Elizabeth , Mapstone Mark , Silverman Wayne , Lott Ira T. , Yassa Michael A. 
Published: January 2025

AbstractBackgroundThere is an increased risk of epilepsy in Down syndrome (DS), especially after the age of 40. The onset of this co‐occurring disease is closely associated with Alzheimer’s disease (AD) related cognitive deterioration. Therefore, understanding the impact of late‐onset epilepsy on AD biomarkers in people with DS is crucial. Here, we aim to test the difference in tau levels and hippocampal volume in people with late‐onset seizures, childhood‐onset seizures, and no seizures.MethodWe analyzed data from 54 participants (52 +/‐ 6.5 years, 66% females) with DS enrolled in the Alzheimer’s disease Down syndrome study. A total of 18 participants had a history of seizures: 9 participants had recent onset of seizures in the last 5 years and 9 participants had childhood‐onset of seizures. A 2‐to‐1 match method was used to identify 36 control match participants based on age, sex, and dementia status. Magnetic resonance imaging (MRI) and flortaucipir (FTP) positron emission tomography (PET) were used to assess atrophy and tau accumulation respectively. Plasma ptau181 levels were assessed using the ultra‐sensitive single molecule array (Simoa) technology platform HDX imager. ANOVA was used to assess group differences.ResultThe results showed significant differences in ptau181 levels between individuals with late‐onset seizure disorder, individuals with childhood‐onset of seizures, and controls (F(2,51)= 9.649; p<.001). Post‐hoc analysis revealed that individuals with late‐onset seizure disorder had significantly higher levels of ptau181 compared to individuals with childhood‐onset (p<.001) and controls (p = 0.002), with no differences between childhood‐onset seizures and controls. No differences were observed in the hippocampus volume among the three groups. Differences in the temporal meta‐ROI tau SUVR were assessed in a subset of our sample. We observed a trend in individuals with history of seizures showing higher tau SUVR in the temporal meta‐ROI compared to controls.ConclusionOur findings suggest that the levels of ptau181 could be impacted by late‐onset seizure disorder. These results shed the light on the importance of assessing the impact of co‐occurring disorder on AD related biomarkers. Future research will explore the impact of late‐onset seizure disorder on AD‐related brain biomarkers longitudinally.
Endocrinological aging drives alterations in white matter architecture: Evidence from a humanized APOE risk model of Alzheimer’s disease
Authors: Raikes Adam C. , Bhattrai Avnish , Wang Tian , Brinton Roberta Diaz 
Published: January 2025

AbstractBackgroundAlzheimer’s affects women 2:1 compared to men, suggesting sex‐specific factors driving risk. Menopause, a female‐specific phenomenon, induces a multi‐system response across endocrine, metabolic, and immune‐inflammatory systems. Despite known effects on these systems, the impact on the brain and AD risk remains incompletely understood, limiting preventative options. Here, we investigated the impact of the menopausal transition on white matter properties in a late‐onset AD mouse model.Methods6‐, 9‐ and 15‐month humanized APOEε3/ε3 (JAX #29018), ε4/ε4 (JAX #27894), and ε3/ε4 (bred in‐house) female mice were stratified into endocrine aging groups based on vaginal cytology profiles: regular (consistent 4–5 day cycles) or irregular (6–9 day cycles) cyclers or acyclic (no cycling >9 days). Ex‐vivo diffusion‐weighted imaging was used to analyze white matter fiber density (FD), cross‐section (FC), and their product (FDC), in addition to anisotropy (FA) and diffusivity (MD). Data were analyzed using generalized additive models with the main effects of endocrine aging (ref: 9‐month regular), hAPOE genotype, and total brain volume (except FD). Findings are reported at FDR corrected p<0.05.ResultsCompared to 9‐month regular cyclers, both 6‐month regular and 15‐month acyclic mice had lower FC, primarily in bilateral fimbria, stria terminalis, corpus callosum, and gray matter regions, including bilateral hippocampal subfields and cingulate cortex (15‐month acyclic mice only). 15‐month acyclic mice showed lower FD/FDC in the left cingulate, piriform, and bilateral entorhinal cortices and greater FD/FDC in the bilateral habenular commissure and dorsal tenia tecta. FA and MD were significantly lower in the 15‐month acyclic mice in most white matter regions. Compared to 15‐month irregular cyclers, 15‐month acyclic mice exhibited lower FA in white matter tracts and striatal projection fibers.ConclusionsIn these mice, menopause, rather than age or APOE genotype, altered white matter bundle properties, shifting toward smaller bundles of varying compactness and reduced bundle coherence. Pronounced differences were seen between 9‐month pre‐menopausal and 15‐month post‐menopausal mice. Differences between peri‐ and post‐menopausal mice at 15 months were only observed in FA. These findings implicate endocrine aging as a driving factor in white matter changes that may precede AD presentation. Ongoing work is focused on conducting translational analyses in the human brain.
Genome‐wide association of Amyloid imaging and plasma biomarkers in Adults with Down Syndrome
Authors: Aslam Muhammad Muaaz , Fan Kang‐Hsien , Dang Lam‐Ha T , Gorijala Priyanka , Shi Ruyu , Feingold Eleanor , Xicota Laura , Cohen Ann D , Handen Benjamin L , Christian Bradley T. , Head Elizabeth , Mapstone Mark , Cruchaga Carlos , Lee Joseph H. , Kamboh M. Ilyas ,   Alzheimer’s Biomarker Consortium – Down Syndrome (ABC‐DS)
Published: January 2025

AbstractBackgroundAdults with Down Syndrome (DS) are at higher risk for Alzheimer's disease (AD) compared to the general population due to trisomy of chromosome 21. Thus, it is important to investigate the role AD‐related biomarkers in adults with DS. Here we have performed genome‐wide association analyses on amyloid‐PET and plasma amyloid levels in the participants of the Alzheimer’s Biomarker Consortium – Down Syndrome (ABC‐DS).MethodGenome‐wide analyses were performed on 294 non‐Hispanic whites with DS (ranging in age from 25 to 81, Male 54.8%) having biomarker data from amyloid‐PET imaging and plasma levels of Aβ40, Aβ42, and the Aβ42/Aβ40 ratio. The association of two APOE SNPs, rs429358 (E4) and rs7412 (E2) was also examined. We used a joint model of multiple phenotypes to investigate the genetic factors contributing to all amyloid biomarkers levels simultaneously in those participants having the complete phenotypic and genotypic data.ResultAPOE4 was not associated with any Aβ biomarker, but APOE2 was significantly associated with lower Amyloid‐PET levels compared to those without APOE2 (p=0.0002). Genome‐wide association analyses identified multiple genome‐wide significant (GWS) hits including six SNPs for amyloid PET (rs532620170 on chr1, p=2.93E‐09; rs144406757 on chr3, p=3.49E‐08; rs1880432 on chr7, p=4.76E‐08; rs143578940 on chr7, p=4.95E‐09; rs8024654 on chr15, p=1.40E‐08; and rs148455801 on chr19, p=5.98E‐09), one SNP for Aβ40 on chromosome 2 (rs78338676, p=1.50E‐08) and one SNP for Aβ42/Aβ40 ratio also on chromosome 2 (rs75126438, p=1.37E‐08). The multiple amyloid phenotype analysis revealed 14 independent GWS loci on chromosomes 2, 4, 5, 7, 8, 10, 12, 15, and 16, indicating a robust association with both imaging and plasma Aβ biomarkers.ConclusionDespite the limited number of sample of DS, we identified a total of 22 potential GWS loci associated with Aβ. These findings highlight the potential of research with the DS population as a valuable resource for identifying genetic elements contributing to AD pathology.
Generalizability of Alzheimer’s disease plasma biomarkers phospho‐Tau and beta amyloid in individuals of diverse genetic ancestries
Authors: Griswold Anthony J. , Rajabli Farid , Gu Tianjie , Arvizu Jamie , Golightly Charles G. , Whitehead Patrice L. , Hamilton‐Nelson Kara L. , Adams Larry D. , Celis Katrina , Celis Katrina , Sanchez Jose Javier , Mena Pedro R. , Starks Takiyah D. , Illanes‐Manrique Maryenela Z. , Silva‐Vergara Concepcion , Cuccaro Michael L. , Vance Jeffery M. , Feliciano‐Astacio Briseida E. , Cornejo‐Olivas Mario , Byrd Goldie S. , Beecham Gary , Haines Jonathan L. , Pericak‐Vance Margaret A 
Published: January 2025

AbstractBackgroundPlasma concentrations of phosphorylated threonine‐181 of Tau (pTau181) and the ratio of amyloid beta isoforms Aβ42/Aβ40 are biomarkers for differential diagnosis and preclinical detection of Alzheimer disease (AD). However, assessment of the utility of these biomarkers has been in non‐Hispanic, European individuals. Given differences in AD risk across populations, generalizability of these findings is not assured in individuals of diverse ancestries. Here we evaluate the levels of plasma pTau181 and Aβ42/Aβ40 and assess their utility in discriminating clinically diagnosed AD from cognitively unimpaired (CU), age‐matched controls in ancestrally diverse, admixed cohorts.MethodWe measured pTau181 and Aβ42/Aβ40 with Simoa chemistry using the pTau181 AdvantageV2 and NEUROLOGY 3‐PLEX A assays, respectively. Our cohorts consisted of: 923 African Americans (319 AD, 604 CU), 149 Peruvians (49 AD, 100 CU), and 667 Caribbean Hispanics (613 Puerto Ricans (288 AD, 325 CU) and 54 Cubans (24 AD, 30 CI)). Linear mixed‐effect regression models adjusted for age, sex, population substructure and relatedness followed by Bonferroni correction was applied to identify biomarker differences. Diagnostic performance and receiver operator characteristic (ROC) curves were created from logistic regression models.ResultPlasma pTau181 concentrations did not differ across any of the cohorts within AD or CU. There was a clear elevation of pTau181 concentration in AD compared to CU (p < 1.7x10‐13) taking into account all individuals and in each cohort separately (African Americans, p =1.9x10‐8; Caribbean Hispanics, p=3.1x10‐7; Peruvians, p=0.05). There was no significant difference in the plasma Aβ42/Aβ40 ratio, however there was a trend towards a decreasing ratio in AD. Using the area under the ROC, pTau181 was more accurate at predicting status than the Aβ42/Aβ40 ratio, but the classification improved when both biomarkers were combined.ConclusionThese results suggest AD biomarkers are generalizable across ancestries, with baseline values being consistent across diverse populations. Ultimately, combining genomic, biomarker, and social and environmental data from diverse individuals will increase understanding of genetic risk and refine clinical diagnoses in individuals of diverse ancestries.
Development of the set of resource use items to capture costs related to informal care for people with Rare Dementia for RD‐TALK
Authors: Cullen Katherine , Brotherhood Emilie V , Fitzsimmons Deborah , Stott Joshua 
Published: January 2025

AbstractBackgroundNon‐memory‐led dementias pose additional challenges to ‘typical dementias’ including unusual symptoms and younger onset leading to particularly high neuropsychiatric comorbidities. As part of the economic evaluation supporting the RD‐talk research programme, we require the collection of participant level resource use associated with the intervention compared with usual care. The resource use measure (RUM) needs to be sufficiently comprehensive, but still focused to capture the key items of interest (e.g., main drivers of resource use and associated cost) to balance the trade‐off between precision, effort, and burden to research participant.MethodInitial discussion with carers of people with non‐memory‐led dementia and clinical experts informed a draft list of resource items to design a RUM. A modified Delphi survey was carried out with informal carers and healthcare professionals (HCPs). Consensus of each item, using pre‐defined levels to keep or remove items, was summarised using descriptive statistics and percentage agreement. Inter‐rater reliability between rounds was assessed using the intra‐class correlation coefficient; the stability of the raters’ responses was assessed with the Wilcoxon signed rank test.ResultFor round one, 18 participants were recruited (11 HCPs, 9 carers), 14 participants remained for round two (7 HCPs, 7 carers). For primary/community care, general practitioner appointments, psychological interventions (such as talking therapy), and rare dementia support groups or direct calls were all highly rated by both HCPs and carers. The RUM should include time taken off work or taking early retirement due to caring for someone with rare dementia. Categories of caring tasks were listed, from personal care and physical help, to helping with paperwork, financial matters, dealing with care services and benefits, and managing challenging behaviour. All categories were highly rated by HCPs and carers.ConclusionResource use measures are mainly designed for the person with a disease or condition and focus on health and social care use. There can be a considerable burden on informal carers when someone is diagnosed with rare dementia, and it is important to capture key resource items in addition to health and social care relevant to this population when evaluating interventions in rare dementia management.
CU PET Aβ and Tau Positive Individuals Show Impairment in MoCA Delayed Recall
Authors: Felix Cynthia , Ferreira Pamela C.L. , Kollasserry Felix Joy , Snitz Beth E. , Rebok George , Tudorascu Dana , Rodrigues Matheus Scarpatto , Oliveira Markley , Povala Guilherme , Lemaire Peter , Bauer‐Negrini Guilherme , Medeiros Marina Scop , Abbas Sarah , Soares Carolina , Aguzzoli Cristiano Schaffer , Bellaver Bruna , Lussier Firoza Z , Amaral Livia , Pascual Belen , Gordon Brian A. , Lowe Val J. , Oh Hwamee , soleimani‐meigooni David N. , Klunk William E , Rosa‐Neto Pedro , Jagust William J. , Baker Suzanne L. , Pascoal Tharick A. 
Published: January 2025

AbstractBackgroundIdentification of cognitively unimpaired (CU) individuals who may progress to mild cognitive impairment (MCI), is a pressing issue in the Alzheimer’s disease (AD) field, since therapeutic interventions may be more effective in the absence of cognitive impairment and neurodegeneration. CU individuals positive for amyloid and tau PET are very likely in the AD pathway. In out‐patient cognitive screening, we use rapid and simple tests such as The Montreal Cognitive Assessment (MoCA) ‐ a composite of executive, visuospatial, naming, attention, language, abstraction, delayed recall, and orientation performances. We hypothesize that sub‐categorizing the CU group based on the presence of amyloid (A) and tau (T) pathologies, as measured by PET, can reveal subtle cognitive deficits, even in a clinical test with low sensitivity such as MoCA.MethodWe included 88 CU [defined as CDR global score of 0] older adults with available head‐to‐head MK6240 tau‐PET and Flortaucipir tracers from the ongoing HEAD multi‐site observational study. They also underwent Amyloid PET imaging using PiB or NAV4694. MoCA testing was done around the imaging time. To increase similarity with clinical practice, Amyloid and Tau PET positivity was defined using visual reads. Based on tracer uptake status, we categorized the individuals into A‐T‐, A‐T+, A+T‐ and A‐T‐ groups. Unpaired t‐test and one‐way ANOVA were used to test for significant differences between groups.Result2‐tailed p‐values were significant between the A‐T‐ group and the A+T+ group for MoCA total score [p: 0.0025 and p: 0.0025]. When we stratified MoCA in the different cognitive domains, we found that the results were driven by MoCA (memory) Delayed Recall score [p: 0.0007 and p: 0.0162]. A‐T+ vs A+T+ was also significant [p: 0.0099] for MoCA Delayed Recall. Both tau tracers (MK6240 and Flortaucipir) showed similar performance for determining T+ and identifying cognitive decline.ConclusionMoCA, a simple and commonly administered in‐office neuropsychological test, can detect subtle cognitive dysfunction in CU older adults who are Aβ and tau positive (A+/T+). These CU A+/T+ individuals are likely on the path to developing AD dementia.
Sex Differences in the Risk of Alzheimer’s Disease and Associated Risk Factors Among Aging Hispanics: A Cross‐country Study
Authors: Xu Yuexuan , Reyes‐Dumeyer Dolly , Weinfeld Cory , Piriz Angel , Sanchez Danurys , Soriano Belisa , Franco Yahaira , Coronado Zoraida Dominguez , Recio Patricia , Mejia Diones Rivera , Medrano Martin , Lantigua Rafael A. , Vardarajan Badri N. , Mayeux Richard 
Published: January 2025

AbstractBackgroundHispanics, one of the fastest‐growing populations in the United States, are disproportionately affected by Alzheimer’s disease (AD). Understanding the variations in AD risk associated with sex and the impact of relocation from their home country is crucial in designing interventions to address health disparities. This study explores the differential impact of sex and geographic relocation on dementia risk and its associated factors among Hispanics.MethodWe utilized data from two observational samples, encompassing 4,960 individuals from the Estudio Familiar de la Influencia Genética en Alzheimer (EFIGA), primarily based in the Dominican Republic, and 2,614 individuals enrolled in the Washington Heights‐Hamilton Heights‐Inwood Community Aging Project (WHICAP), based in the US. In both, we evaluated AD‐related risk factors and biomarker concentrations by sex and disease status, using two‐sample t‐tests and chi‐squared tests. We assessed AD risk across the full sample and conducted sex‐stratified logistic regression analyses, along with linear regression to compare biomarker concentrations and disease onset age among sexes.ResultsIn the EFIGA study, the risk of AD was found to be lower among women (Odds Ratio [OR] = 0.86, 95% Confidence Interval [CI]: 0.75‐0.98), whereas in WHICAP, no significant sex‐based differences were observed. Concerning the age of onset, women in EFIGA exhibited an earlier onset (β = ‐1.42, p < 0.001), contrasting with a later onset in WHICAP (β = 1.02, p = 0.007). In the sex‐stratified analyses, both men (OR = 1.66, 95% CI: 1.32‐2.09) and women (OR = 1.64, 95% CI: 1.40‐1.91) in EFIGA showed distinct associations of AD with APOE ε4, a pattern only seen among women in WHICAP (OR = 1.34, 95% CI: 1.06‐1.68). With respect to biomarker concentrations, sex‐related differences were noted in Ab42/40 ratio, total tau, phosphorylated tau, glial fibrillary acidic protein, and neurofilament light, although the specific patterns varied between WHICAP and EFIGA.ConclusionSex‐related differences in AD risk and associated factors among Hispanics, were evident in both EFIGA and WHICAP studies, and are potentially further influenced by geographic relocation and migration patterns.
Heneicosapentaenoic acid, a metabolite resulting from the α‐oxidation of α‐Hydroxy‐Docosahexaenoic Acid, exerts neuroprotection against Alzheimer’s disease and reduces astrocytic mitochondrial activity
Authors: Cabot Joan , Parets Sebastià , Miralles Marc , Trujillo‐Estrada Laura , Gutierrez Antonia , Fernández‐García Paula , Lladó Victoria , Escriba Pablo V. , Torres Manuel 
Published: January 2025

AbstractBackgroundReactive astrocytes and neuron death by excitotoxicity are observed in Alzheimer’s disease (AD). DHA‐H (2‐hydroxy‐docosahexaenoic acid; 2‐OH‐C22:6 n‐3) is a molecule under development that has demonstrated therapeutic efficacy in both cellular and 5xFAD mouse model of AD. DHA‐H is metabolized through α‐oxidation to yield HPA (Heneicosapentaenoic acid; C21:5 n‐3). This metabolic conversion is considered necessary for the neuroprotective effect of DHA‐H.MethodsCognitive evaluation was assessed by Radial Arm Maze in 5xFAD mice after 4 months of chronic oral treatment at a daily dose of 20 mg/kg (DHA‐H or HPA). The transformation of DHA‐H to HPA was analyzed in HEK293 cells and in 5xFAD mice by GC‐FID or GC‐MS (Gas Chromatography‐Flame Ionization Detector or Mass Spectrometry). Neuroprotective effect of DHA‐H and HPA was tested in neuron cells differentiated from SH‐SY5Y neuroblastoma cells that were stimulated with NMDA (N‐Methyl‐D‐Aspartate)/Ca to induce excitotoxicity in the presence or absence of oxythiamine (α‐oxidation inhibitor). ATP level reduction was measured with the ATP luminescence assay system ATPlite (Perkin Elmer) while mitochondrial function was assessed by measuring the oxygen consumption rate (OCR) with the Seahorse Cell Mito Stress Test kit (Agilent Technologies).ResultsChronic oral administration of DHA‐H or HPA prevented cognitive decline in 5xFAD mice. DHA‐H is converted to HPA via α‐oxidation in cells and mice. HPA accumulates in 5xFAD mice brain instead of DHA‐H after DHA‐H treatment. Both DHA‐H and HPA prevented NMDA/Ca‐induced neuron death and the neuroprotective effect of DHA‐H was partially reversed in the presence of oxythiamine. HPA decreased ATP production and mitochondrial respiration capacity in astrocytoma cells.ConclusionsThe metabolic intermediate HPA, stemming from the α‐oxidation of DHA‐H, emerges as a prospective candidate for Alzheimer’s therapy. Although the mechanism of action behind its neuroprotective effect is still unknown, here we study the effect of HPA on ATP production and mitochondrial respiratory capacity in astrocytes as a possible mechanism.
Renal Atrophy Relates to Brain Volume Loss on 7,149 MRI Scans
Authors: Meysami Somayeh , Raji Cyrus A. , Hashemi Sam , Garg Saurabh , Akbari Nasrin , Gouda Ahmed , Chodakiewitz Yosef Gavriel , Nguyen Thanh Duc , Niotis Kellyann , Merrill David A. , Attariwala Rajpaul 
Published: January 2025

AbstractBackgroundRenal atrophy may reflect an end organ consequence of chronic vascular disease. Renal volume loss may therefore provide a window into brain aging and Alzheimer disease risk.MethodWe obtained whole‐body 1.5T MRI scans on 7,149 healthy individuals across four sites. The participants had a mean age of 53.06 ± 12.95 years (age range: 18‐97 years), with a gender distribution of 48% women and 52% men; 38% were non‐white. Deep learning with FastSurfer on 3D T1 volumetric MPRAGE trained on 134 participants aged 27‐66 and segmented 96 brain regions. Whole body sequences included coronal T1 that allowed for separate segmentation and quantification of renal volumes. Partial correlation analysis controlling for sex and total intracranial volume was done on kidney volumes and the following brain regions: tissue types, lobar structures and Alzheimer disease risk regions – hippocampus, precuneus, and posterior cingulate gyrus. Renal volumes were normalized to the aggregate abdominal organ volumes and tissues such as the liver, spleen and abdominal fat. Multiple comparisons were corrected for with the Bonferroni method.ResultLower renal volumes were correlated with lower gray matter volumes (rp = ‐0.229, p = 5.18×10−85) as well as total white matter volume (rp = ‐0.204, p = 2.51×10−67). The cerebral ventricles, demonstrated a moderate positive correlation with lower renal volumes (rp = 0.099, p = 5.28×10−16) reflective of a generalized parenchymal volume loss. Lower renal volumes also predicted lower lobar volumes in: frontal lobe (rp = ‐0.204, p = 3.34×10−67), temporal lobe (rp = ‐0.236, p = 9.76×10−90), parietal lobe (rp = ‐0.215, p = 2.69×10−74), and occipital lobe (rp = ‐0.207, p = 8.29×10−69), all showed significant negative correlations with lower renal volumes. Lower renal volumes also correlated to lower volumes in AD risk regions: the Hippocampus (rp = ‐0.203, p = 2.89×10−66) and posterior cingulate (rp = ‐0.18, p = 3.06×10−52), precuneus (rp = ‐0.171, p = 8.00×10−47).ConclusionThis study demonstrates a strong relationship in a large sample between lower renal volumes and reduced volumes in various brain regions, including gray matter, white matter, and specific lobar structures, as well as Alzheimer's disease risk regions.