bluuebunny/crossref_metadata_2025_split huggingface dataset:
Creating human locus coeruleus organoids to study the role of the locus coeruleus in Alzheimer’s disease
Authors: Tish Margaret M , Birey Fikri , Weinshenker David , Ou Zihui 
Published: January 2025

AbstractBackgroundThe locus coeruleus (LC), is the first brain region to develop hyperphosphorylated tau (ptau) inclusions in Alzheimer’s disease (AD) and undergoes catastrophic degeneration in later stages of the disease. Importantly, the LC is the main noradrenergic nucleus in the brain and source of NE in the forebrain, and dysregulation of the neurotransmitter norepinephrine (NE) is associated with AD symptoms, as its release in the forebrain regulates attention, arousal, stress response, and learning and memory. Moreover, the LC may transmit pathogenic tau to the forebrain via its extensive projections. However, nearly all information about the LC in AD has been derived from rodent models and postmortem or human imaging studies. It is not known how the early ptau accumulation in the human LC affects neuronal function, NE transmission, or pathology propagation. We created organoids, which are 3D human cell culture models derived from human induced pluripotent stem cells, that possess many aspects of human LC structure.MethodOrganoids containing neurons resembling the LC were generated from human induced pluripotent stem cells using growth factors that induce a hindbrain fate. These organoids were then characterized using HPLC, immunohistochemistry, RNA‐scope and RNA‐sequencing.ResultLC organoids contained higher levels of norepinephrine and dopamine than cortical organoids. They also expressed many of the proteins and RNA that are indicative of and enriched LC‐NE neurons, including tyrosine hydroxylase, dopamine beta‐hydroxylase, the NE transporter, Phox2A, and Phox2B. Additionally, bulk RNA‐seq revealed that compared to cortical organoids, the LC organoid transcriptome more closely resembled the human LC.ConclusionLC organoids are distinct from cortical organoids and contain many markers of human LC neurons. Studying the structure and function of LC organoids derived from both healthy controls and AD patients may provide new insights into the role of the LC in AD.
P‐tau217 significance as marker of brain Abeta and tau pathologies
Authors: Barthélemy Nicolas R. , He Yingxin , Salvadó Gemma , Janelidze Shorena , Li Yan , Ghoshal Nupur , Mukherjee Soumya , Horie Kanta , Spina Salvatore , VandeVrede Lawren , Paterson Ross W. , Perrin Richard J. , Benzinger Tammie L.S. , Boxer Adam L. , Gabelle Audrey , Sato Chihiro , Schindler Suzanne E. , McDade Eric , Gordon Brian A. , Hansson Oskar , Bateman Randall J. 
Published: January 2025

AbstractBackgroundP‐tau217 has emerged as a compelling alternative to long‐established p‐tau181 to accurately measure tau modifications in biofluids in response to brain Abeta and tau deposition in Alzheimer’s disease (AD). Understanding the specificity and significance of p‐tau217 changes over AD stages is critical to interpret its potential response to treatments against Abeta and tau aggregation.MethodsWe measured p‐tau217 phosphorylation by mass spectrometry. We analyzed brain, cerebrospinal fluid (CSF) and plasma samples from participants with late‐onset AD (LOAD), dominantly‐inherited AD (DIAD) and primary tauopathies.ResultsSoluble and insoluble tau species extracted from LOAD and DIAD brains are p‐tau217 hyperphosphorylated [1‐2]. P‐tau217 abundance in insoluble tau extracts from AD and most primary tauopathies associates with brain tau aggregates level. In LOAD CSF and plasma, slight p‐tau217 phosphorylation changes are detected in response to early Abeta deposition in participants without cognitive symptoms [3‐4]. Early Abeta‐associated changes are observed in DIAD around 20 years before symptoms onset [5]. Subsequently, p‐tau217 increases with brain Abeta build‐up until cognitive symptoms onset. At asymptomatic stages, CSF and plasma p‐tau217/tau ratio better associates with Abeta PET than p‐tau concentration [3,6]. While brain Abeta deposition plateaus at symptoms onset, we observe p‐tau217 increases and significantly associates with Tau PET. This association weakens then disappears at dementia stage when p‐tau217 decreases. Finally, abnormal soluble p‐tau217 is observed sporadically in participants with primary tauopathies in absence of Abeta positivity [7].ConclusionsP‐tau217 is a highly accurate marker of Abeta deposition. The strong association between p‐tau217 and Abeta PET, when tau PET remains negative, supports tau hyperphosphorylation is a neuronal response to Abeta pathology independent from tau aggregation. On the other hand, p‐tau217 associates with tau‐PET at prodromal AD stage and occasionally changes in participants with primary tauopathies free of amyloid deposition. This corroborates soluble p‐tau217 also increases because of the presence of brain tau aggregates. The duality of p‐tau217 response to amyloid and tau pathology in AD complicates its utility as marker of tau aggregation. Lastly, plasma p‐tau217 use as a single marker of Abeta positivity may expose to risk of false positive AD diagnosis for patients with primary tauopathies.
Younger Age of First Exposure to American Football is Associated with Worse Informant‐Reported Clinical Outcomes in Older Age
Authors: Nosek Sophia , Gil Stephanie Gonzalez , Nowinski Christopher J. , Tripodis Yorghos , Martin Brett , Palmisano Joseph N. , Cantu Robert C. , Stern Robert A. , Huber Bertrand Russell , Stein Thor D. , McKee Ann C. , Mez Jesse , Alosco Michael L. , Daneshvar Daniel H. 
Published: January 2025

AbstractBackgroundExposure to repetitive head impacts (RHI) is associated with the neurodegenerative tauopathy chronic traumatic encephalopathy (CTE). There is substantial heterogeneity in the clinical presentation of CTE. Younger age of first exposure (AFE) to American football has not been associated with odds or severity of CTE. Yet, it has been associated with earlier onset and severity of symptoms, potentially by decreasing resilience to RHI‐related neuropathologies. We examined the association between AFE to football and clinical and neurobehavioral outcomes in deceased football players across the age continuum.MethodsThe sample included 677 male football players who donated their brains to the UNITE Brain Bank. Informants of brain donors completed modified scales assessing donor cognitive function (Cognitive Difficulties Scale [CDS], BRIEF‐A Metacognition Index [MI]), daily function (Functional Activities Questionnaire [FAQ]), mood (Geriatric Depression Scale‐15 [GDS‐15], Beck Anxiety Inventory [BAI] Apathy Evaluation Scale [AES]), and neurobehavioral dysregulation (Barratt Impulsiveness Scale [BIS‐11], BRIEF‐A Behavioral Regulation Index [BRI], Brown‐Goodwin Aggression Scale Adult Sum). Dementia was adjudicated through consensus conferences. Neuropathologists were blinded to clinical history. Global p‐tau burden was calculated by summing semi‐quantitative ratings of p‐tau severity across nine brain regions. Regressions tested the association between AFE and each scale, dementia status, and CTE status. Analyses were performed stratified by age 60 to isolate the effect of neurodegenerative disease resilience adjusting for age, global p‐tau burden, and duration of football play.ResultsSample characteristics are in Tables 1‐2. Most donors played football in college and/or professionally (n = 509, 76%). CTE was the most common neuropathological diagnosis (n = 471, 70%). AFE was not associated with CTE neuropathology. Global tau and age were consistent predictors of the clinical scales (Table 3). There were significant associations between AFE and the clinical scales among those older but not younger than age 60. Among those over age 60, younger AFE to football was associated with higher CDS (p = 0.02), BRIEF‐A MI (p = 0.02), and BIS‐11 (p = 0.03) scores.ConclusionsYounger AFE was associated with worse informant‐reported clinical outcomes in older but not younger deceased football players, independent of tau. Youth exposure to RHI from football might decrease resilience to cope with neuropathologies later in life.
Decision‐Making Capacity and Awareness in People with Young‐Onset Alzheimer´s Disease
Authors: Dourado Marcia C. N. , Souza Nataie , Belfort Tatiana , Nogueira Marcela Moreira Lima , Baptista Maria Alice , Baptista Maria Alice 
Published: January 2025

AbstractBackgroundThere is a lack of research on differences between decision‐making capacity and awareness according to age at onset of dementia. We investigated the relationship between decision‐making capacity and awareness domains in people with young‐ (YOAD) and late‐onset Alzheimer´s Disease (LOAD).MethodA cross‐sectional study included 169 consecutively selected people with AD and their caregivers (124 people with LOAD and 45 people with YOAD).ResultPeople with YOAD were more cognitively impaired, but more aware of their cognitive deficits and health condition, with moderate effect sizes. All people with AD presented deficits in the domains of decision‐making capacity, with more impairment in understanding. There was a relationship between understanding and awareness domains, such that awareness was particularly important for decision‐making capacity in the YOAD group.ConclusionBetter awareness involved better understanding in the YOAD group. Clinically, our findings shed light on the need to consider the differences in the domains of awareness and their relationship with other clinical aspects such as decision‐making capacity according to age at onset of AD.
Multi‐omics assessment of genotype and sex‐specific effects of organochlorine pesticide DDT in humanized APOE mice
Authors: Mhatre‐Winters Isha , Eid Aseel , Zhan Jiada J , Hart Ronald P , Barahona Arturo J , Tran ViLinh , Han Yoonhee , Go Young‐Mi , Jones Dean P , Richardson Jason R 
Published: January 2025

AbstractBackgroundThe Apolipoprotein‐E (APOE) ε4 gene variant is the strongest genetic risk factor for late‐onset Alzheimer’s Disease, but is not entirely predictive. Emerging evidence suggests environmental factors contribute to disease etiology, with epidemiological studies associating pesticide exposure with lower cognitive scores. Dichlorodiphenyltrichloroethane (DDT), a pesticide used extensively in the US until 1972, persists in trace amounts due to its long half‐life, bioaccumulation, and existing dumpsites. We have previously reported that DDT induces AD pathology in multiple models and also shown increased serum levels of DDE, the primary metabolite of DDT, in AD patients, where APOE genotype modified MMSE scores and contributed a ∼4‐fold increase in AD risk. Here, we sought to identify the mechanism(s) by which APOE4 genotype alters pathological response to DDT by a multi‐omics approach.MethodTo assess the effects of DDT exposure, three‐month‐old male and female APOE3 (E3) and APOE4 (E4) mice were exposed to 3 mg/kg DDT by oral gavage every 3 days for 5 months. Hippocampus was dissected out and frozen for RNA‐sequencing and metabolomic analysis, while serum was collected for metabolomic analysis and biomarker measurement.ResultRNA‐sequencing analysis between genotypes of female DDT‐exposed mice indicated significantly downregulated pathways and functions (p<0.05) in the hippocampus of E4‐females, including phosphatidylserine decarboxylase activity and neuron projection. Similarly, DDT‐exposed E4‐males indicated downregulation of ion channel regulator activity, nucleotide binding, cell‐cell and synaptic signaling, and neuron projection. Further, untargeted metabolomic analysis of DDT‐exposed mice was compared. Top pathways (p<0.05) altered in E4 vs. E3 female‐DDT hippocampus were carnitine shuttle and glycolysis‐gluconeogenesis, while serum changes included TCA cycle and tryptophan metabolism. In E4 vs. E3 male‐DDT, hippocampal alterations included purine metabolism, fatty acid mitochondrial beta‐oxidation, TCA cycle, glycolysis, and carnitine shuttle, while serum changes involved cholesterol biosynthesis, TCA cycle, and glycolysis‐gluconeogenesis. Finally, DDT increased serum neurofilament light chain (NfL) levels, a biomarker for neurodegeneration, by 1.9 and 2.1‐fold in E4‐male and E4‐female mice compared to respective controls. NfL was 1.4‐fold higher in DDT‐exposed E4‐females compared to E4‐males.ConclusionThese data demonstrate gene‐by‐environment interactions modified by sex, providing a platform to investigate mechanisms in AD‐related neurodegeneration and corroborating previous epidemiological findings.
Validation Study of A Three‐Minute Game‐Based Cognitive Screening Tool For Detecting Cognitive Impairments In Chinese Older Adults
Authors: Wu Jingnan , Li Yatian , Zhou Zhixing , Xia Huanhuan , Chen Nan , Guo Qihao 
Published: January 2025

AbstractBackgroundGame‐based Cognitive Assessment – 3‐Minute Version (G3) is a WeChat mini‐program developed for the early screening of cognitive impairments in Chinese older adults. It consists of three game‐like digital cognitive tests, namely “Number Ordering”, “Species Sorting”, and “Gold Finding”. This study aims to assess the sensitivity, specificity, and diagnostic accuracy of G3 in detecting mild cognitive impairment (MCI) and early‐stage dementia in Chinese older adults.MethodBetween February and December 2023, a total of 475 older adults (aged 50 to 89 years) with subjective cognitive complains were recruited. Participants underwent G3 assessment, neuropsychological assessments, neuroimaging, and blood tests. Among them, 230 individuals were diagnosed with cognitive impairments, including MCI and early‐stage dementia, while the remaining 245 older adults exhibited healthy cognition. We compared the G3 performance between the two groups. And the receiver operating characteristic (ROC) curve of G3 were evaluated with sensitivity and specificity calculated.ResultThe average G3 scores (mean ± standard deviation) in the healthy cognition group (63.2±13.04) were significantly higher than impaired cognition group (41.3±12.50, p<0.001). In both groups, the mean G3 scores tended to decline with increasing age. Meanwhile, the decline was more significant in the impaired cognition group compared to the healthy cognition group (Figure 1). G3 demonstrated high diagnostic accuracy in detecting individuals with MCI or early‐stage dementia, with an area under the ROC curve (AUC) of 0.887 (95% confidence interval [CI] = 0.859‐0.916, Figure 2). The optimal cut‐off score for G3 was determined to be 59.5, with a sensitivity of 0.913 and specificity of 0.624.ConclusionG3 WeChat mini‐program is a precise and user‐friendly screening tool that exhibits high sensitivity and diagnostic accuracy in detecting early‐stage cognitive impairment among community‐dwelling seniors. Further multicenter research is needed to verify the diagnostic value of G3 for different stages and types of cognitive impairments.
Whole‐Genome Sequencing Study in Koreans Identifies Novel Loci for Alzheimer Disease
Authors: Kang Moonil , Farrell John J. , Zhu Congcong , Park Hyeonseul , Kang Sarang , Seo Eun Hyun , Choi Kyu Yeong , Jun Gyungah R , Won Sungho , Gim Jungsoo , Lee Kun Ho , Farrer Lindsay A. 
Published: January 2025

AbstractBackgroundWith a rapidly aging population, South Korea anticipates a surge in Alzheimer disease (AD). However, the genetic basis of AD in Koreans is not well understood.MethodWe sequenced the genomes of 3,540 Koreans (1,583 AD cases and 1,957 controls) older than age 60 and performed a genome‐wide association study (GWAS) of AD using logistic regression models that included covariates for age, sex, five ancestry principal components, and an empirical genetic relationship matrix. We also conducted association tests in subgroups stratified by APOE ε4 status or sex. Findings from the Korean sample were combined with results from two Japanese GWAS datasets using the inverse‐variance meta‐analysis method. We also performed gene‐based tests of aggregated rare variants in the Korean dataset. Novel findings were evaluated by pathway enrichment analysis and by differential gene expression analysis in brain tissue from controls and AD cases who were either cognitively impaired or healthy prior to death.ResultWe identified genome‐wide significant (GWS) associations (P < 5.0 × 10‐8) with two well‐established AD loci (APOE and SORL1) in the total sample and with one novel locus, ROCK2 (rs76484417, P = 2.71 × 10‐8) among APOE ε4 non‐carriers. Another novel study‐wide significant association (P < 2.47 × 10‐6) was found with aggregated rare variants in MICALL1 (P = 9.04 × 10‐7). We also observed suggestive associations (P < 1.0 × 10‐6) with 14 novel loci (MSX1, BCL11A, ARMH3, CTNNA3, YTHDF1P1, GRM3, LINC02479, LRCH1, COL9A1, TTC8, MCTP2, DLGAP2, TBC1D32, and EXD2). Expression of several novel genes, including ROCK2 and MICALL1, was significantly different in multiple cortical regions in AD cases compared to controls (P < 3.33 × 10‐3). ROCK2 was also differentially expressed between AD cases with and without cognitive impairment (P = 1.34 × 10‐4).ConclusionWe identified GWS and suggestive association for AD with several loci in Koreans and Japanese not previously observed in other populations. Our results provide additional insight into genetic mechanisms leading to AD and cognitive resilience, as well as emphasize the need for further genetic studies of East Asian populations.
Pathway‐specific polygenic risk score analysis to explore the inverse association between cancer and Alzheimer’s disease neuropathologic changes
Authors: AUNG KHINE ZIN , Wu Xian , Abner Erin L. , Nelson Peter T. , Karanth Shama D , Fardo David W. , Katsumata Yuriko 
Published: January 2025

AbstractBackgroundRecent research reported that cancer patients had lower risk of Alzheimer’s disease (AD). Common signaling pathways, hormonal systems, and genetic predispositions have been hypothesized as important factors contributing to this inverse association. However, the exact mechanisms are still unknown. Polygenic risk scores (PRS) represent genetic susceptibility and are useful for disease genetic risk prediction. To date, there have been no published findings connecting cancer with AD through PRS. In this study, we investigated the genetic association between various types of cancer and AD/ADRD using biological pathway specific PRS.MethodWe obtained phenotype data from the National Alzheimer’s Coordinating Center (NACC), genotype data from the Alzheimer’s Disease Genetics Consortium (ADGC), and summary statistics for five cancers (liver, lung, prostate, breast, colon cancers) from the United Kingdom (UK) Biobank. We mapped genes to each of the 18,826 Gene Ontology (GO) categories for Homo sapiens and discovered 7,300 biological processes comprised of groups of three or more genes. We removed the APOE region and analyzed the associations between AD and each cancer by using pathway specific PRS. AD neuropathologic changes were evaluated by NACC neuropathology (NP) data including Thal phase, Braak NFT Stage (B0 = no NFTs, B1 = Stage I or ll, B2 = Stage IIl or IV and B3 = V or Vl) and CERAD score (density of neocortical neuritic plaques: C0 = No neuritic plaques, C1 = Sparse neuritic plaques, C2 = Moderate neuritic plaques, C3 = Frequent neuritic plaques).ResultThe most significant biological processes were cell cycle related pathways, apoptotic pathways, angiogenesis, and neurodevelopmental pathways between C scores and B scores (Table 1). Angiogenesis and atherosclerosis pathways were positively significant in TDP‐43 and cerebrovascular pathologies respectively.ConclusionWhile selection and survival bias cannot be completely ruled out, disruptions of specific biological pathways may contribute to the observed inverse relationship of cancer and AD. Further research may clarify the underlying mechanisms between AD and cancer inverse relationship by incorporating with cancer PRS.
AlphaFold 2 predicts a markedly different MTBR conformation for 3‐repeat and 4‐repeat tau isoforms
Authors: Chain Daniel G , Margolin Richard A , Pollack Scott , Goncalves Maria Beatriz de Castro V. 
Published: January 2025

AbstractBackgroundTau abnormalities are a central feature of Alzheimer’s disease (AD) and the defining feature of non‐AD tauopathies, which include frontotemporal lobar degeneration (FTLD) due to Pick’s disease (PiD) or Mapt mutations (FTLD‐tau), as well as progressive supranuclear palsy (PSP), corticobasal degeneration (CBD) and others. Mapt transcripts undergo alternative splicing to produce 6 distinct isoforms. Exon 2 splicing produces 0, 1 or 2 inserts; exclusion or inclusion of exon 10 results in 3‐repeat (3R) or 4‐repeat (4R) forms, respectively. These forms are differentially present in tauopathies, e.g., 3R in PiD; 4R in almost all FTLD‐tau, PSP, and CBD; and equal 3R/4R in AD. 3R tau is reported to have lower microtubule binding affinity and a higher propensity to form soluble oligomers. Combining structural modeling of tau by AlphaFold 2 (AF2) with biochemical analyses may illuminate the impact of repeat and insert differences. While tau is considered generally disordered, AF2 modeling of 4R tau that we performed predicted a mainly ordered structure for the MTBR from Leu243 to Asp368. Biochemically, we found that the MTBR conformation is altered by some FTD associated mutations and caspase‐3 cleavage. In the present study, we studied the MTBR conformations for the 6 isoforms.MethodWe first analyzed FASTA sequences of the tau isoforms by AF2 and aligned them based on the predicted MTBR conformations. We then compared intramolecular distances between selected MTBR residues.ResultAbsence of the second repeat in 3R tau causes a dramatic difference in the MTBR conformation compared to 4R tau. Specifically, the inward fold N‐terminus to Pro301 is lost, thereby producing an “open” conformation (Figure, b vs a). The number of inserts does not affect the conformation of 4R tau (Figure, d vs. a) but significantly alters that of 3R tau (Figure, c vs. b).Conclusion3R tau’s open MTBR conformation may explain its increased propensity to oligomerize and suggests the possibility of additional binding sites that may increase the interactome compared to 4R tau. The absence of the inward fold in 3R tau suggests that this region may be important for microtubule binding.