bluuebunny/crossref_metadata_2025_split huggingface dataset:
Platelet aggregation and ApoE genotypes in the Framingham Heart Study
Authors: Cejudo Jaime Ramos , Figueredo Luisa F , Scott Matthew R , Lu Sophia , Beiser Alexa S , Ghosh Saptaparni , Osorio Ricardo S. , Wisniewski Thomas , Berger Jeffrey S , Seshadri Sudha , Johnson Andrew D 
Published: January 2025

AbstractBackgroundApolipoprotein (Apo) E4, a main susceptibility gene for Alzheimer’s disease (AD) is associated with increased vascular dysfunction, amyloid pathology, and neurodegeneration. The effector pathways leading to increased vascular risk in ApoE4 carriers needs to be established. Platelet aggregation is a key marker of vascular dysfunction and studies need to examine whether a relationship of ApoE4 allele status and platelet biology existsMethodWe examined cross‐sectional associations of platelet aggregation with ApoE genotypes (E2 or E4 against E3, the most common) in middle‐aged cognitively normal participants at the Framingham Heart Study (FHS) Gen3, New Offspring Spouse (NOS), and Omni2 Cohorts. Status was determined by PCR and defined as E4 when at least one copy of the E4 allele was present, or E2 when at least one copy of the E2 was present, after excluding E4 cases. The primary outcome was the platelet aggregation response to 0.98uM ADP stimulation measured by light transmission aggregometry, and additional agonists and stimulation doses were used for sensitivity. Linear regression models adjusted for age, sex, race, CVD risk, and the use of platelet modifying treatments (PMT) were used. Interactions with the same covariates were also examined. Data from the FHS Gen2 Cohort containing platelet aggregation and ApoE status was used for validation.ResultThe final primary sample included 3,169 participants (median [Q1, Q3] age, 55 [48, 61]; 54.2% women) of which 22.1% were on PMT. (Table 1). 716 (22.6%) were ApoE4 positive and 402 were E2 (16.4% of the sample after excluding E4). Being an ApoE4 carrier was not associated with platelet aggregation (β±SE: 0.41±1.05, P>0.05). ApoE2 was also not associated (‐0.72±1.33, P>0.05) (Figure 1). No associations with the secondary outcomes or interactions with covariates were detected. No associations were observed in the external validation cohort (n = 2,469)ConclusionOur results in a middle‐aged cohort indicate that the ApoE genotypes (E2 and E4) are not associated with platelet aggregation. The pathways leading to increased vascular dysfunction in ApoE4 carriers may not involve platelet activity, at least in midlife
Evidence of recent evolutionary selection at eQTLs for APOE
Authors: Ciesielski Timothy H , Tosto Giuseppe , Durodoye Razaq O , Rajabli Farid , Akinyemi Rufus O. , Pericak‐Vance Margaret A , Haines Jonathan L. ,   Alzheimer’s Disease Genetics Consortium (ADGC), Williams Scott M 
Published: January 2025

AbstractBackgroundLate‐onset Alzheimer Disease (LOAD) risk and prevalence differ by ancestral group. Furthermore, the frequency of APOE‐4 and its effect size on LOAD risk also differ by ancestry group. If these patterns are a function of evolutionary history, we may find ancestry group‐specific evidence of recent selection at the APOE locus or APOE eQTLs. This could provide us with additional insights into APOE function, specifically its pleiotropic effects and ethnic specific mechanisms of disease.MethodsWe used chromosome 19 sequence data from 2,504 unrelated individuals in 26 populations from the latest release of the 1000 Genomes Data (phased 30x coverage build 38 data), and we ran separate selection analyses in each population. We calculated two selection measures based on Extension of Haplotype Homozygosity (EHH): iHS (integrated haplotype score) and nSL (number of segregating sites by length). Scores were then normalized in bins of similar allele frequency (AF) to account for frequency effects on EHH. Loci in the top 1% of |iHS| and |nSL| scores were considered evidence of selection.ResultsAmong the two SNPs defining the APOE isoforms and 27 SNPs defining APOE EQTLs (29 sites in total) we observed 9 APOE eQTLs in the top 1% of iHS and three in the top 1% of nSL. Two SNPS demonstrated evidence of selection in both scores: rs1628394 in Kinh Vietnamese (in a SIPA1L3 intron) and rs2909088 in Han Chinese (in a ZFP30 intron). Neither of the APOE SNPs showed evidence of selection in any population.ConclusionsWe identified evidence of recent natural selection in APOE eQTLs in two East Asian populations: rs1628394 in Kinh Vietnamese and rs2909088 in Han Chinese. Prior work has established that rs1628394 is nominally associated with LOAD (p = 2.45 × 10‐3) and the genome Aggregation Database indicates that it is common in Africans (AF = 0.63), less common in Europeans (AF = 0.33), and least common in East Asians (AF = 0.13). The second SNP, rs2909088, is not associated with LOAD, but it is also less common in East Asians (AFEuropean = 0.87, AFAfrican = 0.69, and AFEastAsian = 0.38). Recent selection at rs1628394 may be enhancing the impact of APOE4 on LOAD development in Kinh Vietnamese.
Elevated tau in the piriform cortex in Alzheimer’s but not Parkinson’s disease using MR‐PET
Authors: Taghavi Hossein Moein , Karimpoor Mahta , van Staalduinen Eric , Leventis Samantha , Young Christina B. , Carlson Mackenzie L. , Davidzon Guido A. , Romero America , Trelle Alexandra N. , Zaharchuk Greg , Vossler Hillary , Rosenberg Jarrett , Poston Kathleen L. , Wagner Anthony D. , Henderson Victor W. , Georgiadis Marios , Mormino Elizabeth , Zeineh Michael 
Published: January 2025

AbstractBackgroundOlfactory deficiency can be present in preclinical Alzheimer’s (AD) and Parkinson’s disease (PD), predicting their subsequent manifestation, including mild cognitive impairment (MCI). Analyzing key regions within the olfactory circuit could reveal important insights into the neuropathological progression. Dysfunction in the olfactory circuit has been shown in the olfactory nerve in limited postmortem studies, including involvement of a key region, the piriform cortex. FDG‐positron emission tomography (PET) and fMRI have shown differential and reduced piriform cortex metabolism/activation in AD. Thus, the piriform cortex is a promising candidate in the early identification of neurodegenerative pathology underlying olfaction. We used tau MR‐PET to analyze the piriform cortex, in comparison to the adjacent medial temporal lobe.MethodWe analyzed 115 subjects: 23 were excluded (incomplete data), leaving 31 amyloid‐negative and 25 amyloid‐positive healthy controls, 8 MCI, 15 AD, and 13 PD. All subjects underwent MR‐PET using tau tracer PI‐2620 with a simultaneous coregistered sagittal T1‐weighted 3D IR‐FSPGR and a simultaneous/recently acquired coronal T2‐weighted FSE. Automatic Segmentation of Hippocampal Subfields was performed, including the entorhinal‐perirhinal cortices (Fig. 1D‐F). Referencing published piriform segmentation guidelines, we manually segmented blind to subject diagnosis the frontal/temporal portions of the piriform cortex (Fig. 1C), including multiple independent quality control checks. As tau distributions appeared non‐normal among the five ordinal patient categories (Amyloid–HC, Amyloid+HC, MCI, AD, Normal PD), we used a nonparametric Jonckheere‐Terpstra test in Stata to test for ordinal increase in tau uptake across four regions bilaterally (whole hippocampus = CA1‐4 + DG + subiculum, entorhinal‐perirhinal, amygdala, and piriform).ResultWe found an ordinal increase in piriform tau uptake with increasing disease severity (amyloid‐negative controls, amyloid‐positive controls, MCI and AD) (Figure 2A‐D). Amyloid‐positive controls showed significantly greater uptake than amyloid‐negative controls. Piriform uptake was not elevated in cognitively unimpaired PD compared to Amyloid‐HC. Piriform volume was statistically equivalent across groups, except PD had lower volumes (Figure 2E‐H). Negative correlations were present between memory performance and piriform uptake (Figure 3).ConclusionCross‐sectionally, there is an early increase in tau uptake in the piriform cortex in AD but not in PD.
Development of AI‐4‐AD tools for evaluation and prognosis of AD conversion: multi‐branch network and multi‐task deep learning algorism
Authors: Han Liang , Pang Ran , Ren Qing , Pu Xiujuan , Liu Yuan , Tan Yuanfan , Yang Qing X 
Published: January 2025

AbstractBackgroundAD prevention and early interventions require tools for evaluation of people during aging for diagnosis and prognosis of AD conversion. Since AD is a complicated continuum of neurodegenerative processes, developing of such tools have been difficult because it needs longitudinal and multimodal data which are often complicated and incomplete. To address this challenge, we are developing AI4AD framework using ADNI data.MethodAs shown in Fig. 1, we used the multimodal features of subjects in the initial four time points to predict the disease status after 1.5 years. The informative feature set with available multi‐modal data (MRI, PET and cognitive score (CSs)), is extracted as a multivariate time series. Then, a multi‐scale local temporal attention network (MCLAN) is constructed to extract corresponding deep features from three categories of multivariate time series respectively. Furthermore, a set of statistical features are extracted from multivariate the time series. Subsequently, fusion of selected deep features, statistical features and background knowledge (demographics, CSF, genetics feature) at baseline are performed using a DL feature network. Finally, AD and CSs predictions are realized utilizing multi‐task DL algorism with Adam optimization algorithm and the five‐fold cross‐validation method. 190 CN subjects, 347 MCI subjects and 20 AD subjects were selected according to the first visit diagnosis from TADPOLE database (Table 1a). The longitudinal data for training and ground truth of AD conversion are shown in Table 1(b).ResultThe accuracy (ACC), accuracy (PRE), recall (REC) and F1 score of the proposed AD prediction method in the AD classification were 93.57%, 93.55%, 93.68%, and 93.59%, respectively, which is greatly improved the predictive ability of those by the conventional methods (Table 2). In addition, the root mean square error (RMSE) on the CSs prediction of CDRSB, ADAS11, ADAS13 and MMSE are 0.5863, 0.5238, 0.4747 and 0.5417 respectively.ConclusionOur DL method consolidates multi‐modal medical information at different visits to predict the disease’s progression, which greatly improved AD prognosis from those using traditional DL algorithms (CNN, LeNet and ResNet). The AI4AD framework proposed here can also be tailored to other diseases with similar data characteristics.
Studying Alzheimer’s‐Related Neuronal Dysfunction Using a New Tool: Characterizing a Neurodegenerative Animal Model with Increased Neuronal‐specific miR34
Authors: Pursell India A , Freitas Raul , Wegrowski Laura , Blahusiak Gabrielle , Barahona Natasha B , Engler‐Chiurazzi Elizabeth 
Published: January 2025

AbstractBackgroundAlzheimer’s Disease (AD) is a prevalent age‐related neurodegenerative condition leading to dementia, yet factors regulating its polygenomic etiology and progression remain elusive. MicroRNAs (miRNAs), small RNA molecules regulating protein expression, play a role in neurodegeneration. MicroRNA‐34a (miR‐34a) is a crucial regulator of numerous genes associated with neurodegenerative disorders, protein aggregation and synaptic transmission genes. However, the lack of effective tools for in vivo study impedes comprehensive research in this area. We developed a global miR‐34a overexpressing mouse line in which cognitive deficits, altered amyloid and tau protein processing, and synaptic reorganization were noted.MethodWe generated a CaMKIIα driven, excitatory neuron‐specific Tet‐inducible miR‐34a overexpressing mouse model. Male and female miR‐34a± mice aged 28‐46 weeks were treated with water or Doxycycline to induce miR‐34a overexpression for up to 90 days cognitive and neurobiological consequences were assessed. In this pilot study, we assessed the expression of predicted miR‐34a target genes and associated proteins (SIRT1, NMDAR2B). A subset of mice underwent sequencing analysis in one hemisphere to identify novel miR‐34a targets.ResultAt 30 days of miR‐34a overexpression, we observed trends towards reduced levels of miR‐34a target genes (NMDAR2B, SHANK3) in the hippocampus of mice. However, these findings were non‐significant, likely attributed to the limited power or insufficient exposure duration. With 90 days of exposure, mice exhibited subtle behavior changes, characterized by a decreased percent of spontaneous alternations; no differences observed at 30 days. Distinct nervous system cell populations were isolated for miRNA analysis, hinting at region‐specific changes. Whole brain hemisphere bulk RNA sequencing of Doxy‐treated animals revealed upregulation of the genes Gh and Prl and downregulation of Avp and Drd1 compared to control.ConclusionThe inducible global miR‐34a overexpression mouse model exhibited modest dementia‐like characteristics and warrants further characterization. Further interrogation of contributions from other neural or peripheral cell types in the AD phenotype induced by global miR‐34a overexpression. The cell‐specific nature of our model provides valuable insights into miR‐34a’s role in AD pathology. These findings contribute to understanding the complex, polygenomic mechanisms underlying neurodegeneration in AD and may reveal novel miR‐focused therapeutic targets.
The Impact of Cognitive Reserve on Cognitive Functions in the Elderly: A Neuropsychological Investigation
Authors: Gasparre Daphne , Ricciardi Elisabetta , Abbatantuono Chiara , Prontu Laura , Marocchino Federica , Biasi Madia Marika , Paparella Giulia , Introna Alessandro , Caffò Alessandro , De Caro Maria Fara , Taurisano Paolo 
Published: January 2025

AbstractBackgroundCognitive reserve (CR) represents the susceptibility to age‐related brain changes or Alzheimer’s disease‐related pathology. It is the ability to withstand the effects of aging and neurological damage. Several factors influence CR, including education, work, activites, mental activity, and social networks, which play a crucial role in an individual’s ability to preserve the global cognitive functioning and counteract cognitive decline. Boosting cognitive reserve has become a relevant focus in our efforts. In this study, we aim to investigate how cognitive reserve could influence the cognitive decline in the elderly.MethodTargeted neuropsychological assessment were administered to patients with Mild cognitive Impairment and dementia. We analyse through software R 4.3.2., the relationship between of cognitive reserve and other cognitive functions such as attention and memory capabilities.ResultsOur preliminary findings suggest a clear correlation between higher cognitive reserve and improved performance on these tests. This connection appeared particularly significant in the early stages of deterioration (Mild Cognitive Impairment). In other words the notion of cognitive reserve posits the prospect of interventions capable of mitigating cognitive aging or diminishing the susceptibility to dementia.ConclusionsCR has a key role across the aging. In particular individuals with MCI could prevent and contrast cognitive decline boosting their CR, for example doing more activities, learning new language, gaining new skills, doing physical activities. Further research is needed to fully grasp this relationship and devise methods to extend cognitive reserve in order to promote cognitive health.
Clinical profile of Amnestic Early‐Onset Alzheimer’s disease in Peru: Case Series from a Neurological Care Center
Authors: Castro‐Suarez Sheila , Guevara‐Silva Erik Alberto , Alvarez‐Toledo Kelvin , Caparo‐Zamalloa Cesar , Zegarra‐Valdivia Jonathan Adrian , Meza‐Vega Maria 
Published: January 2025

AbstractBackgroundEarly‐onset Alzheimer’s disease (EOAD) is a rare and devasting form of Alzheimer disease that represents 5‐10% of the total number of Alzheimer disease (AD). It is significantly less well studied than the late‐onset form of AD. The clinical presentation is heterogeneous, the amnestic variant is the most frequent (75%). Clinical aspects of EOAD in Admixed Latin American population are lacking in the literature. We aim to describe clinical features of amnestic EOAD patients followed‐up at a Neurological healthcare center in Peru.MethodWe reviewed medical records of patients with diagnosis of probable EOAD during January‐December 2023. All patients were evaluated by trained neurologists from a dementia outpatient clinic at a specialized neurologic center in Lima, Peru. Relevant information about neurocognitive, neuropsychiatric, and functional assessments were extracted from medical records with further descriptive analysis. IRB approval from local institution was obtained for this study.ResultA total of 45 patients (73% female, age at onset = 56 [50‐61] years) met the selection criteria. The 71% of the cases have more than 6 years of education. The delay for diagnosis in this group was between 2 and 5 years. A first‐degree relative with dementia was present in 15.5% of patients. Clinical and cognitive assessment profile included: MMSE average score was 13.2±6.8. The clinical manifestation characterized by anterograde episodic memory impairment were accompanied by executive disfunction (97.8%), attention and calculation impairment (84.4%), and visuospatial impairment (71%); impaired repetition of phrases and anomia were present in 67 and 44% respectively. Based on NPI the most frequent neuropsychiatric symptoms were depression (57%) irritability (51%), and anxiety (38%). Severity of dementia was CDR = 3 for 31.1%, CDR = 2 for 35.6%, CDR = 1 for 33.3%.ConclusionThe clinical features of our Peruvian amnestic EOAD cohort are mostly consistent with previous reports. There is a significant delay of EOAD diagnosis. Implementing training strategies for clinicians, neurologists, and no‐neurologists, will improve a timely and accurate diagnosis of EOAD.
The association between cognitive tests and stages of cognitive decline in Caribbean Hispanics
Authors: McInerney Katalina F , Zaman Andrew F , Prough Michael B. , Mena Pedro R. , Adams Larry D. , Sanchez Jose Javier , Rodriguez Vanessa C , Valladares Glenies S , Celis Katrina , Hamilton‐Nelson Kara L. , Rajabli Farid , Beecham Gary , Feliciano‐Astacio Briseida E. , Vance Jeffery M. , Pericak‐Vance Margaret A , Cuccaro Michael L. 
Published: January 2025

AbstractBackgroundThe utility of neuropsychological measures commonly used to diagnose individuals with suspected MCI or AD was recently explored in European cohorts, however their utility in Caribbean Hispanic (CH) populations is not well understood.MethodOur sample consisted of 507 CH individuals from ongoing studies of Puerto Rican and Cuban American older adults (74%% Female, mean age = 74.1, mean education = 12.7 years, 209 Unaffected, 185 MCI, 113 with AD) who completed cognitive measures from the NACC UDS2 battery (Logical Memory, Semantic Fluency [animals and vegetables], and Digit Span). Participants were clinically adjudicated as unaffected, MCI, or AD, and had a CDR global score ≤1. Individuals with disorders known to affect cognition were excluded. An ordinal regression explored which cognitive tests were most strongly associated with clinical diagnoses. We ran this analysis again on a subset of participants who also completed the Trails Making Test (n = 242, 103 unaffected, 97 MCI, 42 AD). We examined both the log‐odds estimate and Wald value.ResultAn ordinal regression on the full sample showed that the tests associated with differences in clinical diagnosis in order of their predictive value are Delayed Logical Memory (log‐odds = 1.29, Wald = 40.1, p<0.001), Digit Span Backwards (log‐odds = 0.70, Wald = 25.2, p<0.001), Animals (log‐odds = 0.44, Wald = 12.0, p<0.001), Vegetables (log‐odds = 0.32, Wald = 7.3, p<0.01), and Digit Span Forwards (log‐odds = 0.24, Wald = 6.3, p = 0.012). On the subset that completed the Trails Making Test, Trails B emerged as most predictive (log‐odds = 0.70, Wald = 26.8, p <0.001), but Vegetables (p = 0.26), Logical Memory Immediate (p = 0.43), and Trails A (p = 0.70) were not significant predictors of differences in clinical diagnosis in this smaller group.ConclusionIn our sample of CH individuals, we found performance on measures of delayed contextual memory (Logical Memory), working memory (Digit Span Backwards and Trails B) and semantic fluency (Animals) to be most useful in differentiating individuals clinically diagnosed as unaffected, MCI, or AD. These results highlight possible performance patterns specific to CH that can inform adjudication efforts with this population.
Transmission of Alzheimer’s disease‐associated microbiota dysbiosis and its impact on cognitive function: evidence from mice and patients
Authors: Zhang Yiying , Shen Yuan , Li Wei , xie zhongcong 
Published: January 2025

AbstractBackgroundSpouses of Alzheimer’s disease (AD) patients are at a higher risk of developing incidental dementia. However, the causes and underlying mechanism of this clinical observation remain largely unknown. One possible explanation is linked to microbiota dysbiosis, a condition that has been associated with AD. However, it remains unclear whether gut microbiota dysbiosis can be transmitted from AD individuals to non‐AD individuals and contribute to the development of AD pathogenesis and cognitive impairment.MethodWe, therefore, set out to perform both animal studies and clinical investigation by co‐housing wild‐type mice and AD transgenic mice, analyzing microbiota via 16S rRNA gene sequencing, measuring short‐chain fatty acid amounts, and employing behavioral test, mass spectrometry, site‐mutations and other methods.ResultThe present study revealed that co‐housing between wildtype mice and AD transgenic mice or administrating feces of AD transgenic mice to wild‐type mice resulted in AD‐associated gut microbiota dysbiosis, Tau phosphorylation, and cognitive impairment in the wild‐type mice. Gavage with Lactobacillus and Bifidobacterium restored these changes in the wild‐type mice. The oral and gut microbiota of AD patient partners resembled that of AD patients but differed from healthy controls, indicating the transmission of microbiota. The underlying mechanism of these findings includes that the butyric acid‐mediated acetylation of GSK3β at lysine 15 regulated its phosphorylation at serine 9, consequently impacting Tau phosphorylation.ConclusionThis initial proof‐of‐concept study demonstrated the potential transmission of microbiota from AD patients or ADTg mice to non‐AD controls or WT mice housed together. This transmission may contribute to the development of AD‐associated microbiota dysbiosis and metabolite alterations, ultimately leading to AD pathogenesis and cognitive impairment. However, these findings should be validated in future studies. The results of this study are expected to drive further research to explore gut microbiota dysbiosis and its connection to AD in both preclinical and clinical contexts.