bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Alzheimer’s Disease Sequencing Project Follow Up Study (ADSP‐FUS): increasing ethnic diversity in Alzheimer’s disease (AD) genetics research.
Authors: Mena Pedro Ramon , Kunkle Brian W. , Faber Kelley M. , Adams Larry D. , Inciute Jovita D. , Whitehead Patrice L. , Foroud Tatiana M. , Reyes‐Dumeyer Dolly , Kuzma Amanda B , Leung Yuk Yee , Naj Adam C. , Martin Eden R. , Dalgard Clifton L. , Schellenberg Gerard D. , Wang Li‐San , Mayeux Richard , Vardarajan Badri N. , Vance Jeffery M. , Cuccaro Michael L. , Pericak‐Vance Margaret A. 
Published: December 2022

AbstractBackgroundThe ADSP‐FUS is a National Institute on Aging (NIA) initiative focused on identifying genetic risk and protective variants for Alzheimer Disease (AD) by expanding the ADSP Discovery and Discovery Extension cohorts beyond non‐Hispanic Whites of European Ancestry (NHW‐EA). Given the lack of diversity in the ADSP, the ADSP‐FUS was designed to sequence existing ethnically diverse and unique cohorts. The upcoming phase for ADSP‐FUS, ADSP‐ FUS 2.0: The Diverse Population Initiative, focuses on Hispanic/Latino (HL), non‐Hispanic Black with African Ancestry (NHB‐AA), and Asian populations (e.g., the Asian cohort for Alzheimer’s disease). The ADSP‐FUS enables the utility of new discoveries for individuals from all populations.MethodADSP‐FUS cohorts consist of studies of AD, dementia, and age‐related conditions. Clinical classifications (AD, dementia, and cognitively intact) are assigned based on standard criteria and derived from clinical measures and history. Data dictionaries are curated for each cohort by the FUS clinical staff. The ADSP‐FUS initiatives intend to sequence over 100,000 individuals from diverse ancestries.Biospecimens are processed and DNA is prepared and allocated for whole genome sequencing (WGS) at designated NIA sequencing centers. All raw sequence data is transferred to the Genome Center for Alzheimer’s Disease (GCAD) for processing and harmonization following QC analysis at the University of Pennsylvania and University of Miami, resulting in analysis‐ready genotype and sequence data. All clinical, genotype and sequence data are housed at the NIA Genetics of Alzheimer Disease Data Storage Site (NIAGADS), which stores, manages, and distributes ASDP‐FUS data to AD researchers.ResultsOver 50,152 samples have been ascertained with ancestry groupings as follows: 10,166 NHB‐AA; 10,531 HL; 22,002 NHW‐EA (including 1,400 EOAD and 3,745 autopsy); 89 Amerindian; and 7,364 Asian (Korean and Indian) individuals. Currently, we have sequenced up to a total of 31,990 individuals.ConclusionThe ADSP‐FUS continues to identify shared and novel genetic risk factors for AD among diverse populations. This genomic resource is crucial to expanding our knowledge of potential genetic risk and protective variants for AD across all populations with the hope of developing new treatments for everyone.
Different criteria modify Alzheimer’s disease diagnosis and prognosis
Authors: Bieger Andrei , Brum Wagner S. , De Bastiani Marco Antônio , Benedet Andréa Lessa , Moreira Amanda Gressler , Borelli Wyllians Vendramini , Pascoal Tharick A , Schumacher‐Schuh Artur Francisco , Castilhos Raphael Machado , Rosa‐Neto Pedro , Souza Diogo O. , Schilling Lucas Porcello , Zimmer Eduardo R 
Published: December 2022

AbstractBackgroundAlzheimer’s disease (AD) has recently been reconceptualized into a dual entity, a biological disease, and a clinical syndrome. Following these advances, the National Institute on Aging – Alzheimer’s Association (NIA‐AA) and the International Working Group (IWG) released four updated diagnostic guidelines for AD diagnosis: NIA‐AA 2011, IWG 2016, NIA‐AA 2018, and IWG 2021. Although many studies still rely solely on a clinical diagnosis of AD, and a consensus on diagnostic criteria is still lacking. Here, we aim to elucidate how the aforementioned AD guidelines affect the individuals’ diagnostic label.MethodClinical, demographic and biomarker data were extracted from ADNI (n = 1215), and used to build classification algorithms according to diagnostic criteria from NIA‐AA 2011, IWG 2016, NIA‐AA 2018, and IWG 2021. Subjects then were labeled as Not AD (NA), At Risk of Developing AD (AR), or AD. Results were compared according to cognitive stage, cognitively unimpaired (CU) or cognitively impaired (CI), and to AD biomarkers profile. Kaplan‐Meier curves were used to evaluate conversion to CI in CU individuals using each diagnostic guideline. All analyses were performed in R (v 4.0.3).ResultIndividuals were diagnosed using criteria from the NIA‐AA 2011 [NA = 36.8%, AR = 23.2%, AD = 40%], IWG 2016 [NA = 37.9%, AR = 28.8%, AD = 33.3%], NIA‐AA 2018 [NA = 40.5%, AR = 11.1%, AD = 48.4%], and the IWG 2021 [NA = 51.3%, AR = 8.7%, AD = 40%] (Figure 1). Diagnoses were discordant between criteria in 39.8% of the individuals, with 69.4% of those being in the A+T‐ or A‐T+ biomarker groups. Conversion to CI of CU individuals AR compared to NA were calculated for the NIA‐AA 2011 [log‐rank 0,001], IWG 2016 [log‐rank 0,000], NIA‐AA 2018 [log‐rank 0,24], and IWG 2021 [log‐rank 0,000].ConclusionOur findings indicated that almost 40% of the studied population presented discordant diagnoses using different AD criteria. Most of these had only one positive biomarker (amyloid or tau). All guidelines except for the NIA‐AA 2018 managed to differentiate asymptomatic individuals at risk of developing cognitive impairment. Our findings have important implications in clinical practice and the design of future clinical trials.
Two year cognitive and biomarker change in a racially diverse, middle‐aged, cohort at risk for Alzheimer’s disease
Authors: Butts Brittany , Hu William T. , Huang Hanfeng , Kehoe Patrick G , Miners Scott , Verble Danielle D , Zetterberg Henrik , Zhao Liping , Wharton Whitney 
Published: December 2022

AbstractBackgroundAlzheimer’s disease (AD) incidence among Black/African Americans (B/AA) is 64% higher than non‐Hispanic Whites (NHW). Studies show CSF total and phosphorylated tau are lower in cognitively unimpaired middle‐aged B/AAs compared to NHWs. Cognitive changes in B/AA adults are associated with smaller increases in CSF tau. We examined rate of cognitive and CSF AD biomarker change, over two years, in a cognitively unimpaired, racially diverse, middle‐aged cohort with a parental history of AD.MethodCognitive tests (MOCA, Trails B, Digit Span, Benson Delay, Buschke Delay, and MINT) were collected at baseline (BL), 1 year (Y1), and 2 years (Y2). CSF was collected at BL and Y2 for AD biomarkers (Aβ and tau) and sPDGFRβ, an index of blood brain barrier damage. Analyses controlled for age, sex, race, education, and APOE4.ResultParticipants (N=80) were mostly female (69%), highly educated (81% ≥college), and 34% B/AA. B/AAs exhibited lower levels of p‐tau, t‐tau, and sPDGFRβ at BL and Y2 compared to NHWs (p≤0.02). P‐tau increased from BL to Y2 for all participants (p<0.01). NHWs outperformed B/AAs in 7/7 cognitive tests at baseline and 6/7 at Y2. Digit Span improved from BL to Y2 (p=0.014) for all participants. Analyses by race demonstrated improvements for MOCA and Buschke Delay among B/AAs, and improvements for Trails B and Benson Delay among NHWs. There was a difference in rate of change over time by race in Benson Delay (F=8.22, p=0.0055). Linear models showed positive associations between Trails B and p‐tau and sPDGFRβ (p≤0.05). Negative associations were found between Benson Delay and p‐tau and t‐tau (p≤0.04), between MINT and sPDGFRβ, p‐tau, and t‐tau (p=0.04), and between Bushcke Delay and sPDGFRβ (p=0.03).ConclusionWhile cognitive scores changed over time, group analyses showed improvements among B/AA participants in verbal memory and global cognition, while NHW participants improved in tests of processing speed and visuospatial memory. CSF p‐tau increased over 2 years. As CSF AD biomarkers were predictive of cognitive function scores, AD pathologic processes may begin earlier in at‐risk adults. Further study of race‐associated differences in AD biomarkers is needed, as these differences may contribute to AD‐related health disparities.
Belgian Carriers of Rare ABCA7 Mutations Present with Pronounced Cerebral Amyloid Angiopathy and Alzheimer’s Disease
Authors: de Craen Elisabeth Henndrickx Van , Bossaerts Liene , Sieben Anne , Loos Caroline , Yperzeele Laetitia , Engelborghs Sebastiaan , De Deyn Peter Paul , Van Broeckhoven Christine 
Published: December 2022

AbstractBackground
ABCA7 is a major risk gene for Alzheimer’s disease (AD) and rare premature termination codon (PTC) and missense mutations are enriched in AD patients. In preliminary studies we obtained that ABCA7 PTC and missense mutation carriers present with a classic AD phenotype, but severe levels of cerebral amyloid angiopathy (CAA) were also found (table 1, figures 1‐2). We aim to delineate the clinicopathological phenotype of rare ABCA7 mutation carriers in Belgian CAA patients.MethodsGenetic screening of ABCA7 in a Belgian CAA cohort (n = 83), with genotype‐phenotype comparison of the ABCA7 carriers using demographics and clinicopathology data.ResultsIn 21.4% (18/84) of CAA patients a rare ABCA7 mutation was identified. Seven patients carried a PTC mutation, 10 a rare missense variant, and in one CAA patient we found a deletion. The mean onset age was 66.4±12.8 (range 47‐84) years, while the mean age at death was 68.0±10.3 (range 48‐92) years. In 87.5% (7/8) of patients a positive family history of disease was mentioned. Cognitive decline was present in 52.9% (9/17). Nine patients were diagnosed as probable CAA, and four as possible CAA. In six patients postmortem examination showed moderate‐to‐severe levels of CAA in all but one patient (83.3%, 5/6) and AD neuropathological hallmarks (100%, 6/6). Extensive levels of CAA were present in both the meningeal and capillary blood vessels, and moderate to high levels of CAA in the parenchymal blood vessels (Figure 3).ConclusionsOur data suggests that rare ABCA7 mutations are frequently present in CAA patients. Carriers show signs of severe levels of CAA, as well as AD neuropathological hallmarks. The findings of this study have important implications for future research and clinical practice.
Machine learning‐enabled epileptiform spike detection stratifies patient subpopulations with Alzheimer’s disease
Authors: Pathmanathan Jay , Laberinto Kim , Robertson Hannah , Hanson Eric , Donoghue Jacob 
Published: December 2022

AbstractBackgroundA subpopulation of patients with Alzheimer’s disease exhibit epileptiform activity and have more rapidly progressing disease. Manual identification of these pathological events is infeasible at scale and machine learning tools may establish epileptiform activity as an actionable biomarker for stratification and endpoints within clinical trials.MethodsRoutine EEGs from 90 subjects with AD and 39 subjects with MCI from the Beacon data repository were analyzed via the Beacon Platform harnessing an ML‐enabled interictal epileptiform discharge (IED) detection algorithm, and by expert visual inspection.ResultsIEDs were found in 17 of the 90 subjects with AD (19%), and 8 out of the 39 MCI subjects (20%). In subcategorization, 13% (9 / 71) of AD subjects without epilepsy had IEDs, while 42% (8/19) of AD subjects with epilepsy had IEDs. In the AD/no epilepsy subgroup there were 24 patients taking an Anti‐Seizure Medication (ASM), and 4% (1/24) had IEDs (versus 17% (8/47) of the AD without epilepsy group that were not on ASMs).ConclusionMachine learning augmented detection of IEDs allows for rapid, quantitative identification of individuals with subclinical epileptiform activity in patients with AD and MCI. These results demonstrate that AI‐detectable IEDs are seen in a sizable minority of AD patients without epilepsy and in MCI patients, and more commonly in AD patients with epilepsy. Ultimately, automated analysis of EEG data is a promising way to stratify patients and track disease progression while enriching clinical trials with subjects most likely to respond to next‐generation treatments.
MultiTEP‐based conjugated vaccines targeting various phosphorylated tau epitopes are immunogenic and effective in the PS19 mouse model
Authors: Zagorski Karen , King Olga , Hovakimyan Armine , Antonyan Tatevik , Chailyan Gor , Ghazaryan Manush , Petrushina Irina , Cribbs David H. , Davtyan Hayk , Blurton‐Jones Mathew , Ghochikyan Anahit , Agadjanyan Michael G 
Published: December 2022

AbstractBackgroundPathological tau correlates well with cognitive impairments in Alzheimer’s disease (AD) patients and represents a promising immunotherapy target. In theory, targeting an appropriate B‐cell epitope in pathological tau could effectively reduce the pathology without affecting normal native tau. Hyperphosphorylation of tau is a well‐known feature of Alzheimer’s and other tauopathies, with many disease‐specific phosphorylation sites documented. Accordingly, we attached several disease‐related phosphorylated tau peptides to our universal vaccine platform, MultiTEP that is safe and extremely immunogenic in various disease models of AD, rabbits, and aged monkeys. We hypothesized that high immunogenicity of MultiTEP‐based vaccines, coupled with the selectivity of the immune responses, will allow the identification of pathological and protective phosphorylation sites, thus leading to the generation of vaccines, which would preferentially clear the toxic forms of tau without disrupting the normal brain homeostasis.MethodA genetically engineered variant of MultiTEP was generated to enable chemoselective bioconjugation of synthetic peptides under mild aqueous conditions. MultiTEP‐based vaccines targeting p‐tau 202/205, p‐tau 396/404, p‐tau 422 were tested in the PS19 mouse model of AD and other tauopathies. Antibody specificity and titers were tested via ELISA. Brain total and phosphorylated soluble and insoluble tau were measured by ELISA and IHC.ResultAll three vaccines generated robust and selective immune responses specific to phosphorylated tau in mice. The generated antibodies selectively bound to the appropriate phosphorylated, but not non‐phosphorylated form of the same peptide. Importantly, these antibodies effectively reduce/cleared pathological tau in the brains of immunized mouse model of tauopathy. The MultiTEP immunogenicity was sufficient to generate robust immune responses after two immunizations, even without adjuvant.ConclusionMultiTEP‐based conjugated vaccines could be used to generate robust immune responses selective to multiple phosphorylation sites of tau. This, in conjunction with a previous report on MultiTEP‐based pE3Aβ vaccine, suggests that the methodology is universally applicable for various post‐translational modifications. Our technology can facilitate the identification of optimal therapeutic targets of p‐tau for generating an active immunotherapeutic strategy that can be used in conjunction with pE3Aβ vaccine. If successful, preventive vaccinations targeting disease‐related tau and/or Aβ molecules could at least delay AD and related neurodegenerative disorders.
Natural premature menopause relates to higher risk of mild cognitive impairment and Alzheimer’s disease and related dementias in APOE‐ε4 carriers only
Authors: Sundermann Erin E. , Saelzler Ursula G , Shadyab Aladdin H. , Banks Sarah J , Jacobs Emily Goard , Rapp Stephen R. , Wactawski‐Wende Jean , Casanova Ramon , Panizzon Matthew S. 
Published: December 2022

AbstractBackgroundOverall risk of Alzheimer’s disease (AD) and APOE‐ε4‐related risk for AD is higher among women than men, but the sex‐specific biological underpinnings of these sex differences are unknown. Earlier age at menopause has been associated with higher risk of AD and related dementias (ADRD); however, it is unclear whether this relationship holds among naturally menopausal (versus surgically menopausal) women only or whether it is impacted by APOE‐ε4 genetic risk. We examined the association of natural premature (occurring ≤40 years of age) menopause with MCI and ADRD risk among older women and whether this relationship was moderated by APOE‐ε4 genotype.MethodThis study included 3,557 older women (age range: 65‐79 years at baseline; all White; 5.3% premature menopause; 25.5% APOE‐ε4 carriers) from the Women’s Health Initiative Memory Study (WHIMS) who experienced menopause spontaneously and not as a result of hysterectomy or bilateral oophorectomy. All participants had data on reproductive history, APOE genotype and longitudinal cognitive evaluations, and were cognitively unimpaired at baseline (follow‐up time: range = 0.92‐24.19, mean = 9.92 years). Incident MCI and ADRD were determined with a comprehensive neuropsychological battery and centrally adjudicated by a panel of specialists with expertise in dementia diagnosis. A set of Cox regression models was applied to determine whether premature menopause and its interaction with APOE‐ε4 carrier status was associated with risk of MCI or ADRD, adjusting for age, education, cardiovascular risk factors, parity, age at menarche, past contraceptive use and current or past hormone therapy use and the timing of initiation relative to menopause.ResultThe APOE‐ε4 X premature menopause interaction was significant (p = .04). Among APOE‐ε4 allele carriers, premature (vs. non‐premature) menopause was associated with an approximate two‐fold increased risk of MCI/ADRD (HR = 2.05, 95%CI: 1.22‐3.44). No such association was present among women without an APOE‐ε4 allele (HR = 1.16, 95%CI: 0.72‐1.86).ConclusionNatural premature vs non‐premature menopause was associated with two‐fold higher risk of MCI/ADRD but only among APOE‐ε4 carriers. Results suggest interactive effects of premature menopause and the APOE‐ε4 genotype. Future studies are needed to determine whether the menopause and APOE‐ε4 pathophysiological mechanisms of dyslipidemia, inflammation and brain metabolism deficiencies may explain this association.
Baseline regional Tau distribution predicts fast cognitive decline in subjects with mild cognitive impairment
Authors: Charil Arnaud , Devanarayan Viswanath , Murali Leema , Qi Xin , Krause Stephen , Sachdev Pallavi , Reyderman Larisa , Koyama Akihiko , Dhadda Shobha , Irizarry Michael C 
Published: December 2022

AbstractBackgroundNeurofibrillary tangles represent a pathological hallmark of AD that spreads throughout the brain in a relatively stereotypical spatio‐temporal fashion along Braak stages. Understanding the impact of regional Tau distribution and spread on future cognitive decline would be highly valuable for targeted patient selection and treatment strategy in drug development.MethodRegional flortaucipir (FTP) PET SUVR in 77 brain regions, and Braak stage regions I‐VI, were available from 638 ADNI subjects (89 AD, 117 MCI, 432 age‐matched normal controls). Baseline FTP data, processed at UC Berkeley, was partial volume corrected to reduce off‐target binding contamination. Braak stage II (i.e., hippocampus) was excluded from the analysis due to known off‐target binding in this region.A machine‐learning (ML) approach via stochastic gradient boosting was applied to determine the characteristics of regional Tau distribution that uniquely reflect AD relative to control subjects. This signature was then applied to PET scans of an independent group of 117 MCI subjects to predict their 24‐month cognitive decline, as defined by an increase in the clinical dementia rating sum of boxes (CDR‐SB). MCI subjects predicted to have ‘control‐like’ Tau deposition signature were considered as slow cognitive decliners while those predicted to have ‘AD‐like’ signature were considered as fast decliners. Prediction performance was evaluated and the regions of Tau deposition indicative of faster cognitive decline were identified.ResultMCI subjects predicted as fast cognitive decliners had odds ratio of 7.3 relative to those predicted as slow decliners (7.3‐fold greater odds of decline), with the median and 75th percentile increase in CDR‐SB of 1 and 3 respectively, compared to an increase of 0 and 0.5 among those predicted as slow decliners. Subjects with Tau deposition in Braak I (entorhinal cortex) and Braak III at baseline, and particularly in the amygdala, were predicted to be fast decliners. Further presence of Tau in parahippocampal, fusiform and precuneus regions at baseline were strongly associated with fast cognitive decline.ConclusionThe nature of baseline regional Tau distribution in MCI subjects is a strong indicator of fast cognitive decline that can help inform targeted patient selection and treatment strategy in drug development.
Alternative Theory of AD Pathogenesis: Membrane Delimitation of the Histone Acetyltransferase Tip60/Kat5
Authors: Wiley Jesse C , Young Jessica E. , Jayadev Suman , Darvas Martin , Swerdlow Russell H , Wolfe Michael S. , Heath Laura M , Gockley Jake , Cary Gregory A. , Poehlman William L. , Ladiges Warren , Carter Gregory W , Bothwell Mark A , Greenwood Anna K , Mangravite Lara M 
Published: December 2022

AbstractBackgroundFor decades, mounting genetic and physiological data have pointed to the APP proteolysis as a seminal event in AD pathogenesis. This data has been viewed as supporting the amyloid hypothesis. However, growing data from multiple disciplines disputes that amyloid is a causal mechanism of neurodegeneration. Evidence suggests that FAD mutations are loss of function, inhibiting normal proteolytic processing of APP. APP extracellular and intracellular domains exhibit a broad array of binding interactions. Tip60 (a histone acetyltransferase, also known as Kat5) is an intracellular binding partner that supports the long‐standing speculation that APP functions as a signaling receptor. Recently, a conditional knockout (cKO) of Tip60 demonstrated neurodegenerative pathology and massive reactive gliosis, supporting a role for Tip60 in neurodegeneration. Reports that Tip60 is restricted from the nucleus in AD patient brains bolsters this idea.MethodTo assess the overlap of the cKO Tip60 model and human AD pathogenesis, we compared the dysregulated gene sets (DEGs) in the cKO Tip60 mouse and late‐onset AD postmortem brains. We break DEGs from mouse and human models into AD “biological domains” (BDs), and perform GSEA of GO enrichment within each BD. We then perform downstream analyses using network reconstruction applications and by examining the enriched BDs with pseudotime measures of disease progression in LOAD patients.ResultWe find significant overlap between DEGs in LOAD patients and the Tip60 cKO in multiple BDs, including, mitochondrial metabolism, immune response, structural stabilization, synaptic function, and endolysosomal trafficking. GSEA of LOAD and cKO Tip60 further implicates similar deficits in both models. The network analysis shows a convergence of gene dysregulation at core nodes, further implicating similar processes of dysregulation may impact particularly significant genes in human and mouse models. The pseudotime analysis shows that this dysfunction is an early signature of AD, suggesting Tip60 dysregulation may trigger early‐stage homeostatic destabilization.ConclusionWe propose that aberrant APP proteolysis traps Tip60 at the membrane, preventing the nuclear localization of Tip60, and altering both positive and negative gene regulation that is necessary for neuronal and glial homeostasis, and hypothesize that this is an explanation for the genetic linkage of APP proteolytic processing and AD.