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| Open AccessThe effects of genetic and modifiable risk factors on brain regions vulnerable to ageing and disease
A network of brain regions degenerates earlier in aging. Here the authors show that, this network is most vulnerable to diabetes, traffic-related pollution and alcohol consumption in terms of risk factors for dementia, and associated with the XG blood group genes.
- Jordi Manuello
- , Joosung Min
- & Gwenaëlle Douaud
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Article
| Open AccessA blood-based biomarker workflow for optimal tau-PET referral in memory clinic settings
A screening strategy with plasma p-tau217, evaluated in two independent cohorts from Sweden and Canada, showed that this biomarker may effectively streamline tau-PET referrals in memory clinic settings, optimizing the prognostic work-up of Alzheimer’s disease.
- Wagner S. Brum
- , Nicholas C. Cullen
- & Oskar Hansson
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Article
| Open AccessA single nuclear transcriptomic characterisation of mechanisms responsible for impaired angiogenesis and blood-brain barrier function in Alzheimer’s disease
Vascular pathology may play important early role in Alzheimer’s disease (AD). Here, the authors show that β-amyloid induces transcriptomic signatures associated with accelerated apoptosis, impaired function and AD risk in human brain microvasculature.
- Stergios Tsartsalis
- , Hannah Sleven
- & Paul M. Matthews
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Article
| Open AccessReduced progranulin increases tau and α-synuclein inclusions and alters mouse tauopathy phenotypes via glucocerebrosidase
Neurodegenerative diseases often co-accumulate several disease-associated proteins. Here, the authors show that reduction of progranulin, a protein associated with TDP-43, also increases accumulation of tau and a-synuclein via glucocerebrosidase.
- Hideyuki Takahashi
- , Sanaea Bhagwagar
- & Stephen M. Strittmatter
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| Open AccessThe structure of tyrosine-10 favors ionic conductance of Alzheimer’s disease-associated full-length amyloid-β channels
The structural basis of membrane permeabilization by Alzheimer’s disease-related amyloid β (Aβ) peptides is elucidated. Membrane insertion of tyrosine-10 supports the most effective ionic conductance of the full-length Aβ1-42 compared to other isoforms.
- Abhijith G. Karkisaval
- , Rowan Hassan
- & Suren A. Tatulian
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Article
| Open AccessAmyloid-β aggregates activate peripheral monocytes in mild cognitive impairment
Alzheimer’s Disease (AD) is commonly preceded by a prodromal period. Here, the authors report the presence of large plasma Aβ aggregates from patients with mild cognitive impairment, which associate with low level AD-like brain pathology as observed by 11C-PiB PET and 18F-FTP PET and lowered CD18-rich monocytes.
- Kristian Juul-Madsen
- , Peter Parbo
- & Thomas Vorup-Jensen
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Article
| Open AccessSynaptic density affects clinical severity via network dysfunction in syndromes associated with frontotemporal lobar degeneration
Translational neurodegeneration needs characterisation of the downstream consequences of synaptic loss. A multimodal imaging approach reveals that synaptic loss affects clinical severity via reduced connectivity in frontotemporal lobar degeneration.
- David J. Whiteside
- , Negin Holland
- & James B. Rowe
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| Open AccessFatal iatrogenic cerebral β-amyloid-related arteritis in a woman treated with lecanemab for Alzheimer’s disease
A 79-year-old woman received three doses of lecanemab, an experimental drug for Alzheimer’s disease, and suffered a seizure and cerebral edema. Neuropathological evaluation showed severe cerebral amyloid angiopathy, arteritis and microhemorrhages.
- Elena Solopova
- , Wilber Romero-Fernandez
- & Matthew Schrag
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Article
| Open AccessAmplified fluorogenic immunoassay for early diagnosis and monitoring of Alzheimer’s disease from tear fluid
Accurate diagnosis of Alzheimer’s disease in its earliest stage can prevent the disease and delay the symptoms. Here the authors identify a potential Alzheimer’s biomarker from tear fluid, and develop a nanoparticle-based immunoassay for its detection, demonstrating potential in Alzheimer’s diagnosis.
- Sojeong Lee
- , Eunjung Kim
- & Seungjoo Haam
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Article
| Open AccessPlasma biomarkers predict Alzheimer’s disease before clinical onset in Chinese cohorts
Performance of plasma biomarkers of amyloid (A), tau (T) and neurodegeneration (N) for Alzheimer’s disease (AD) in Chinese cohorts is unknown. Here, the authors report that plasma ATN biomarkers can predict AD 8–10 years before symptoms in Chinese cohorts.
- Huimin Cai
- , Yana Pang
- & Longfei Jia
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Article
| Open AccessHealthy dietary patterns and the risk of individual chronic diseases in community-dwelling adults
Dietary patterns have been linked to a limited number of major chronic diseases. Here, the authors show greater adherence to healthy dietary patterns, especially Alternate Mediterranean Diet, is associated with a lower risk of most of the 48 tested chronic diseases.
- Xianwen Shang
- , Jiahao Liu
- & Mingguang He
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Article
| Open AccessPhenylalanine-tRNA aminoacylation is compromised by ALS/FTD-associated C9orf72 C4G2 repeat RNA
GGGGCC repeat expansion in the C9orf72 gene causes amyotrophic lateral sclerosis and frontotemporal dementia. Here the authors show that CCCCGG antisense repeat RNA binds and inhibits phenylalanine-tRNA synthetase resulting in decreased levels of tRNAphe and phenylalanine rich proteins.
- Mirjana Malnar Črnigoj
- , Urša Čerček
- & Boris Rogelj
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| Open AccessDivergent single cell transcriptome and epigenome alterations in ALS and FTD patients with C9orf72 mutation
Non-coding repeat expansion in the C9ORF72 gene is the most frequent cause of ALS and frontotemporal dementia. Here, the authors performed single cell analyses of gene expression and epigenetic regulation in these patients’ brains and emphasized the role of astrocytes and neurons in neurodegeneration.
- Junhao Li
- , Manoj K. Jaiswal
- & Stella Dracheva
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Article
| Open AccessCSF proteome profiling reveals biomarkers to discriminate dementia with Lewy bodies from Alzheimer´s disease
This study characterizes the CSF proteome changes underlying Dementia with Lewy Bodies (DLB) and identifies pathophysiological and diagnostic leads associated to this cause of dementia. Findings have been translated into a biomarker panel that could identify DLB patients with high accuracy across different cohorts.
- Marta del Campo
- , Lisa Vermunt
- & Charlotte E. Teunissen
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| Open AccessEffect of apolipoprotein genotype and educational attainment on cognitive function in autosomal dominant Alzheimer’s disease
PSEN1 E280A carriers develop dementia by midlife, but there is variability in disease trajectory. Cognitive decline is accelerated in E280A carriers who also have an APOE e4 allele. Educational attainment moderates the effect of APOE on cognition.
- Stephanie Langella
- , N. Gil Barksdale
- & Yakeel T. Quiroz
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Article
| Open AccessCompilation of reported protein changes in the brain in Alzheimer’s disease
Proteomic studies in Alzheimer’s disease may be useful for understanding disease mechanisms and potential therapeutic targets. Here the authors describe a resource collating known protein changes throughout the progression of Alzheimer’s disease in human brain tissue.
- Manor Askenazi
- , Tomas Kavanagh
- & Eleanor Drummond
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Article
| Open AccessEvidence against a temporal association between cerebrovascular disease and Alzheimer’s disease imaging biomarkers
Whether a relationship exists between cerebrovascular disease and Alzheimer’s disease has been a source of controversy. Here, the authors show there is a very weak temporal relationship between the progression of Alzheimer’s disease biomarkers and those of cerebrovascular disease.
- Petrice M. Cogswell
- , Emily S. Lundt
- & Clifford R. Jack Jr
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Article
| Open AccessAssociation of gout with brain reserve and vulnerability to neurodegenerative disease
The potential association between neurodegenerative disease risk and gout is not fully understood. Here the authors showed that gout is causally related to several measures of brain structure which may explain their higher vulnerability to dementia.
- Anya Topiwala
- , Kulveer Mankia
- & Thomas E. Nichols
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Article
| Open AccessBrain proteomic analysis implicates actin filament processes and injury response in resilience to Alzheimer’s disease
Resilience to Alzheimer’s disease (RAD) is an uncommon combination of high disease burden without dementia. The authors perform proteomic analysis of RAD brains and show lower isocortical and hippocampal soluble Aβ levels, actin filament-based processes, cellular detoxification, and wound healing are significant features.
- Zhi Huang
- , Gennifer E. Merrihew
- & Thomas J. Montine
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| Open AccessForecasting individual progression trajectories in Alzheimer’s disease
Accurate prediction of disease progression in Alzheimer’s disease (AD) is necessary for optimal recruitment of patients to clinical trials. Here, the authors present AD Course Map, a statistical model which helps to predict disease progression in participants, thus decreasing the required sample size for a hypothetical trial.
- Etienne Maheux
- , Igor Koval
- & Stanley Durrleman
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| Open AccessOptimal deep brain stimulation sites and networks for stimulation of the fornix in Alzheimer’s disease
Deep brain stimulation has been investigated as a potential treatment for cognitive impairments in Alzheimer’s disease. Here the authors carry out post hoc analysis of multi-center cohorts to investigate the anatomical and functional correlates of effective deep brain stimulation, and find that stimulating circuit of Papez, fornix and bed nucleus of the stria terminalis, and a multi-region functional network, were associated with clinical improvement.
- Ana Sofía Ríos
- , Simón Oxenford
- & Andreas Horn
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Article
| Open AccessCausal inference in medical records and complementary systems pharmacology for metformin drug repurposing towards dementia
Previous observational studies of the diabetes drugs metformin vs. sulfonylureas have yielded mixed results about whether metformin reduces the risk of dementia, relative to the sulfonylureas. Here, the authors apply a novel competing risks approach to emulate dementia-related target trials in electronic health records of diabetic patients and a complementary systems pharmacology evaluation on human neural cells.
- Marie-Laure Charpignon
- , Bella Vakulenko-Lagun
- & Mark W. Albers
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Article
| Open AccessAmyloid-associated increases in soluble tau relate to tau aggregation rates and cognitive decline in early Alzheimer’s disease
The interplay between amyloid and tau pathology in Alzheimer’s disease is still not well understood. Here, the authors show that amyloid-related increased in soluble p-tau is related to subsequent accumulation of tau aggregates and cognitive decline in early stage of the disease.
- Alexa Pichet Binette
- , Nicolai Franzmeier
- & Oskar Hansson
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| Open AccessPreclinical and randomized clinical evaluation of the p38α kinase inhibitor neflamapimod for basal forebrain cholinergic degeneration
The authors show in an animal model and in a study in patients with dementia with Lewy bodies (DLB) that the drug neflamapimod has potential to treat diseases, such as DLB, associated with loss of neurons that produce the neurotransmitter acetylcholine.
- Ying Jiang
- , John J. Alam
- & Ralph A. Nixon
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Article
| Open AccessEarlier Alzheimer’s disease onset is associated with tau pathology in brain hub regions and facilitated tau spreading
Individuals with young onset sporadic Alzheimer’s disease show faster pathological and clinical progression. Here the authors report that earlier symptom onset in Alzheimer’s disease is associated with higher tau pathology in globally connected brain hubs, accelerated connectivity-mediated tau spreading and faster cognitive decline.
- Lukas Frontzkowski
- , Michael Ewers
- & Nicolai Franzmeier
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Article
| Open AccessCross-tissue analysis of blood and brain epigenome-wide association studies in Alzheimer’s disease
DNA methylation differences in Alzheimer’s disease have been previously reported, although the interpretation of the differences is unclear. Here, the authors performed epigenome-wide meta-analyses of DNA methylation in blood and brain, and developed a methylation-based risk prediction model for AD.
- Tiago C. Silva
- , Juan I. Young
- & Lily Wang
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Article
| Open AccessMulti-cohort and longitudinal Bayesian clustering study of stage and subtype in Alzheimer’s disease
Different types of atrophy in Alzheimer’s disease may reflect different disease stages or biologically distinct subtypes. Here the authors use longitudinal neuroimaging data to demonstrate five distinct patterns of atrophy with different demographical and cognitive characteristics.
- Konstantinos Poulakis
- , Joana B. Pereira
- & Eric Westman
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Article
| Open Access[11C]Martinostat PET analysis reveals reduced HDAC I availability in Alzheimer’s disease
The link between amyloid and tau proteins with Alzheimer’s disease progression remains unclear. Here, the authors propose HDACs I downregulation as an element linking the deleterious effects of brain proteinopathies with disease progression.
- Tharick A. Pascoal
- , Mira Chamoun
- & Pedro Rosa-Neto
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| Open AccessMultimodal deep learning for Alzheimer’s disease dementia assessment
Here the authors present a deep learning framework for dementia diagnosis, which can identify persons with normal cognition, mild cognitive impairment, Alzheimer’s disease, and dementia due to other etiologies.
- Shangran Qiu
- , Matthew I. Miller
- & Vijaya B. Kolachalama
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Article
| Open AccessPresenilin 2 N141I mutation induces hyperactive immune response through the epigenetic repression of REV-ERBα
Hyperimmunity is associated with Alzheimer disease. Here the authors show that the Presenilin 2 N141I mutation causes overproduction of clock-controlled cytokines and memory deficits through suppression of REV-ERBα gene by hypermethylation.
- Hyeri Nam
- , Younghwan Lee
- & Seong-Woon Yu
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Article
| Open AccessA robust and interpretable machine learning approach using multimodal biological data to predict future pathological tau accumulation
The authors present a machine learning approach that combines baseline multimodal data to accurately predict individualised trajectories of future pathological tau accumulation at asymptomatic and mildly impaired stages of Alzheimer’s disease.
- Joseph Giorgio
- , William J. Jagust
- & Zoe Kourtzi
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| Open AccessA computational model of neurodegeneration in Alzheimer’s disease
Low-dimensional representations of functional brain anatomy relevant for dementia syndromes may exist. Here the authors propose a computational model of mental functions to catalogue this anatomy in Alzheimer’s and related dementias.
- D. Jones
- , V. Lowe
- & C. Jack
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Article
| Open AccessLower novelty-related locus coeruleus function is associated with Aβ-related cognitive decline in clinically healthy individuals
Older individuals exhibiting diminished function of the locus coeruleus while learning new information show faster cognitive decline that is typical for Alzheimer’s disease.
- Prokopis C. Prokopiou
- , Nina Engels-Domínguez
- & Heidi I. L. Jacobs
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| Open AccessDeep phenotyping of Alzheimer’s disease leveraging electronic medical records identifies sex-specific clinical associations
Sex modifies Alzheimer’s Disease vulnerability, but the reasons for this are largely unknown. Here, the authors utilize two independent electronic medical record systems to perform deep clinical phenotyping and network analysis to gain insight into clinical characteristics and sex-specific clinical associations.
- Alice S. Tang
- , Tomiko Oskotsky
- & Marina Sirota
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| Open AccessA deep learning framework identifies dimensional representations of Alzheimer’s Disease from brain structure
Alzheimer’s disease is heterogeneous in its neuroimaging and clinical phenotypes. Here the authors present a semi-supervised deep learning method, Smile-GAN, to show four neurodegenerative patterns and two progression pathways providing prognostic and clinical information.
- Zhijian Yang
- , Ilya M. Nasrallah
- & Balebail Ashok Raj
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| Open AccessA national cohort study (2000–2018) of long-term air pollution exposure and incident dementia in older adults in the United States
Air pollution has been linked to neurodegenerative disease. Here the authors carried out a population-based cohort study to investigate the association between long-term exposure to PM2.5, NO2, and warm-season O3 on dementia and Alzheimer’s disease incidence in the United States.
- Liuhua Shi
- , Kyle Steenland
- & Joel Schwartz
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Article
| Open AccessAccelerated functional brain aging in pre-clinical familial Alzheimer’s disease
Alzheimer’s disease has been associated with increased structural brain aging. Here the authors describe a model that predicts brain aging from resting state functional connectivity data, and demonstrate this is accelerated in individuals with pre-clinical familial Alzheimer’s disease.
- Julie Gonneaud
- , Alex T. Baria
- & Etienne Vachon-Presseau
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Article
| Open AccessA machine learning approach to brain epigenetic analysis reveals kinases associated with Alzheimer’s disease
Array-based epigenome-wide association studies only test about 2% of the CpG sites in the genome. Here, the authors describe EWASplus, a supervised machine learning strategy that extends EWAS coverage to the entire genome, and use it to identify novel brain CpGs associated with Alzheimer’s disease.
- Yanting Huang
- , Xiaobo Sun
- & Zhaohui S. Qin
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Article
| Open AccessHigher CSF sTNFR1-related proteins associate with better prognosis in very early Alzheimer’s disease
Neuroinflammation is observed in Alzheimer’s disease. Here the authors show that 15 proteins related to inflammation found in CSF can potentially be used as a prognostic biomarker.
- William T. Hu
- , Tugba Ozturk
- & Gloria Chiang
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Article
| Open AccessKL-VS heterozygosity is associated with lower amyloid-dependent tau accumulation and memory impairment in Alzheimer’s disease
The KL-VS haplotype of the Klotho gene has been associated with reduced risk of Alzheimer’s disease and dementia. Here the authors show an association between the KL-VS haplotype and amyloid-dependent tau accumulation using PET data.
- Julia Neitzel
- , Nicolai Franzmeier
- & Michael Ewers
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Article
| Open AccessIncreased excitatory to inhibitory synaptic ratio in parietal cortex samples from individuals with Alzheimer’s disease
Synaptic loss may disturb the excitatory to inhibitory balance (E/I ratio) in circuits vulnerable in Alzheimer’s disease (AD). The authors find reduced synaptic levels of PSD-95 and gephyrin and show that individuals with AD exhibit a pro-excitatory shift of postsynaptic densities and the electrophysiological synaptic E/I ratio in the parietal cortex.
- Julie C. Lauterborn
- , Pietro Scaduto
- & Agenor Limon
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Article
| Open AccessAssociation of sleep duration in middle and old age with incidence of dementia
Sleep dysregulation has been linked to dementia, but it is unknown whether sleep duration earlier in life is associated with dementia risk. Here, the authors show higher dementia risk associated with short sleep duration (six hours or less) in a longitudinal study of middle and older age adults.
- Séverine Sabia
- , Aurore Fayosse
- & Archana Singh-Manoux
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Article
| Open AccessTherapeutic B-cell depletion reverses progression of Alzheimer’s disease
Alzheimer’s disease is characterized by progressive dementia and amyloid beta plaque deposition. Here the authors show in three relevant transgenic animal models that accumulation of activated B cells is central to AD pathology and depletion of B cells interferes with both histological and behavioural manifestations of the disease.
- Ki Kim
- , Xin Wang
- & Arya Biragyn
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Perspective
| Open AccessIncreasing the reproducibility of fluid biomarker studies in neurodegenerative studies
Many fluid biomarker findings have had low reproducibility despite initially promising results. Here, the authors review possible sources for low reproducibility of studies on fluid biomarkers for neurodegenerative diseases and suggest guidelines for the biomarker community to agree on and implement.
- Niklas Mattsson-Carlgren
- , Sebastian Palmqvist
- & Oskar Hansson
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Article
| Open AccessMolecular estimation of neurodegeneration pseudotime in older brains
The limited understanding of the temporal molecular changes in late-onset Alzheimer’s disease hinder the development of therapeutic treatment. The authors use manifold learning to develop a molecular model for disease progression from RNASeq data from human postmortem brain samples.
- Sumit Mukherjee
- , Laura Heath
- & Benjamin A. Logsdon
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Article
| Open AccessRisk prediction of late-onset Alzheimer’s disease implies an oligogenic architecture
Despite the identification of genetic risk loci for late-onset Alzheimer’s disease (LOAD), the genetic architecture and prediction remains unclear. Here, the authors use genetic risk scores for prediction of LOAD across three datasets and show evidence suggesting oligogenic variant architecture for this disease.
- Qian Zhang
- , Julia Sidorenko
- & Peter M. Visscher
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Article
| Open AccessA unified neurocognitive model of semantics language social behaviour and face recognition in semantic dementia
Semantic dementia patients present with a core semantic impairment and variations of language, behavioural and face recognition abilities. Here, the authors build a unified multidimensional model to capture all these graded symptoms and map them to the variations in the patients’ frontotemporal atrophy.
- Junhua Ding
- , Keliang Chen
- & Matthew. A. Lambon Ralph
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Article
| Open AccessCerebrospinal fluid p-tau217 performs better than p-tau181 as a biomarker of Alzheimer’s disease
Cerebrospinal fluid (CSF) p-tau181 (tau phosphorylated at threonine 181) is an established biomarker of Alzheimer’s disease (AD) reflecting abnormal tau metabolism in the AD brain. Here the authors demonstrate that CSF p-tau217 shows better performance as an AD biomarker than p-tau181.
- Shorena Janelidze
- , Erik Stomrud
- & Oskar Hansson
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Article
| Open AccessCerebrospinal fluid lipocalin 2 as a novel biomarker for the differential diagnosis of vascular dementia
Diagnosis of vascular dementia is hampered by the lack of biochemical markers for this disease. Here, the authors show that vascular dementia is associated with increased lipocalin-2 in cerebrospinal fluid, compared to controls and patients with other forms of dementia.
- Franc Llorens
- , Peter Hermann
- & Inga Zerr