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News & Views |
APOE4 homozygosity is a new genetic form of Alzheimer’s disease
New data confirm that APOE4 homozygosity is a major genetic cause of Alzheimer’s disease, warranting the development of specialized research strategies, treatment approaches and clinical trials.
- Qin Xu
- , Zherui Liang
- & Yadong Huang
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Article |
APOE4 homozygozity represents a distinct genetic form of Alzheimer’s disease
The study on APOE4 homozygosity indicates a genetic variant of Alzheimer’s disease with early symptom onset and distinct biomarker progression, highlighting the need for specialized treatment approaches.
- Juan Fortea
- , Jordi Pegueroles
- & Víctor Montal
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Research Highlight |
A timeline of biomarker changes before Alzheimer’s disease
Longitudinal data from the China Cognition and Aging Study map the sequential biomarker changes that begin almost two decades before clinical onset of Alzheimer’s disease.
- Karen O’Leary
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Article
| Open Access
Highly accurate blood test for Alzheimer’s disease is similar or superior to clinical cerebrospinal fluid tests
The performance of plasma %p-tau217 is clinically equivalent in classification of Aβ PET status and superior in classification of tau PET status compared to clinically used and FDA-approved CSF tests in cognitively impaired participants.
- Nicolas R. Barthélemy
- , Gemma Salvadó
- & Oskar Hansson
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Article
| Open Access
Iatrogenic Alzheimer’s disease in recipients of cadaveric pituitary-derived growth hormone
A small number of patients who received growth hormone preparations contaminated with seeds of the amyloid-beta protein developed Alzheimer’s disease many years after treatment.
- Gargi Banerjee
- , Simon F. Farmer
- & John Collinge
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Research Highlight |
Modeling real-world data to repurpose drugs for Alzheimer’s disease
Researchers used machine-learning models to emulate thousands of clinical trials from over 10 years’ worth of real-world data, generating a shortlist of five candidate drugs for repurposing.
- Karen O’Leary
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Article |
Senolytic therapy in mild Alzheimer’s disease: a phase 1 feasibility trial
The first feasibility study of orally delivered senolytic therapy in Alzheimer’s disease reports favorable safety data and penetrance of dasatinib into the brain with a modest impact on Alzheimer’s and aging biomarkers.
- Mitzi M. Gonzales
- , Valentina R. Garbarino
- & Miranda E. Orr
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Review Article |
Emerging diagnostics and therapeutics for Alzheimer disease
This Review summarizes recent advances in biomarkers and therapies for Alzheimer disease—the products of decades of research—and discusses the challenges, gaps and clinical implications.
- Wade K. Self
- & David M. Holtzman
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Article
| Open Access
Sex differences in brain protein expression and disease
Analyses of 1,277 human brain proteomes reveal the extent of sex differences in the brain and identify genes associated with neuropsychiatric traits that have differential regulation between males and females.
- Aliza P. Wingo
- , Yue Liu
- & Thomas S. Wingo
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Research Briefing |
Events in the brain during the evolution of Alzheimer’s disease
Alzheimer’s disease is a complex and chronic disease that evolves over decades. Proteomic analysis of cerebrospinal fluid from people with dominantly inherited forms of the disease reveals the temporal progression of pathological changes in Alzheimer’s disease and identifies extracellular matrix proteins as some of the earliest biomarkers of the disease.
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Article
| Open Access
Cerebrospinal fluid proteomics define the natural history of autosomal dominant Alzheimer’s disease
Proteomic analysis of cerebrospinal fluid from individuals with autosomal dominant Alzheimer’s disease reveals how this complex and chronic disease evolves over many decades.
- Erik C. B. Johnson
- , Shijia Bian
- & John Ringman
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Research Briefing |
A fluid biomarker accurately detects tau aggregate pathology in Alzheimer’s disease
Cost-effective fluid biomarkers for tau aggregate pathology would improve the diagnostic and prognostic work-up of Alzheimer’s disease and facilitate the discovery of anti-tau therapies. We identified MTBR-tau243 as a specific marker for tau aggregate pathology that could be implemented in clinical practice and trials.
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Research Highlight |
Putting the brakes on Alzheimer’s disease
The monoclonal antibody donanemab, which clears amyloid plaques in the brain, slowed clinical progression of early symptomatic Alzheimer’s disease.
- Karen O’Leary
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Article
| Open Access
Cognitive effects of Lewy body pathology in clinically unimpaired individuals
A longitudinal study of clinically unimpaired individuals reveals that Lewy body pathology measured in vivo is associated with worse smell and cognitive functions and predicted subsequent cognitive decline and progression to Parkinson’s disease or dementia with Lewy bodies.
- Sebastian Palmqvist
- , Marcello Rossi
- & Oskar Hansson
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Article
| Open Access
Clinical effects of Lewy body pathology in cognitively impaired individuals
Prospective and longitudinal analyses of patients with cognitive impairment reveal that in vivo detection of Lewy body pathology is independently associated with hallucinations, worse attention/executive, visuospatial and motor function and predicted future cognitive decline.
- Corinne Quadalti
- , Sebastian Palmqvist
- & Piero Parchi
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Article
| Open Access
CSF MTBR-tau243 is a specific biomarker of tau tangle pathology in Alzheimer’s disease
CSF MTBR-tau243 is more related to tau tangles and clinical cognitive impairment in Alzheimer’s disease than phospho-tau biomarkers, which are more related to amyloid plaques.
- Kanta Horie
- , Gemma Salvadó
- & Randall J. Bateman
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News & Views |
Clonal hematopoiesis, aging and Alzheimer’s disease
Unexpectedly, new data show that clonal hematopoiesis is associated with protection from Alzheimer’s disease; it is imperative that future studies unravel the complex tissue–disease contexts in which clonal hematopoiesis arises and contributes to aging-associated diseases.
- Pablo Sánchez Vela
- , Jennifer J. Trowbridge
- & Ross L. Levine
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Article
| Open Access
Astrocyte reactivity influences amyloid-β effects on tau pathology in preclinical Alzheimer’s disease
Cross-sectional and longitudinal analyses of tau pathology in preclinical Alzheimer’s disease reveal that tau tangles accumulate as a function of amyloid-β burden only in individuals positive for an astrocyte reactivity biomarker.
- Bruna Bellaver
- , Guilherme Povala
- & Tharick A. Pascoal
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Correspondence |
In global approaches to dementia research, do not forget care
- Fanny Monnet
- , Charlèss Dupont
- & Lara Pivodic
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Article
| Open Access
Resilience to autosomal dominant Alzheimer’s disease in a Reelin-COLBOS heterozygous man
Case report of an individual heterozygous for a rare RELN-COLBOS variant that confers resilience, via a gain-of-function mechanism, to Alzheimer’s disease.
- Francisco Lopera
- , Claudia Marino
- & Yakeel T. Quiroz
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Article
| Open Access
Tau-targeting antisense oligonucleotide MAPTRx in mild Alzheimer’s disease: a phase 1b, randomized, placebo-controlled trial
Evaluation of a tau-targeting antisense oligonucleotide in a phase 1 trial of patients with mild AD found it was well tolerated and resulted in a sustained reduction of tau protein levels.
- Catherine J. Mummery
- , Anne Börjesson-Hanson
- & Roger M. Lane
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Article
| Open Access
Amyloid and tau PET-positive cognitively unimpaired individuals are at high risk for future cognitive decline
Abnormal amyloid and tau PET in cognitively unimpaired individuals is strongly associated with short-term cognitive decline and subsequent development of dementia.
- Rik Ossenkoppele
- , Alexa Pichet Binette
- & Oskar Hansson
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Brief Communication
| Open Access
Plasma p-tau231 and p-tau217 as state markers of amyloid-β pathology in preclinical Alzheimer’s disease
A comprehensive comparison of Alzheimer’s disease blood biomarkers in cognitively unimpaired individuals reveals that plasma p-tau231 and p-tau217 capture very early Aβ changes, showing promise as markers to enrich a preclinical population for Alzheimer’s disease clinical trials
- Marta Milà-Alomà
- , Nicholas J. Ashton
- & Kaj Blennow
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Article |
Anti-inflammatory clearance of amyloid-β by a chimeric Gas6 fusion protein
An engineered protein engages the efferocytosis pathway to induce amyloid-β engulfment, resulting in behavioral rescue in Alzheimer’s disease mouse models without the increased inflammation or vascular pathology associated with conventional antibody therapy
- Hyuncheol Jung
- , Se Young Lee
- & Chan Hyuk Kim
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News & Views |
Comorbidities confound Alzheimer’s blood tests
The concentrations of two key blood biomarkers for Alzheimer’s disease are affected by some medical conditions, which could potentially lead to misdiagnosis.
- Suzanne E. Schindler
- & Thomas K. Karikari
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Article |
Performance of plasma phosphorylated tau 181 and 217 in the community
Multiple comorbidities are associated with higher plasma P-tau181 and P-tau217 levels, and affects their normal reference ranges and cutpoints.
- Michelle M. Mielke
- , Jeffrey L. Dage
- & Ronald C. Petersen
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Research Highlight |
Mapping the mediators of Alzheimer’s disease
A novel technique enables molecular profiling of cell types in the brain vasculature and expands understanding of the pathophysiology of Alzheimer’s disease.
- Karen O’Leary
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Article |
Microglial activation and tau propagate jointly across Braak stages
Microglial activation and tau accumulation propagate together in patients with Alzheimer’s disease, suggesting an interaction that determines disease progression.
- Tharick A. Pascoal
- , Andrea L. Benedet
- & Pedro Rosa-Neto
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World View |
Why aducanumab is important
Approval of aducanumab will herald a new era in Alzheimer’s disease care and research.
- Jeffrey Cummings
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News & Views |
Tau-targeting antibody therapies: too late, wrong epitope or wrong target?
Two phase 2 studies of N-terminal tau–targeting antibody therapy fail to show clinical efficacy in progressive supranuclear palsy, despite evidence of target engagement.
- Edwin Jabbari
- & Karen E. Duff
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News & Views |
Dominantly inherited Alzheimer’s disease: a compass for drug development
The first phase 3 trial of amyloid-β-targeting monoclonal antibodies in dominantly inherited Alzheimer’s disease failed to slow cognitive decline in patients. Could it still help to inform future study design and drug development in this setting?
- Gil D. Rabinovici
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Article |
A trial of gantenerumab or solanezumab in dominantly inherited Alzheimer’s disease
Results from the phase 2/3 clinical trial of gantenerumab or solanezumab in dominantly inherited Alzheimer’s disease reveal no beneficial effects on cognitive measures despite a significant reduction in amyloid plaques and other key biomarkers in those treated with gantenerumab.
- Stephen Salloway
- , Martin Farlow
- & Christopher H. van Dyck
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Article |
Prediction of future Alzheimer’s disease dementia using plasma phospho-tau combined with other accessible measures
Plasma P-tau, in combination with clinical measures, predicts future Alzheimer’s disease dementia in two independent cohorts with high accuracy and is superior to the clinical diagnostic predictions of specialists.
- Sebastian Palmqvist
- , Pontus Tideman
- & Oskar Hansson
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Article |
Four distinct trajectories of tau deposition identified in Alzheimer’s disease
Systematic characterization of longitudinal tau variability in human Alzheimer’s disease using an unbiased subtyping algorithm reveals four trajectories of tau deposition with distinct clinical features.
- Jacob W. Vogel
- , Alexandra L. Young
- & Oskar Hansson
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Letter |
Tau molecular diversity contributes to clinical heterogeneity in Alzheimer’s disease
A molecular analysis of tau from patients with sporadic Alzheimer’s disease reveals striking diversity in biochemical properties between patients, which influences seeding activity and correlates with the aggressiveness of the disease.
- Simon Dujardin
- , Caitlin Commins
- & Bradley T. Hyman
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Resource |
Large-scale proteomic analysis of Alzheimer’s disease brain and cerebrospinal fluid reveals early changes in energy metabolism associated with microglia and astrocyte activation
Large-scale, comprehensive proteomic profiling of Alzheimer’s disease brain and cerebrospinal fluid reveals disease-associated protein coexpression modules and highlights the importance of glia and energy metabolism in disease pathogenesis.
- Erik C. B. Johnson
- , Eric B. Dammer
- & Nicholas T. Seyfried
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News & Views |
Another step forward in blood-based diagnostics for Alzheimer’s disease
Measurement of phosphorylated tau protein in blood plasma allows Alzheimer’s disease to be distinguished from other neurological diseases and may assist in disease detection during the prodromal stage.
- Randall J. Bateman
- , Nicolas R. Barthélemy
- & Kanta Horie
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Article |
Diagnostic value of plasma phosphorylated tau181 in Alzheimer’s disease and frontotemporal lobar degeneration
Plasma pTau181 concentrations are elevated specifically in patients diagnosed with Alzheimer’s disease compared to those diagnosed with frontotemporal lobar degeneration or elderly controls, supporting its further development as a blood-based biomarker for AD.
- Elisabeth H. Thijssen
- , Renaud La Joie
- & Bradford C. Dickerson
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Article |
Plasma P-tau181 in Alzheimer’s disease: relationship to other biomarkers, differential diagnosis, neuropathology and longitudinal progression to Alzheimer’s dementia
Plasma P-tau18 level increased with progression of Alzheimer’s disease (AD) and differentiated AD dementia from other neurodegenerative diseases, supporting its further development as a blood-based biomarker for AD.
- Shorena Janelidze
- , Niklas Mattsson
- & Oskar Hansson
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News & Views |
Imaging the glutamate synapse
A new positron emission tomography radiotracer enables imaging of the human glutamate receptor AMPA-R, a fundamental component of neurotransmission involved in neuropsychiatric disorders.
- John H. Krystal
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Article |
Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and TREM2-independent cellular responses in Alzheimer’s disease
Single-nucleus RNA sequencing in a mouse model of Aβ accumulation and postmortem brain tissue from people with Alzheimer’s disease reveals substantial species-specific differences in transcriptional signatures, but both point to the contribution of glia and the importance of TREM2.
- Yingyue Zhou
- , Wilbur M. Song
- & Marco Colonna
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News & Views |
An Alzheimer’s-disease-protective APOE mutation
Homozygous APOE3-Christchurch (R136S) mutation protects a presenilin 1 (PSEN1) mutation carrier from developing Alzheimer’s disease until her seventies.
- Kelly A. Zalocusky
- , Maxine R. Nelson
- & Yadong Huang
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Letter |
Genetic predisposition, modifiable-risk-factor profile and long-term dementia risk in the general population
Genetic predispositions and lifestyle factors can interact to either confer protection against, or elevate risk for, development of clinical dementia in a prospective cohort of over 6,000 individuals from the population-based Rotterdam Study.
- Silvan Licher
- , Shahzad Ahmad
- & M. Kamran Ikram
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Letter |
Adult hippocampal neurogenesis is abundant in neurologically healthy subjects and drops sharply in patients with Alzheimer’s disease
Newborn neurons are continuously incorporated into the healthy adult human hippocampus up to the ninth decade of life. However, robust adult hippocampal neurogenesis sharply declines during the progression of Alzheimer’s disease.
- Elena P. Moreno-Jiménez
- , Miguel Flor-García
- & María Llorens-Martín
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News & Views |
Biomarkers for Alzheimer’s disease beyond amyloid and tau
Two new biomarkers for Alzheimer’s disease include one in the blood that relates to neurodegeneration and another that reflects blood–brain barrier dysfunction and is identifiable in cerebrospinal fluid analysis.
- Henrik Zetterberg
- & Jonathan M. Schott
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Article |
ApoE attenuates unresolvable inflammation by complex formation with activated C1q
ApoE is a direct checkpoint inhibitor of unresolvable inflammation in neurodegenerative and cardiovascular diseases
- Changjun Yin
- , Susanne Ackermann
- & Andreas J. R. Habenicht
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Letter |
Serum neurofilament dynamics predicts neurodegeneration and clinical progression in presymptomatic Alzheimer’s disease
In a longitudinal cohort of familial Alzheimer’s disease patients, the rate of change of blood biomarker levels identifies disease carriers much earlier than absolute levels and predicts both neurodegeneration and cognitive decline.
- Oliver Preische
- , Stephanie A. Schultz
- & Xiong Xu
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Letter |
Blood–brain barrier breakdown is an early biomarker of human cognitive dysfunction
Neuroimaging and cerebrospinal fluid analyses in humans reveal that loss of blood–brain barrier integrity and brain capillary pericyte damage are early biomarkers of cognitive impairment that occur independently of changes in amyloid-β and tau.
- Daniel A. Nation
- , Melanie D. Sweeney
- & Berislav V. Zlokovic
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News & Views |
An exercise-induced messenger boosts memory in Alzheimer’s disease
An exercise-linked hormone, FNDC5/irisin, mediates the benefit of exercise in Alzheimer’s disease models by enhancing synaptic plasticity and memory.
- Xu Chen
- & Li Gan
p75 neurotrophin receptor modulation in mild to moderate Alzheimer disease: a randomized, placebo-controlled phase 2a trial