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The APOE-ε4 allele is the strongest genetic risk factor for late-onset Alzheimer’s disease, but it is not deterministic. Here, the authors show that common genetic variation changes how APOE-ε4 influences cognition.

Two new phosphorylation sites, p-tau₂₆₂ and p-tau₃₅₆, detect the formation of prefibrillar tau aggregates and may serve as early-stage biofluid-based biomarkers of tau neurofibrillary tangle pathology in Alzheimer’s disease.

A European working group has provided a new set of recommendations for the use of cerebrospinal fluid (CSF) biomarkers in the diagnostic evaluation of Alzheimer disease and mild cognitive impairment. These recommendations represent an important step towards the implementation of CSF biomarker tests in the clinic, but several challenges remain.

A range of blood-based biomarkers have shown high specificity for Alzheimer’s disease (AD) pathophysiology with phosphorylated-tau (p-tau) being the most promising test. Here, the authors show the utility of plasma p-tau212 in autopsy-confirmed AD and memory clinic patient cohorts.

Large genome-wide meta-analysis of clinically diagnosed late-onset Alzheimer’s disease (LOAD) from 94,437 individuals identifies new LOAD risk loci and implicates Aβ formation, tau protein binding, immune response and lipid metabolism.

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.

An integrated analysis of several cohorts shows that clonal, antigen-experienced T cells are found in the cerebrospinal fluid of patients with Alzheimer’s disease, suggesting that the adaptive immune system has a role in age-related neurodegeneration.

Whole-genome sequence analysis identifies five independent risk loci for Lewy body dementia and demonstrates overlapping genetic architecture with Alzheimer’s and Parkinson’s diseases.

Genome-wide analyses identify common variants associated with 11 distinct neuropathology endophenotypes, providing insights into the mechanisms underlying the genetic risk of Alzheimer’s disease and related dementias.

Therriault et al. provide a framework for the individual-level interpretation of plasma biomarkers by determining their positive and negative predictive values for amyloid positron emission tomography status in relation to patient age and clinical symptoms.

Saloner et al. used large-scale cerebrospinal fluid proteomics to uncover molecular signatures in frontotemporal dementia, revealing RNA splicing and synaptic protein candidate markers for genetic and sporadic disease progression.

Meta-analysis of genome-wide association studies on Alzheimer’s disease and related dementias identifies new loci and enables generation of a new genetic risk score associated with the risk of future Alzheimer’s disease and dementia.

Empirically based models of disease progression in familial frontotemporal dementia reveal the relative ordering of clinical, neuroimaging, and fluid biomarker changes and facilitate novel clinical trial designs

Márquez et al. examine associations between blood-based biomarkers of neurodegenerative processes and cognitive performance in over 5,700 Hispanic/Latino adults in the United States. They find that higher levels of phosphorylated tau and neurofilament light are linked to poorer cognitive performance.

APOE is the major genetic risk factor for Alzheimer’s disease. In a large number of neuropathologically confirmed cases and controls, the impact of different APOE genotypes on Alzheimer’s dementia risk was greater than previously thought and APOE2 homozygotes had an exceptionally low risk.

A phase 2 clinical trial of active immunization against a pathological form of the tau protein provides evidence for feasibility of this approach. Although active treatment did not show benefits on clinical outcome measures, analyses of fluid biomarkers and of a subset of patients with predicted pathology provide hints of efficacy.

Metabolomics is improved by using a reference library of both known and unknown molecules.

Parkinson’s diseases and other synucleinopathies are on the verge of a major paradigm shift toward being defined and staged by their biology, rather than symptoms; this Perspective offers context on progress, needs and opportunities toward this goal.

The authors present a small noncoding RNA atlas characterizing two longitudinal Parkinson’s disease cohorts and reveal potential biomarkers for disease detection, their relation to molecular hallmarks of PD and regulatory disease-progression modules.

Sven van der Lee, Julie Williams, Gerard Schellenberg and colleagues identify rare coding variants in PLCG2, ABI3 and TREM2 associated with Alzheimer's disease. These genes are highly expressed in microglia and provide additional evidence that the microglia-mediated immune response contributes to the development of Alzheimer's disease.

Gerard Schellenberg and colleagues report a genome-wide association study of late-onset Alzheimer's disease (LOAD), as part of the Alzheimer Disease Genetics Consortium. They identify common variants in MS4A4/MS4A6E, CD2AP, CD33 and EPHA1 associated with LOAD.

Vivianna Van Deerlin and colleagues report that common variants at 7p21 are associated with a subtype of frontotemporal lobar degeneration marked by TDP-43 inclusions. They further show that the risk alleles are associated with elevated brain expression of TMEM106B, which resides at the peak of association on 7p21.

David Whitcomb, Bernie Devlin and colleagues report the results of a genome-wide association study of pancreatitis. They identify common variants at two loci associated with risk of this disease, including one on the X chromosome that shows strong evidence of interaction with alcohol consumption.

Anti-amyloid treatments for early symptomatic Alzheimer disease have greatly increased the need for biomarker confirmation of amyloid pathology and blood biomarker tests offer an accessible and scalable biomarker test. This Consensus Statement provides recommendations for the minimum acceptable performance of blood biomarker tests for clinical use.

ASLPrep is a software suite for reproducible processing of arterial spin labeled magnetic resonance imaging data.

Gerard Schellenberg and colleagues report a genome-wide association study for progressive supranuclear palsy, a movement disorder with prominent tau neuropathology. They identified three new risk loci and confirmed the known risk locus at MAPT.