Claude Wischik on TauRx Parses Subgroups to Make the Case for Methylene Blue Derivative, Again

COMMENT commentators take exception to the difference in outcomes between participants receiving HMTM as monotherapy

Thomas Beach on Etiology of White Matter Hyperintensities in Autosomal Dominant and Sporadic Alzheimer Disease.

COMMENT Agree that it is no longer correct to assume that white matter rarefaction is equivalent to or completely accounted for by small vessel disease. Our comprehensive postmortem study suggests that neuofibrillary tangles are statistically a much greater predi

Thomas Beach on Skin Deep: Punch Biopsies Detect Synucleinopathies

COMMENT The publication of Gibbons et al., like most clinical biomarker studies, suffers first and foremost from the use of an inadequate gold standard. The clinical diagnoses of Parkinson’s disease, dementia with Lewy bodies, and multiple system atrophy are all

Suzanne Schindler on Could New Alzheimer’s Marker p-Tau212 Rival p-Tau217?

COMMENT Kac and colleagues validated an immunoassay for plasma p-Tau212 in multiple clinical and autopsy cohorts. They demonstrated that their p-Tau212 antibody does not cross-react with p-Tau217. However, the results for their plasma p-Tau212 and p-Tau217 assays

Markus Zweckstetter on Could Sumoylation Take Down Tangles?

COMMENT This highly interesting study supports an important role of sumoylation as a post-translational modification that solubilizes aggregation prone proteins. The study focuses on SUMO2, and it will be interesting to see how modification by SUMO2 compares to m

Amy Pooler on Could Sumoylation Take Down Tangles?

COMMENT It’s been almost a decade since the exciting initial discovery of tau SUMOylation by SUMO1, which inhibits degradation of tau and promotes its accumulation. However, it is unknown whether other SUMO isoforms have a similar role. Perhaps surprisingly, thes

Dervis Salih on Easing Microglial Brakes Alleviates Amyloid Pathology in Mice

COMMENT This is an exciting study by Hou and colleagues showing that modulating LILRB4 using an antibody likely inhibits LILRB4 binding to APOE, activating microglia and attenuating Aβ-related measures, such as plaque load and neuronal dystrophy. This study follo

Martine Therrien on Easing Microglial Brakes Alleviates Amyloid Pathology in Mice

COMMENT Microglia with unique transcriptional signatures have been identified in Alzheimer’s disease patients and animal models (Keren-Shaul et al., 2017). Understanding the regulation and impact of these states is essential if we want to know how to modulate mic

Renzo Mancuso on Easing Microglial Brakes Alleviates Amyloid Pathology in Mice

COMMENT This is very interesting work, as it dives into the plethora of receptors that control microglial function. For very good reasons, the field has focused extensively on some specific molecules, such as TREM2 or CD33, but microglia express a vast diversity

Markku Kurkinen on Shrunken FDA Advisory Committee Is Unanimous: Leqembi Works

COMMENT Lecanemab did not work for women, which is bad news because there are twice as many women as men with AD. Lecanemab did not work for APOE4 carriers, which is bad news for AD patients, 60–75 percent of whom have one or two APOE4 genes. Remarkably, for some

Steven Clapcote on Disrupted mitochondrial response to nutrients is a presymptomatic event in the cortex of the APPSAA knock-in mouse model of Alzheimer disease

COMMENT The original paper on the App-SAA knock-in mouse model of Alzheimer’s disease (JAX: 034711) reported that FDG-PET uptake, a surrogate for glucose utilization in brain, revealed cortical hypermetabolism across the studied lifespan of 5-20 months in homozyg

David Sanders on At ADPD, Scientists Dissect the Ins and Outs of Tau Propagation

COMMENT A word of caution for those who are trying to extract biological meaning from tau RD biosensor cell lines: Nuclear tau aggregates are an artifact of the truncation used in the model. Disease-relevant full-length tau aggregates never localize to the nucleu

Charlotte Teunissen, Wilma D.J. Van de Berg on Skin Deep: Punch Biopsies Detect Synucleinopathies

COMMENT In Parkinson’s as in Alzheimer’s disease, biological markers are important to improve early diagnostics. This paper provides strong evidence that cutaneous phosphorylated α-synuclein may serve as diagnostic biomarker for Parkinson’s disease (PD), dementia

Oskar Hansson on Skin Deep: Punch Biopsies Detect Synucleinopathies

COMMENT This study confirms previous smaller studies showing that the levels of phosphorylated α-synuclein are increased in peripheral nerve terminals in the skin in neurological diseases characterized by accumulation of α-synuclein aggregates in the brain. The s

Guojun Bu on In AD, Effects of Some Genetic Variants Limited to Cell Subtypes

COMMENT In this comprehensive work by the de Jager team, the authors addressed the effects of genetic variants on cell type- and cell subtype-specific gene expression in human brains. Using a large number of human brains and a wealth of genetic and new single-nuc