In a therapy-like paradigm, suppressing astrocyte ApoE4 toned down tau accumulation, reined in microglia, and assuaged neurodegeneration. Treated mice resumed building nests.
New research implicates IL-6 signaling and even Aβ42 itself as BACE targets, complicating scientists’ efforts to resurrect BACE inhibitors at a lower dose.
Data from Phase 3 trials of elenbecestat show no harm to cognition, leaving open a chance that the drugs could be used safely in the future.
The first whole-genome manipulation of protein expression in neurons by CRISPR uncovers a deadly chain of events. Poor processing by lysosomes leads to a build-up of lipids and iron that revs up oxidative stress, killing neurons via ferroptosis.
African Americans are more likely than non-Hispanic Caucasians to carry variants that curtail expression of TREM2, and are less likely to inherit a variant that enhances it. As a result, they have less soluble TREM2 in their cerebrospinal fluid.
By shifting to home nursing and telemedicine, clinical researchers kept inching ahead during lockdowns.
At AD/PD 2021, clinicians described neurological symptoms and tissue damage in the brains of older people who died from severe COVID-19.
In the negative Phase 2 trial of prasinezumab, populations with more rapid decline benefited; this informed the design of a new Phase 2b study.
Virtual Exhibit Hall
Alzforum encourages users to visit the Virtual Exhibit Hall, where companies showcase their newest initiatives, products, and services. We welcome F. Hoffmann-La Roche, joining our other exhibitors — Biogen, BioLegend, Abcam, BrainXell, and the Jackson Laboratory.
ApoE4, the strongest genetic risk factor for late-onset AD, is known to exacerbate the havoc caused by tau pathology. Now, researchers report that removing ApoE4 only from astrocytes assuages neurodegeneration, tau pathology, and even keeps microglia from devouring synapses. The findings paint astrocytic ApoE as an orchestrator of neurodegeneration.
BACE Inhibition: Not Quite Dead, But Complicated
Research presented at the 2021 AD/PD conference provides a glimmer of hope for BACE inhibitor therapy. Full data from the terminated Phase 3 elenbecestat trials finds no cognitive deficit, demonstrating that this side effect can be avoided. Meanwhile, basic research turns up a new BACE1 substrate, Gp130, which may affect synaptic transmission through IL-6 signaling. Other evidence implicates BACE1 in degrading Ab42, as well as forming it, suggesting inhibitor dosing might have to balance these roles. Altogether, BACE experts still see a pathway for low-dose BACE inhibition as a preventative strategy. Read Madolyn Bowman Rogers’ Drop of Hope? No Cognitive Worsening on BACE Inhibitor and What BACE Hits: New Substrates Create New Headaches.
The first-ever genome-wide CRISPR screen in human neurons discovered that a toxic brew of lysosomal lipids, reactive iron atoms, and oxidative stress can spell doom for this cell type specifically. Researchers led by Martin Kampmann at the University of California, San Francisco, used the genome-editing tool to dial up or down expression of each protein-coding gene in the human neuronal genome. They uncovered a surprising connection between endolysosomal processing and the iron-dependent cell-death pathway called ferroptosis. In a separate CRISPR screen, the scientists implicated endosomal-transport genes—particularly the enzyme PIK-fyve—in α-synuclein aggregation.
Compared to non-Hispanic Caucasians, African Americans are more likely to carry TREM2 gene variants that curtail its expression, and are less likely to inherit a variant that enhances its processing. As a result, they have less soluble TREM2 in their cerebrospinal fluid. Understanding differences in TREM2 biology could be important when deciding cutoffs for diagnostic biomarkers or enrolling in clinical trials.
How SARS-CoV-2 Messes with the Brain, Alzheimer’s Clinical Trials
At this year’s virtual AD/PD, scientists grappled with how SARS-CoV-2 manages to worsen people’s pre-existing neurologic conditions. (Hint: activated microglia.) They shared their experiences of trying to save ongoing clinical trials through the COVID-19 waves and lockdowns in their respective regions. And they discussed how to handle COVID-19 cases that crop up during current and future dementia trials. Meanwhile, U.S. national 2020 mortality data came out, confirming scientists’ worry that, in this year of COVID, Alzheimer’s deaths indeed rose disproportionately. Read Chelsea Weidman-Burke’s update in two parts, COVID-19 Worsens Neurological Problems, Delirium and Clinical Trials in COVID Era: How To Keep Moving Forward.
- Jesse Hanson on Squelching ApoE in Astrocytes of Tau-Ravaged Mice Dampens Degeneration
- Priyanka Narayan on Squelching ApoE in Astrocytes of Tau-Ravaged Mice Dampens Degeneration
- John Fryer on Squelching ApoE in Astrocytes of Tau-Ravaged Mice Dampens Degeneration
- Robert Vassar on What BACE Hits: New Substrates Create New Headaches
- Robert Vassar on Drop of Hope? No Cognitive Worsening on BACE Inhibitor
- Stefan Lichtenthaler on Drop of Hope? No Cognitive Worsening on BACE Inhibitor
- Justin Ichida on Dysfunctional Lysosomes Cause Ferroptosis in Neurons
- Nathaniel Safren on Dysfunctional Lysosomes Cause Ferroptosis in Neurons
- William Hu on Dysfunctional Lysosomes Cause Ferroptosis in Neurons
- Jessica Young on Dysfunctional Lysosomes Cause Ferroptosis in Neurons
- Ellen Sidransky on Dysfunctional Lysosomes Cause Ferroptosis in Neurons
- Minerva Carrasquillo on TREM2 Variants and CSF sTREM2 Levels Differ by Race
- Arnon Rosenthal and Hervé Rhinn on TREM2 Variants and CSF sTREM2 Levels Differ by Race
- Mark Gluck on TREM2 Variants and CSF sTREM2 Levels Differ by Race
- William Hu on TREM2 Variants and CSF sTREM2 Levels Differ by Race
- Frank Gunn-Moore on Field Loses David Allsop, First to Isolate Amyloid
- Colin Masters and Konrad Beyreuther on Field Loses David Allsop, First to Isolate Amyloid
- Delphine Boche, Claire Paquet, Jacques Hugon and James Nicoll on Donanemab Confirms: Clearing Plaques Slows Decline—By a Bit
- Michael Lardelli on New Mouse Models Better Mimic Tauopathy, Alzheimer's
- Ashley Bush on Field Loses David Allsop, First to Isolate Amyloid
- Martin Citron on N-Terminal Tau Antibodies Fade, Mid-Domain Ones Push to the Fore