Antisense oligonucleotides (ASOs) have shown promise in reducing amyloid precursor protein (APP) levels in neurons, but their effects in astrocytes, key contributors to neurodegenerative diseases, remain unclear. This study evaluates the efficacy of APP ASOs in astrocytes derived from an individual with Down syndrome (DS), a population at high risk for Alzheimer's disease (AD).
Human induced pluripotent stem cells (hiPSCs) from a healthy individual and an individual with DS were differentiated into astrocytes. Astrocytes were treated with APP ASOs for 10 days, and APP levels were quantified. Mitochondrial morphology and superoxide production in DS astrocytes were analyzed using super-resolution and confocal microscopy.
APP ASOs significantly reduced APP levels in astrocytes from both control and DS individuals. In DS astrocytes, treatment restored mitochondrial health, increasing mitochondrial number and size while reducing superoxide production.
APP ASOs effectively reduce APP levels and improve mitochondrial health in astrocytes, suggesting their potential as a therapeutic approach for DS and DS-related AD. Further in vivo studies are required to confirm these findings.
Plasma phosphorylated tau (p-tau) biomarkers have improved Alzheimer's disease (AD) diagnosis, but data from diverse Asian populations are limited. This study evaluated plasma p-tau217 and p-tau181 levels in Korean and Taiwanese populations.
All participants (n = 270) underwent amyloid positron emission tomography (PET) and blood tests. Plasma p-tau model-derived probabilities of amyloid PET positivity (amyloid beta [Aβ]+) classified participants into low-, intermediate-, or high-risk groups.
In both cohorts, plasma p-tau217 outperformed p-tau181, especially in cognitively unimpaired participants (area under the curve = 0.921 [p-tau217] vs. 0.769 [p-tau181], Pdifference = 0.022). Including apolipoprotein E status and glial fibrillary acidic protein improved model fit. The negative predictive value of the low-risk group and positive predictive value of the high-risk group were 97.5% and 86.0%, respectively.
Plasma p-tau217 and p-tau181 effectively predict Aβ+ among culturally different Asian populations. P-tau217 performed better, especially in the early stages of AD. Plasma p-tau217–based models reduced intermediate-risk classifications, suggesting fewer amyloid PET scans needed to confirm the diagnosis.
The phase 3 trial CLARITY AD found lecanemab slowed cognitive decline by 27%. However, subgroup analyses indicated a significant 31% sex difference in the effect and suggested no or limited effectiveness in females. We used simulations constrained by the trial design to determine whether that difference reflects a pre-existing sex difference in Alzheimer's disease progression or was a random event.
Simulations were generated using linear mixed models of cognitive decline fit to data from Alzheimer's Disease Neuroimaging Initiative participants satisfying CLARITY AD inclusion criteria.
The statistically non-significant 7.9% smaller cognitive decline rate in our cohort's males versus females does not explain CLARITY AD's 31% sex difference in lecanemab's effect. A ≥ 31% difference occurred randomly in only 12 of our 10,000 simulations (0.0012 probability).
CLARITY AD's sex difference was probably not random. Lecanemab is likely less effective in females than males, but we cannot conclude the drug is ineffective in females.
The link between overload brain iron and transcriptional/cellular signatures in Alzheimer's disease (AD) remains inconclusive.
Iron deposition in 41 cortical and subcortical regions of 30 AD patients and 26 healthy controls (HCs) was measured using quantitative susceptibility mapping (QSM). The expression of 15,633 genes was estimated in the same regions using transcriptomic data from the Allen Human Brain Atlas (AHBA). Partial least square (PLS) regression was used to identify the association between the healthy brain gene transcription and aberrant regional QSM signal in AD. The biological processes and cell types associated with the linked genes were evaluated.
Gene ontological analyses showed that the first PLS component (PLS1) genes were enriched for biological processes relating to the “protein phosphorylation” and “metal ion transport”. Additionally, these genes were expressed in microglia (MG) and glutamatergic neurons (GLUs).
Our findings provide mechanistic insights from transcriptional and cellular signatures into regional iron accumulation measured by QSM in AD.
Iron-mediated cell death (ferroptosis) is a proposed mechanism of Alzheimer's disease (AD) pathology. While iron is essential for basic biological functions, its reactivity generates oxidants which contribute to cell damage and death.
To further resolve mechanisms of iron-mediated toxicity in AD, we analyzed post mortem human brain and ApoEFAD mice.
AD brains had decreased antioxidant enzymes, including those mediated by glutathione (GSH). Subcellular analyses of AD brains showed greater oxidative damage and lower antioxidant enzymes in lipid rafts, the site of amyloid processing, than in the non-raft membrane fraction. Apolipoprotein E ε4 carriers had lower lipid raft yield with greater membrane oxidation. The hypothesized role of iron in AD pathology was tested in ApoEFAD mice by iron chelation with deferoxamine, which decreased fibrillar amyloid and lipid peroxidation, together with increased GSH-mediated antioxidants.
These novel molecular pathways highlight iron-mediated damage to lipid rafts during AD.
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