Alzheimer's Research & Therapy最新文献

Background: Accurate plasma biomarker interpretation is essential for diagnosing Alzheimer's disease (AD). This study evaluated how patient factors influence the association between plasma biomarkers and amyloid status in a memory clinic population.

Methods: A cross-sectional study of 1199 participants from the Amsterdam Dementia Cohort analysed plasma biomarkers (pTau217, pTau181, Aβ_42/40, GFAP, NfL, and a combined panel) and patient factors (comorbidities, medication use, vital signs, body mass index, and kidney function). Amyloid status was determined via amyloid PET (n = 309) or CSF pTau181/Aβ_1-42 (n = 890).

Results: Stroke, hypercholesterolemia, antidepressant use and Charlson Comorbidity Index (CCI) influenced biomarker performance. Stroke reduced the diagnostic value of pTau217, Aβ_42/40 and the biomarker panel, while hypercholesterolemia and antidepressant use enhanced pTau217 and Aβ_42/40, respectively. A CCI ≥ 2 reduced the biomarker panel's performance.

Conclusions: Overall, patient factors had limited impact on biomarkers, but caution is needed for patients with stroke or high CCI.

Background: Defective Wnt/β-catenin signaling is closely associated with the pathogenesis of Alzheimer's disease (AD), thus validating this pathway as a therapeutic target for AD. ISX9 is a potent agonist of the Wnt/β-catenin pathway. However, it remains unknown whether ISX9 exerts anti-AD effects by enhancing the Wnt/β-catenin signaling pathway. We therefore explored the neuroprotective potential of ISX9 using both hippocampal neuron-derived HT22 cells and 5×FAD transgenic mouse model of AD.

Methods: In HT22 cells, we employed the SuperTOPFlash reporter gene, Co-IP and Western blot assays to investigate the mechanism by which ISX9 activates the Wnt signaling pathway. The effects of ISX9 on the biological behavior of HT22 cells were further evaluated through MTT, BrdU and IF staining. To study the therapeutic effect of ISX9 on AD, six-month-old 5×FAD transgenic mice were randomly divided into four groups: WT, WT/ISX9, AD and AD/ISX9. The mice were intraperitoneally injected with ISX9 or vehicle at an interval of one day for 2 months. Behavioral tests were conducted to evaluate the cognitive and learning abilities of mice, while the expression levels of Aβ peptides, Tau-related proteins, neuroinflammatory factors, blood-brain barrier (BBB)-related proteins and the components of Wnt/β-catenin signaling were investigated.

Results: Our results demonstrated that ISX9 potently activated Wnt/β-catenin signaling by promoting the association of LRP6 with AXIN1, and increased the viability and proliferation of hippocampal cells. At the behavioral level, ISX9 improved learning and memory abilities in 5×FAD mice, and ameliorated hippocampal neuronal damage. Furthermore, ISX9 treatment effectively reduced the expression of Aβ peptides, total Tau, and phosphorylated Tau (S404) proteins in the AD mice. Mechanistically, ISX9 exhibited its neuroprotective effects, activating the Wnt/β-catenin signaling pathway via potentiating the interaction of LRP6 with AXIN1, upregulating the expression of BBB-related proteins and downregulating neuroinflammatory factors in AD mice.

Conclusion: Our findings indicate that ISX9 potently activates the Wnt/β-catenin signaling pathway and confers cognitive protection in hippocampal cells and AD mice. This compound may serve as a promising therapeutic agent for the treatment of AD.

Background: Following the positive outcomes of the Clarity-AD trial, Lecanemab received marketing authorization from the European Medicines Agency (EMA) and is expected to become available across Europe. However, the trial did not specifically evaluate frailty, making it difficult to estimate the potential effects of Lecanemab among frail individuals. This study aimed to apply Lecanemab eligibility criteria-based on both the Clarity-AD trial and the Appropriate Use Recommendations (AUR) from the United States and France-to a real-world population of pre-frail and frail older adults with confirmed positive amyloid status, and to evaluate differences in frailty status between eligible and non-eligible patients.

Methods: Eligibility criteria from the Clarity-AD trial, the American and the French AUR, were applied to all participants with confirmed amyloid positivity (n = 120), assessed through amyloid-PET (visual reading) or cerebrospinal fluid (CSF) analysis (Aβ42 levels or Aβ42/Aβ40 ratio). Frailty was defined using the Fried phenotype.

Results: The median age of the sample was 82.0 years (IQR: 79-85); 65% (n = 78) were women, and 36.7% (n = 44) were frail. Overall, 20.0% (n = 24) met the Clarity-AD eligibility criteria, while 50.8% (n = 61) and 47.5% (n = 57) were potentially eligible according to the American and French AURs, respectively. Only 9.1% (n = 4) of frail individuals met the Clarity-AD criteria, compared to 26.3% (n = 20) of pre-frail participants (p = 0.042). In contrast, 50.0% (n = 22) and 45.5% (n = 20) of frail individuals were potentially eligible according to the American and French AURs, respectively.

Conclusion: Although less than one in five participants would have been eligible for the Clarity-AD trial, approximately half the cohort would be potentially treatable with Lecanemab under real-world recommendations. While a considerable proportion of frail patients may have access to Lecanemab treatment in real-life, the low proportion of potentially eligible frail individuals for Clarity-AD in our cohort indirectly suggests that frailty may have been underrepresented in the trial, raising concerns about the generalizability of its findings to this population. Caution is warranted when targeting amyloid burden without previously addressing the underlying frailty.

Trial registration: NCT03129269.

Background: Published data suggest that compared to APOE3, APOE4 could increase the risk of neurodegeneration via higher cerebrovascular permeability. We recently proposed the concept that brain endothelial cell APOE is protective for cerebrovascular function in a genotype specific manner, APOE3 > APOE4, and therefore APOE4 brain endothelial cells may be predisposed to dysfunction during aging and disease. In addition to mechanistic implications, our concepts and methods may have therapeutic applications; identifying compounds that protect APOE4 brain endothelial cells. The goal of this proof-of-concept study was to determine whether APOE4 brain endothelial cells can be used as a phenotypic compound screen.

Methods: Previously we found that APOE4 brain endothelial cells are particularly sensitive to lipopolysaccharide- (LPS) induced permeability disruption when measured by trans endothelial cell electrical resistance (TEER) in vitro. Here, we followed the NIH Assay guidance manual to convert our in vitro assay to a phenotypic screen. We scaled the isolation protocol, selected conditions for the min, mid and max signals, statistically validated the phenotypic assay, screened compounds, validated hits and tested the top hits in vivo.

Results: We scaled the isolation protocol and selected conditions for min (0.8 µg/ml LPS), mid (10 µM sildenafil/LPS) and max conditions (vehicle). Our final protocol met the reproducibility acceptance criteria for a statistically validated assay. We then screened a subset of ~ 900 molecules from the TargetMol Bioactive Library and identified two main groups compounds. The first group disrupted APOE4 brain endothelial cells as they were toxic or lowered TEER and many inhibited mTOR. The second group protected against LPS-induced TEER reduction. With relatively stringent criteria we identified 33 protective compounds that are grouped into those that inhibit growth factor receptor signaling and a range of intracellular signaling pathways. We compared the most active compounds and selected four to test in vivo. Tadalafil (PDE5 inhibitor), vorinostat (HDAC inhibitor), CCT196969 (raf inhibitor) and SGI-7079 (AXL inhibitor) mitigated acute LPS-induced cerebrovascular dysfunction in mice that express APOE4.

Conclusions: Overall, our data supports the potential of our in vitro screen to identify compounds that prevent LPS-induced dysfunction in APOE4 brain endothelial cells.