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INTRODUCTION: Alzheimer's Prevention Initiative Generation Study 1 evaluated amyloid beta (Aβ) active immunotherapy (vaccine) CAD106 and BACE‐1 inhibitor umibecestat in cognitively unimpaired 60‐ to 75‐year‐old participants at genetic risk for Alzheimer's disease (AD). The study was reduced in size and terminated early. Results from the CAD106 cohort are presented. METHODS: Sixty‐five apolipoprotein E ε4 homozygotes with/without amyloid deposition received intramuscular CAD106 450 μg (n = 42) or placebo (n = 23) at baseline; Weeks 1, 7, 13; and quarterly; 51 of them had follow‐up Aβ positron emission tomography (PET) scans at 18 to 24 months. RESULTS: CAD106 induced measurable serum Aβ immunoglobulin G titers in 41/42 participants, slower rates of Aβ plaque accumulation (mean [standard deviation] annualized change from baseline in amyloid PET Centiloid: −0.91[5.65] for CAD106 versus 8.36 [6.68] for placebo; P < 0.001), and three amyloid‐related imaging abnormality cases (one symptomatic). DISCUSSION: Despite early termination, these findings support the potential value of conducting larger prevention trials of Aβ active immunotherapies in individuals at risk for AD. Highlights: This was the first amyloid‐lowering prevention trial in persons at genetic risk of late‐onset Alzheimer's disease (AD).Active immunotherapy targeting amyloid (CAD106) was tested in this prevention trial.CAD106 significantly slowed down amyloid plaque deposition in apolipoprotein E homozygotes.CAD106 was generally safe and well tolerated, with only three amyloid‐related imaging abnormality cases (one symptomatic).Such an approach deserves further evaluation in larger AD prevention trials. [ABSTRACT FROM AUTHOR]

Abstract Mathematical models of viral dynamics in vivo provide incredible insights into the mechanisms for the nonlinear interaction between virus and host cell populations, the dynamics of viral drug resistance, and the way to eliminate virus infection from individual patients by drug treatment. The integration of these mathematical models with high-throughput genetic and genomic data within a statistical framework will raise a hope for effective treatment of infections with HIV virus through developing potent antiviral drugs based on individual patients’ genetic makeup. In this opinion article, we will show a conceptual model for mapping and dictating a comprehensive picture of genetic control mechanisms for viral dynamics through incorporating a group of differential equations that quantify the emergent properties of a system.

Abstract Background Despite our increasing recognition of the mechanisms that specify and propagate epigenetic states of gene expression, the pattern of how epigenetic modifications contribute to the overall genetic variation of a phenotypic trait remains largely elusive. Results We construct a quantitative model to explore the effect of epigenetic modifications that occur at specific rates on the genome. This model, derived from, but beyond, the traditional quantitative genetic theory that is founded on Mendel’s laws, allows questions concerning the prevalence and importance of epigenetic variation to be incorporated and addressed. Conclusions It provides a new avenue for bringing chromatin inheritance into the realm of complex traits, facilitating our understanding of the means by which phenotypic variation is generated.

Introduction: The Alzheimer's Prevention Initiative (API) Generation Studies evaluated the BACE inhibitor umibecestat for Alzheimer's disease (AD) prevention. The studies were terminated early, and the reversibility of umibecestat's side effects was assessed., Methods: Cognitively unimpaired 60- to 75-year-old apolipoprotein E (APOE) ε4 homozygotes and heterozygotes (the latter with elevated brain amyloid deposition) (n = 1556) received umibecestat (50 or 15 mg daily) or placebo for 7 months on average and were followed for a median (interquartile range) of 4 (3 to 6) months after washout., Results: Compared to placebo, umibecestat-treated participants had small, non-progressive, but statistically significant decline in performance on certain cognitive batteries including Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) and API Preclinical Composite Cognitive test, but not Clinical Dementia Rating-Sum of Boxes. RBANS differences were no longer significant at the end of follow-up., Discussion: In people at genetic risk for AD, high-dose beta-site amyloid precursor protein cleaving enzyme (BACE) inhibition was associated with early mild cognitive worsening, which reversed shortly after washout, suggesting a symptomatic side effect not associated with neurodegeneration. Fully anonymized data, images, and samples are available upon request for further research on BACE inhibition., Highlights: This is the first trial with blinded assessment of reversibility of BACE inhibitor side effects. Umibecestat was tested in cognitively unimpaired persons at genetic risk for AD. Umibecestat led to early mild cognitive decline that reversed shortly after washout. This suggests a potentially manageable effect not associated with neurodegeneration. Further research may determine the future of BACE inhibition in AD prevention., (© 2024 Novartis Pharma AG. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Introduction: Alzheimer's Prevention Initiative Generation Study 1 evaluated amyloid beta (Aβ) active immunotherapy (vaccine) CAD106 and BACE-1 inhibitor umibecestat in cognitively unimpaired 60- to 75-year-old participants at genetic risk for Alzheimer's disease (AD). The study was reduced in size and terminated early. Results from the CAD106 cohort are presented., Methods: Sixty-five apolipoprotein E ε4 homozygotes with/without amyloid deposition received intramuscular CAD106 450 μg (n = 42) or placebo (n = 23) at baseline; Weeks 1, 7, 13; and quarterly; 51 of them had follow-up Aβ positron emission tomography (PET) scans at 18 to 24 months., Results: CAD106 induced measurable serum Aβ immunoglobulin G titers in 41/42 participants, slower rates of Aβ plaque accumulation (mean [standard deviation] annualized change from baseline in amyloid PET Centiloid: -0.91[5.65] for CAD106 versus 8.36 [6.68] for placebo; P < 0.001), and three amyloid-related imaging abnormality cases (one symptomatic)., Discussion: Despite early termination, these findings support the potential value of conducting larger prevention trials of Aβ active immunotherapies in individuals at risk for AD., Highlights: This was the first amyloid-lowering prevention trial in persons at genetic risk of late-onset Alzheimer's disease (AD). Active immunotherapy targeting amyloid (CAD106) was tested in this prevention trial. CAD106 significantly slowed down amyloid plaque deposition in apolipoprotein E homozygotes. CAD106 was generally safe and well tolerated, with only three amyloid-related imaging abnormality cases (one symptomatic). Such an approach deserves further evaluation in larger AD prevention trials., (© 2023 Novartis. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)