Donanemab: Not two without a third.

Recently, the U.S. Food and Drug Administration (FDA) approved 2 anti-amyloid monoclonal antibodies, aducanumab (June 7, 2021) and lecanemab (July 6, 2023), for the treatment of Alzheimer's disease (AD) patients, and will most likely also approve a 3rd one, donanemab, soon. While these antibodies have been shown to significantly reduce amyloid in the brain, there is little, if any, evidence that they provide clinically meaningful benefit for AD patients by slowing cognitive decline. I have said it before, and I say it again: the reported benefits of anti-amyloid antibodies observed in clinical trials are erroneous and based on misinterpretation of data and a trivial miscalculation. For example, Sims et al. (2023) reported in a phase III clinical trial that donanemab treatment of early symptomatic AD patients with amyloid and tau pathology provided 35% and 36% slowing of clinical progression and cognitive decline, respectively, as measured using the Integrated Alzheimer's Disease Rating Scale (iADRS) and Clinical Dementia Rating-Sum of Boxes (CDR-SB) psychometric tests. Here, in this editorial, I show that 2.5% and 9.6% would be better estimates for less cognitive impairment with donanemab treatment.

Lecanemab (Leqembi) is not the right drug for patients with Alzheimer's disease.

On July 6, 2023, the U.S. Food and Drug Administration (FDA) approved lecanemab (Leqembi) for the treatment of Alzheimer's dementia (AD) patients. In 2 clinical trials, lecanemab reduced amyloid in the brain and slowed cognitive decline. Here, I review in detail the clinical trial by van Dyck et al. (2023) entitled "Lecanemab in early Alzheimer's disease", published in The New England Journal of Medicine on January 5, 2023. In this 18-month trial, lecanemab did not slow cognitive decline in women. This is especially significant because women have a twofold increased risk of AD compared to men, that is, there are 2 times more women than men living with AD. Lecanemab did not slow cognitive decline in APOE4 carriers; rather, it enhanced the decline in study participants with 2 APOE4 genes. This is bad news for AD patients, 60-75% of whom carry at least 1 APOE4 gene. These negative results regarding lecanemab's therapeutic value make me wonder if the approval of lecanemab was the worst decision of the FDA up till now, after the approval of aducanumab on June 7, 2021.

The Amyloid Cascade Hypothesis in Alzheimer's Disease: Should We Change Our Thinking?

Old age increases the risk of Alzheimer's disease (AD), the most common neurodegenerative disease, a devastating disorder of the human mind and the leading cause of dementia. Worldwide, 50 million people have the disease, and it is estimated that there will be 150 million by 2050. Today, healthcare for AD patients consumes 1% of the global economy. According to the amyloid cascade hypothesis, AD begins in the brain by accumulating and aggregating Aß peptides and forming ß-amyloid fibrils (Aß42). However, in clinical trials, reducing Aß peptide production and amyloid formation in the brain did not slow cognitive decline or improve daily life in AD patients. Prevention studies in cognitively unimpaired people at high risk or genetically destined to develop AD also have not slowed cognitive decline. These observations argue against the amyloid hypothesis of AD etiology, its development, and disease mechanisms. Here, we look at other avenues in the research of AD, such as the presenilin hypothesis, synaptic glutamate signaling, and the role of astrocytes and the glutamate transporter EAAT2 in the development of AD.

Alzheimer's trials: A cul-de-sac with no end in sight.

We don't understand Alzheimer, its origin and disease mechanisms. The absence of disease-modifying treatments for Alzheimer today is due to the amyloid hypothesis, a misguided hypothesis of Alzheimer's disease etiology, which has dominated Alzheimer research, drug development, and clinical trials for 30 years. However, the hypothesis is not dead yet, as exemplified by the recent resurrection of clinical trials with aducanumab. Recent advances in Alzheimer research include astrocytes, synaptic function and glutamate signaling. Many studies indicate EAAT2 as a promising target in drug discovery and clinical development for novel therapies in Alzheimer's disease, and other neurologic and psychiatric diseases.

Ovarian cancer evolution through stochastic genome alterations: defining the genomic role in ovarian cancer.

Ovarian cancer is the fifth leading cause of death among women worldwide. Characterized by complex etiology and multi-level heterogeneity, its origins are not well understood. Intense research efforts over the last decade have furthered our knowledge by identifying multiple risk factors that are associated with the disease. However, it is still unclear how genetic heterogeneity contributes to tumor formation, and more specifically, how genome-level heterogeneity acts as the key driving force of cancer evolution. Most current genomic approaches are based on 'average molecular profiling.' While effective for data generation, they often fail to effectively address the issue of high level heterogeneity because they mask variation that exists in a cell population. In this synthesis, we hypothesize that genome-mediated cancer evolution can effectively explain diverse factors that contribute to ovarian cancer. In particular, the key contribution of genome replacement can be observed during major transitions of ovarian cancer evolution including cellular immortalization, transformation, and malignancy. First, we briefly review major updates in the literature, and illustrate how current gene-mediated research will offer limited insight into cellular heterogeneity and ovarian cancer evolution. We next explain a holistic framework for genome-based ovarian cancer evolution and apply it to understand the genomic dynamics of a syngeneic ovarian cancer mouse model. Finally, we employ single cell assays to further test our hypothesis, discuss some predictions, and report some recent findings.

Genome based cell population heterogeneity promotes tumorigenicity: the evolutionary mechanism of cancer.

Cancer progression represents an evolutionary process where overall genome level changes reflect system instability and serve as a driving force for evolving new systems. To illustrate this principle it must be demonstrated that karyotypic heterogeneity (population diversity) directly contributes to tumorigenicity. Five well characterized in vitro tumor progression models representing various types of cancers were selected for such an analysis. The tumorigenicity of each model has been linked to different molecular pathways, and there is no common molecular mechanism shared among them. According to our hypothesis that genome level heterogeneity is a key to cancer evolution, we expect to reveal that the common link of tumorigenicity between these diverse models is elevated genome diversity. Spectral karyotyping (SKY) was used to compare the degree of karyotypic heterogeneity displayed in various sublines of these five models. The cell population diversity was determined by scoring type and frequencies of clonal and non-clonal chromosome aberrations (CCAs and NCCAs). The tumorigenicity of these models has been separately analyzed. As expected, the highest level of NCCAs was detected coupled with the strongest tumorigenicity among all models analyzed. The karyotypic heterogeneity of both benign hyperplastic lesions and premalignant dysplastic tissues were further analyzed to support this conclusion. This common link between elevated NCCAs and increased tumorigenicity suggests an evolutionary causative relationship between system instability, population diversity, and cancer evolution. This study reconciles the difference between evolutionary and molecular mechanisms of cancer and suggests that NCCAs can serve as a biomarker to monitor the probability of cancer progression.