J. Dement. Alzheimer's Dis., Volume 1, Issue 2 (December 2024) – 3 articles

Alzheimer’s disease (AD) is a brain disorder that is more prevalent in developed nations and remains one of most intractable conditions so far. It is characterized by a gradual onset, a prolonged progression, and an unclear pathophysiology. At the present time, there are no effective treatments available for the disease. However, human neural stem cells (hNSCs) have the capacity to substitute lost neurons in a functional manner, strengthen synaptic networks that have been compromised, and repair the damaged brain. Due to the unavailability of restorative therapeutics, there is a significant global burden on the economy. When it comes to the treatment of neurodegenerative diseases, NSCs provide a potentially game-changing approach to treating Alzheimer’s disease. Through the delivery of trophic factors that promote the viability and regeneration of lost neurons in experimental animals suffering from neurodegenerative disorders, these treatments have the potential to facilitate beneficial recuperation. Positive restorative outcomes may be achieved in a variety of ways, including the replacement of lost cells, the combining of cells, the secretion of neurotrophic factors, the formation of endogenous stem cells, and transdifferentiation. Conversely, there are obstacles that need to be overcome before NSC-based treatments can be used in clinical settings. This review article discusses current developments in the use of neural stem cells (NSCs) for the treatment of Alzheimer’s disease (AD). In addition, we highlight the difficulties and opportunities that are involved with the use of neural stem cell transplant treatment for Alzheimer’s disease. Full article

Background: The heavily right-skewed data seen in recently reported Alzheimer’s disease (AD) clinical trials influenced treatment contrasts when data were analyzed via the typical mixed-effects model for repeated measures (MMRM). Methods: An MMRM analysis similar to what is commonly used in AD clinical trials was compared versus robust regression (RR) and the non-parametric Hodges–Lehman estimator (HL). Results: Results in simulated data patterned after AD trials showed that imbalance across treatment arms in the number of patients in the extreme right tail (those with rapid disease progression) frequently occurred. Each analysis method controlled Type I error at or below the nominal level. The RR analysis yielded smaller standard errors and more power than MMRM and HL. In data sets with appreciable imbalance in the number of rapid progressing patients, MMRM results favored the treatment arm with fewer rapid progressors. Results from HL showed the same trend but to a lesser degree. Robust regression yielded similar results regardless of the ratio of rapid progressors. Conclusions: Although more research is needed over a wider range of scenarios, it should not be assumed that MMRM is the optimal approach for trials in early Alzheimer’s disease. Full article

Endoplasmic reticulum (ER) stress is a detrimental cellular phenomenon in the cells and is activated by the accumulation of unfolded or misfolded proteins in the ER. The unfolded protein accumulation activates the unfolded protein response (UPR), an adaptive mechanism designed to mitigate cellular stress by enhancing the ER’s protein-folding capacity and protecting cells from apoptotic stimuli in neuroinflammation and neurodegenerative diseases. However, chronic ER stress and prolonged activation of the UPR can have adverse effects, including the activation of pro-apoptotic and inflammatory signaling pathways, which contribute to the development and progression of neurodegenerative disorders. Neurodegenerative diseases are complex and devastating conditions with underlying pathogenesis that are not fully understood. Genetic mutations leading to the accumulation of misfolded or phosphorylated tau proteins and amyloid-beta in the ER can induce ER stress, resulting in neuroinflammation and neuronal death. Several studies have reported the involvement of increased ER stress and UPR signaling proteins in the pathogenesis and progression of neurodegenerative diseases. Thus, inhibiting ER stress and neuroinflammation and targeting their associated signaling pathways represent a significant area of research interest. This review discusses the critical signaling molecules involved in ER stress, their mechanisms in the progression of neurodegenerative diseases, and the latest developments in the available ER stress inhibitors. Despite the extensive development of ER stress inhibitors over the years, only a limited number have been approved as pharmaceutical drugs. There remains a critical need for effective ER stress inhibitors to provide efficient treatments for neurodegenerative diseases, including Alzheimer’s disease. Full article