Journal of Dementia and Alzheimer's Disease

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

Episodic memory is affected early and is a basic indication of neurodegeneration especially for Alzheimer’s disease. The aim of this study was to examine whether adults with vascular risk factors are differentiated in their episodic memory performance from individuals with mild cognitive impairment (MCI). The episodic memory of adults diagnosed with MCI, adults with vascular risk factors (VRF; blood pressure, diabetes mellitus, or hypercholesterolemia), and healthy controls was assessed using the Doors and People test. Statistical processing included mediation analyses which were performed separately for the VRF and healthy control groups, and the MCI and healthy control groups. ANOVA was used for the MCI and VRF groups which were matched in age and education. ANOVA showed that the MCI adults had significantly lower performance than the VRF adults in verbal recall only, F (1, 83) = 9.541, p = 0.003, and η_p² = 0.10. A direct effect of diagnosis on verbal recall was found via mediation analysis as concerns individuals with MCI and healthy controls, b = 0.506, SE = 0.128, p < 0.001, and 95%CI: 0.221–0.771, in favor of the healthy controls. Concerning the VRF and healthy groups, a tendency of diagnosis to directly affect verbal recall was shown (α = 0.005) in favor of the healthy controls, b = 0.388, SE = 0.150, p = 0.010, and 95%CI: 0.043–0.720. In conclusion, it is supported that patients with MCI present deficit performance in verbal recall; in addition, the diagnostic category affects all the groups’ performance on the same condition. These results indicated that the verbal recall aspect of episodic memory can be a sensitive indicator that can differentiate healthy adults from adults with mild cognitive impairment and vascular risk factors, as well as the two pathological groups from each other. Full article

The entrance of cells into a permanent state of cell cycle arrest with the ability to resist apoptosis is termed “cellular senescence”. The accumulation of senescent cells within the body can lead to tissue aging and the dysfunction of organs. Whether due to external stressors or the passage of time, aging is an inevitable process that afflicts every living being. Current studies that investigate aging rely on the use of cells or rodent models. Although cells present a cost-effective and quick way to analyze aging, they lack the complexity of whole-body systems and therefore require the use of an in vivo model post-in vitro assays. The zebrafish, Danio rerio, presents a cost-effective model with quick development and large numbers of offspring. These fish share 70% similarity of their genes with humans, including genes known to be associated with human diseases, such as those diseases of aging and/or senescence, like Alzheimer’s disease. Major tissues and organs of humans are also found in these fish, and therefore, zebrafish can serve as a useful model when studying diseases, aging, Alzheimer’s disease, and other disorders. In this review, we will discuss some of the major senescence biomarkers and detection methods, as well as discuss how zebrafish models can be used for the study of aging and age-related disorders. Full article

The gut microbiota (GM) communicates with the brain via biochemical signaling constituting the gut–brain axis, which significantly regulates the body’s physiological processes. The GM dysbiosis can impact the digestive system and the functioning of the central nervous system (CNS) linked to the onset of neurodegenerative diseases. In this review, the scientific data compiled from diverse sources primarily emphasize the neuropathological characteristics linked to the accumulation of modified insoluble proteins (such as β-amyloid peptides and hyperphosphorylated tau proteins) in Alzheimer’s disease (AD) and the potential impact of gut microbiota (GM) on AD susceptibility or resilience. The specific GM profile of human beings may serve as an essential tool for preventing or progressing neurodegenerative diseases like AD. This review focuses mainly on the effect of gut microfauna on the gut–brain axis in the onset and progression of AD. The GM produces various bioactive molecules that may serve as proinflammatory or anti-inflammatory signaling, contributing directly or indirectly to the repression or progression of neurodegenerative disorders by modulating the response of the brain axis. Human studies must focus on further understanding the gut–brain axis and venture to clarify microbiota-based therapeutic strategies for AD. Full article

Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by motor and non-motor symptoms due to the loss of dopamine-producing neurons and the presence of Lewy bodies in the brain. While current treatments such as dopamine replacement with levodopa and deep brain stimulation mainly manage symptoms and do not stop disease progression, recent advancements in nanomedicine provide promising new therapy options. These include drug-loaded nanocarriers that improve drug delivery to the brain, enhancing effectiveness and reducing side effects. This review explores novel nanomedical approaches like solid lipid nanocarriers (SLNs), which could improve drug profiles and decrease the adverse effects seen with traditional PD treatments. Additionally, it discusses the challenge of crossing the blood–brain barrier, which is crucial for treating central nervous system disorders, and how nanocarriers facilitate targeted brain delivery. Despite these advancements, the review emphasizes more research into the safety and long-term impacts of nanomedicine in PD, highlighting the challenge of moving these treatments from lab to clinical use. Full article