The recent, controversial approval of antibody-based treatments for Alzheimer’s disease (AD) is fueling a heated debate on the molecular determinants of this condition. The discussion should also incorporate a critical revision of the limitations of preclinical mouse models in advancing our understanding of AD. We critically discuss the limitations of animal models, stressing the need for careful consideration of how experiments are designed and results interpreted. We identify the shortcomings of AD models to recapitulate the complexity of the human disease. We dissect these issues at the quantitative, qualitative, temporal, and context-dependent levels. We argue that these models are based on the oversimplistic assumptions proposed by the amyloid cascade hypothesis (ACH) of AD and fail to account for the multifactorial nature of the condition. By shedding light on the constraints of current experimental tools, this review aims to foster the development and implementation of more clinically relevant tools. While we do not rule out a role for preclinical models, we call for alternative approaches to be explored and, most importantly, for a re-evaluation of the ACH.

Fifty years ago, the seminal work by John Olney provided the first evidence of the neurotoxic properties of the excitatory neurotransmitter glutamate. A process hereafter termed excitotoxicity. Since then, glutamate-driven neuronal death has been linked to several acute and chronic neurological conditions, like stroke, traumatic brain injury, Alzheimer’s, Parkinson’s, and Huntington’s diseases, and Amyotrophic Lateral Sclerosis. Mechanisms linked to the overactivation of glutamatergic receptors involve an aberrant cation influx, which produces the failure of the ionic neuronal milieu. In this context, zinc, the second most abundant metal ion in the brain, is a key but still somehow underappreciated player of the excitotoxic cascade. Zinc is an essential element for neuronal functioning, but when dysregulated acts as a potent neurotoxin. In this review, we discuss the ionic changes and downstream effects involved in the glutamate-driven neuronal loss, with a focus on the role exerted by zinc. Finally, we summarize our work on the fascinating distinct properties of NADPH-diaphorase neurons. This neuronal subpopulation is spared from excitotoxic insults and represents a powerful tool to understand mechanisms of resilience against excitotoxic processes.

Wilson’s disease (WD) is a hereditary disorder of copper metabolism, producing abnormally high levels of non-ceruloplasmin-bound copper, the determinant of the pathogenic process causing brain and hepatic damage and dysfunction. Although the disease is invariably fatal without medication, it is treatable and many of its adverse effects are reversible. Diagnosis is difficult due to the large range and severity of symptoms. A high index of suspicion is required as patients may have only a few of the many possible biomarkers. The genetic prevalence of ATP7B variants indicates higher rates in the population than are currently diagnosed. Treatments have evolved from chelators that reduce stored copper to zinc, which reduces the toxic levels of circulating non-ceruloplasmin-bound copper. Zinc induces intestinal metallothionein, which blocks copper absorption and increases excretion in the stools, resulting in an improvement in symptoms. Two meta-analyses and several large retrospective studies indicate that zinc is equally effective as chelators for the treatment of WD, with the advantages of a very low level of toxicity and only the minor side effect of gastric disturbance. Zinc is recommended as a first-line treatment for neurological presentations and is gaining acceptance for hepatic presentations. It is universally recommended for lifelong maintenance therapy and for presymptomatic WD.

Recent trials with monoclonal antibodies targeting amyloid-β (Aβ) in Alzheimer's disease (AD) have sparked a renewed interest in disease-modifying therapies. Despite their promise, these trials leave the issue open and posit some doubts about the validity of the Amyloid Cascade Hypothesis (ACH). While some scores of neurocognitive tests improved upon treatment, real-world clinical benefits were minimal. This Viewpoint discusses additional, often overlooked findings from these trials. We also emphasize the multifactorial nature of AD and the need for a broader research perspective beyond the simplistic disease model provided by the ACH.

Alzheimer’s disease (AD) is a multifactorial neurological condition associated with a genetic profile that is still not completely understood. In this study, using a whole gene microarray approach, we investigated age-dependent gene expression profile changes occurring in the hippocampus of young and old transgenic AD (3xTg-AD) and wild-type (WT) mice. The aim of the study was to assess similarities between aging- and AD-related modifications of gene expression and investigate possible interactions between the two processes. Global gene expression profiles of hippocampal tissue obtained from 3xTg-AD and WT mice at 3 and 12 months of age (m.o.a.) were analyzed by hierarchical clustering. Interaction among transcripts was then studied with the Ingenuity Pathway Analysis (IPA) software, a tool that discloses functional networks and/or pathways associated with sets of specific genes of interest. Cluster analysis revealed the selective presence of hundreds of upregulated and downregulated transcripts. Functional analysis showed transcript involvement mainly in neuronal death and autophagy, mitochondrial functioning, intracellular calcium homeostasis, inflammatory response, dendritic spine formation, modulation of synaptic functioning, and cognitive decline. Thus, overexpression of AD-related genes (such as mutant APP, PS1, and hyperphosphorylated tau, the three genes that characterize our model) appears to favor modifications of additional genes that are involved in AD development and progression. The study also showed overlapping changes in 3xTg-AD at 3 m.o.a. and WT mice at 12 m.o.a., thereby suggesting altered expression of aging-related genes that occurs earlier in 3xTg-AD mice.