Disease-Modifying Treatments and Their Future in Alzheimer's Disease Management

Abstract

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by memory impairment, a loss of cholinergic neurons, and cognitive decline that insidiously progresses to dementia. The pathoetiology of AD is complex, as genetic predisposition, age, inflammation, oxidative stress, and dysregulated proteostasis all contribute to its development and progression. The histological hallmarks of AD are the formation and accumulation of amyloid-β plaques and interfibrillar tau tangles within the central nervous system. These histological hallmarks trigger neuroinflammation and disrupt the physiological structure and functioning of neurons, leading to cognitive dysfunction. Most treatments currently available for AD focus only on symptomatic relief. Disease-modifying treatments (DMTs) that target the biology of the disease in hopes of slowing or reversing disease progression are desperately needed. This narrative review investigates novel DMTs and their therapeutic targets that are either in phase three of development or have been recently approved by the U.S. Food and Drug Administration (FDA). The target areas of some of these novel DMTs consist of combatting amyloid or tau accumulation, oxidative stress, neuroinflammation, and dysregulated proteostasis, metabolism, or circadian rhythm. Neuroprotection and neuroplasticity promotion were also key target areas. DMT therapeutic target diversity may permit improved therapeutic responses in certain subpopulations of AD, particularly if the therapeutic target of the DMT being administered aligns with the subpopulation's most prominent pathological findings. Clinicians should be cognizant of how these novel drugs differ in therapeutic targets, as this knowledge may potentially enhance the level of care they can provide to AD patients in the future.

Keywords: alzheimers disease; anti-amyloid; anti-tau therapies; neuro inflammation; neurodegenerative disesase.

Figure 1. Amyloid plaque formation

Under normal conditions, Amyloid precursor protein (APP) is predominantly cleaved by the enzyme, -secretase. However, in Alzheimer's disease, an abnormal increase in the enzymatic activity of -secretase and -secretase leads to the misfolding and aggregation of APP proteolytic fragments. These fragments aggregate to form plaques, which subsequently trigger inflammation through oxidative damage from reactive oxygen species (ROS) and the activation of cytokine producing microglia. Chronic neuroinflammation leads to neurodegeneration. The illustration was originally created by the authors.

Figure 2. Neurofibrillary tau tangle formation

Tau protein has a key role in stabilizing microtubule structure and function in neurons. The abnormal hyperphosphorylation of tau protein results in decreased affinity for microtubules and increased affinity for aggregation. As phosphorylated tau proteins aggregate, they form tau tangles, ultimately leading to the development of neurofibrillary tangles. The illustration was originally created by the authors.

Figure 3. Therapeutic target diversity among novel disease-modifying treatments

The image showing the therapeutic target diversity among novel disease modifying treatments (DMTs) recently approved by the United States Food and Drug Administration, or that are in phase 3 of clinical trials. The illustration was originally created by the authors.