Alzheimer's Disease Puzzle: Delving into Pathogenesis Hypotheses

Abstract

Alzheimer's disease (AD) is a prevalent neurodegenerative disease characterized by both amnestic and non-amnestic clinical manifestations. It accounts for approximately 60-70% of all dementia cases worldwide. With the increasing number of AD patients, elucidating underlying mechanisms and developing corresponding interventional strategies are necessary. Hypotheses about AD such as amyloid cascade, Tau hyper-phosphorylation, neuroinflammation, oxidative stress, mitochondrial dysfunction, cholinergic, and vascular hypotheses are not mutually exclusive, and all of them play a certain role in the development of AD. The amyloid cascade hypothesis is currently the most widely studied; however, other hypotheses are also gaining support. This article summarizes the recent evidence regarding major pathological hypotheses of AD and their potential interplay, as well as the strengths and weaknesses of each hypothesis and their implications for the development of effective treatments. This could stimulate further studies and promote the development of more effective therapeutic strategies for AD.

Figure 1.

The major identified risk factors of AD. NAFLD: non-alcoholic fatty liver disease.

Figure 2.

The proposed neurobiological mechanisms involved in the pathogenesis of AD.

Figure 3.

A diagram illustrating various modes of neuroinflammation in the AD brain for triggering a significant number of Aβ aggregates. The inability of microglia and astrocytes to phagocytose Aβ aggregates and consequent inflammatory responses lead to the accumulation of Aβ deposits. Aβ aggregates bind to the pattern recognition receptors (PRRs) of microglia to activate downstream target genes, NF-κB, and activated protein 1 (AP-1), thus resulting in the production of cytokines. These cytokines stimulate astrocyte activation and contribute to neuronal damage and neurotoxicity. In addition, the binding of Aβ aggregates to microglia triggers ROS production through NADPH oxidase and inducible nitric oxide synthase pathways, thereby leading to neurotoxicity. Similarly, the binding of Aβ aggregates to astrocyte receptors activates downstream target genes NF-κB and AP-1, thus leading to the production of cytokines. The disrupted communication between neurons, astrocytes, and microglia causes an imbalance in brain homeostasis and promotes neuronal death.

Figure 4.

The complex relationship exists between oxidative stress for triggering mitochondrial dysfunction, and mitochondrial damage for leading to further increased oxidative stress. Aβ and Tau hyperphosphorylation are also engaged in mitochondrial dysfunction.

Figure 5.

Schematic diagram describing the healthy and AD neurons according to Tau hypothesis.