Alzheimer's disease: insights into pathology, molecular mechanisms, and therapy

Abstract

Alzheimer's disease (AD), the leading cause of dementia, is characterized by the accumulation of amyloid plaques and neurofibrillary tangles in the brain. This condition casts a significant shadow on global health due to its complex and multifactorial nature. In addition to genetic predispositions, the development of AD is influenced by a myriad of risk factors, including aging, systemic inflammation, chronic health conditions, lifestyle, and environmental exposures. Recent advancements in understanding the complex pathophysiology of AD are paving the way for enhanced diagnostic techniques, improved risk assessment, and potentially effective prevention strategies. These discoveries are crucial in the quest to unravel the complexities of AD, offering a beacon of hope for improved management and treatment options for the millions affected by this debilitating disease.

Keywords: Alzheimer’s disease; biomarkers; pathophysiology; prevention; risk factors.

Figure 1.

Illustration of APP processing pathways. In the amyloidogenic pathway, APP undergoes cleavage by β- and γ-secretase, leading to the production of Aβ. Alternatively, the anti-amyloidogenic pathway results in the generation of neuroprotective sAPPα instead of Aβ. The processing of APP is also influenced by the action of η-secretase and caspases.

Figure 2.

Tau protein and the formation of neurofibrillary tangles. The diagram illustrates the structural features of the 2N4R tau protein. In the adult human brain, six isoforms of tau are produced through alternative splicing of the MAPT gene, with variations in the inclusion of exons at the N-terminus and exon 10 in the MBRD. In addition to genetic mutations, PTMs such as phosphorylation, ubiquitination, acetylation, and C-terminal truncation initiate the accumulation of tau into oligomers and filaments, including paired helical filaments (PHFs) and straight filaments (SFs). This accumulation culminates in the formation of NFTs, which are toxic and play a crucial role in the pathogenesis of tauopathies, thereby contributing to their detrimental impacts.

Figure 3.

Impact of systemic inflammation on AD pathogenesis. Beyond Aβ and tau, systemic inflammation, triggered by chronic conditions (such as obesity, diabetes, cardiovascular and cerebrovascular diseases) and microbial infections (including those caused by bacteria and viruses), compromises the BBB. This disrupted BBB integrity allows peripheral immune cells (such as T cells and myeloid cells), along with proinflammatory cytokines and microbes, to penetrate the brain parenchyma. This invasion initiates a chain of inflammatory responses that leads to the activation of reactive microglia and astrocytes, thereby accelerating the formation of amyloid plaques and tau pathology, which results in neuronal degeneration. Consequently, this cascade significantly contributes to AD progression. Abbreviations: Aβ, β-amyloid; AS, astrocyte; B2M, β2-microglobulin; BBB, blood‒brain barrier; EC, endothelial cell; MG, microglia; NFT, neurofibrillary tangle.

Figure 4.

Diverse risk factors contributing to AD pathogenesis. AD is a complex neurodegenerative disease influenced by a multitude of risk factors. These include genetic predisposition, the natural aging process, systemic inflammation, the presence of chronic diseases (type 2 diabetes, cardiovascular and cerebrovascular diseases), infections, traumatic brain injury (TBI), lifestyle choices (sleep patterns, high-fat, and high-salt diets), and environmental exposures. Additional factors that may affect AD incidence include neuropsychiatric symptoms, social engagement, alcohol consumption, hearing impairment, and educational attainment. The intricate interactions among these factors lead to the progressive neurodegeneration characteristic of AD.