Annotated Bibliography on The Pathophysiology of Alzheimer’s Disease

Abubakar MB, Sanusi KO, Ugusman A, Mohamed W, Kamal H, Ibrahim NH, Khoo CS, Kumar J. 2022. Alzheimer’s disease: an update and insights into pathophysiology. Front Aging Neurosci. [accessed 2025 Apr 11];14:742408. doi:10.3389/fnagi.2022.742408.

The article “Alzheimer’s Disease: An Update and Insights into Pathophysiology” by Abubakar et al. (2022) provides insight into the pathophysiology of Alzheimer’s Disease, which explains new knowledge about molecular, neuronal, and glial alterations involved in the disease. This source may be greatly beneficial from the perspective of characterizing the multifaceted pathophysiology of AD with a focus on the signaling, angiopathy, and neuroinflammation aspects of the disease, which are most relevant to our project regarding the molecular mechanisms underlying AD. It aids in compiling existing research on the disease and incorporates this into future studies that may enhance the approach toward diagnostics and management of AD.

Abubakar et al. (2022) set the stage for this article by first describing what Alzheimer’s disease is, its occurrences, its essential symptoms, including impaired thinking and reasoning, changes in behavior and personality, and lastly, neurodegeneration. They underline that AD is defined by the gradual dysphasic increase of amyloid-beta (Aβ) plaques and neurofibrillary tangles formed by tau proteins. These proteins are associated with neural dysfunction and impaired cognitive function, which is evident clinically in affected patients. The article also illustrates the Presence of pathological changes before clinical manifestation is made, where AD is known to progress for many years before apparent deficits can be detected in early stages. As it has been established that amyloid plaques and tau tangles are the primary hallmarks of AD, this article points out that studies have recently revealed other critical aspects that are involved in the disease, like neuroinflammation and vascular disease. This changes the perspective from the pre-established protein-dependent process of AD pathogenesis to new ways of looking at cellular environments, including glial cells. The topic of neuroinflammation, especially in relation to astrocytes and microglia, introduces one of the latest trends in AD research into the molecular and cellular processes involved in the disease, which is closely related to the objectives of our project.

One of the main points described in the article is the signaling pathways in AD, especially the JAK/STAT signaling pathway. This is an essential pathway in various cellular functions such as growth, differentiation, and inflammation. The author states that the JAK/STAT signaling pathway is initiated when cytokines and growth factors bind to their receptors on the cell membrane of receptor-expressing cells, and subsequently, it relays extracellular stimuli into the nucleus to induce a transcriptional response. This was evidenced by experimental models that exhibited increased phosphorylation of JAK2 and STAT3 in the AD pathway, especially in the hippocampus and cerebral cortex areas most affected. Abubakar et al. (2022) also explain how increased levels of JAK/STAT contribute to neuroinflammation in AD, especially with astrogliosis and microgliosis. This neuroinflammation is proposed to be responsible for synapse and neuronal degeneration, a cardinal event in AD. The review points out the possibility of using the JAK/STAT signaling pathway as a potential therapeutic target for AD, reducing inflammation within the brain and stopping synaptic loss associated with cognitive function decline. This is especially helpful for our project because from a list of multiple signal transduction pathways implicated in AD, this article focuses on one and identifies molecular targets that could be exploited in developing new therapies.

Another significant component mentioned in the article is the role of glial cells, such as astrocytes and microglia. In the past, neurons were the main target in AD studies, while the authors assert that glial cells are implicated in the progression of the disease more significantly than neurons. For instance, astrocytes exist to support the synaptic structure and/or help heal if they are damaged. In AD, astrocytes become reactive, with upregulation of GFAP and other reactive astrocyte markers. Reactive astrocytes escalate neuroinflammation and promote neuronal dysfunction by secreting pro-inflammatory cytokines and other injurious molecules. Additionally, Microglia, which are the brain’s immunocompetent cells of the brain foster inflammation in response to the amyloid formation to contribute to AD pathology. The review points out that while microglia are initially involved in phagocytosis of amyloid-beta, prolonged activation of such cells leads to toxic by-products that augment neuro-path generation. This dual role of microglia—initially protective, but later harmful—adds to the complexity of AD’s pathogenesis. From the given article, the part devoted to glial participation is essential to our project as it highlights the biological processes occurring in the cells related to AD progression.

Another strength of this article is that it gives a comprehensive overview of vascular dysfunction in AD. Vascular health is pointed out by Abubakar et al. (2022) as being almost synergistic to cognitive decline, with hypertension, diabetes, and atherosclerosis being potent precursors to AD. Such vascular dysfunction results in decreased CBF, increasing neuronal degeneration, and enhancing the formation of amyloid plaques. One of the key factors for the onset of AD is the impaired blood-brain barrier (BBB), which prevents certain toxins from entering the brain. The review also explains the process of damaging the BBB due to amyloid-beta deposition in the blood vessels to worsen the leakage of toxic substances in the brain, thereby increasing the rate of neurodegeneration. The article also highlighted that when other vascular factors combine with amyloid-beta, they enhance the cognitive deterioration witnessed in patients with AD. This understanding of the relationship between vascular disease and AD is essential in the development of understanding how overall health issues can affect the disease, as well as how therapeutic interventions may need to focus on not only the cerebral but also the cardiovascular systems. The following information is very pertinent to our project as it incorporates vascular compromise within the framework of the pathogenesis of AD.

Abubakar et al. (2022) also gives an insight into the involvement of nerve growth factor (NGF) in AD since the latter is one of the significant neurotrophic factors involved in the sustenance of neurons. Abubakar et al. (2022) show how the NGF metabolic pathway is affected in AD, and consequently, the degeneration of BFCNs takes place. NGF is a peptide initially produced as proNGF and processed to its bioactive form, mNGF. However, this conversion does not occur in AD, and degradation of mNGF is enhanced, leading to atrophy of cholinergic neurons and cognitive decline. In the present context, the author reviews some experimental evidence to claim that either the restoration of NGF or the blockage of mNGF degradation benefits cognitive function; thus, NGF-based treatment could be a potential AD treatment strategy.

The review section of the article ends by demonstrating the possibility of applying genomics, transcriptomics, proteomics, and metabolomics in diagnosing and treating AD. These technologies are gaining popularity in the discovery of biomarkers for AD and in mapping the molecular pathways involved in the disease. Specifically, the review discusses how this new method in a multi-omics approach is able to offer new targets for therapy and potential diagnosis, thus paving the way for early and effective pharmaceutical solutions.

In conclusion, the article provides a current understanding of the molecular mechanism of Alzheimer’s disease, emphasizing the role of inflammation, the endothelium, and glial cells involved in the condition. It is useful in understanding the multifaceted process of AD, which is essential to our study, as our work is aimed at studying the pathophysiological basis of the disease. The review also points up promising directions, including the role of NGF and “omics” research that are topical for our project targeting the search for new targets for AD treatment. Since this source gives a comprehensive and contemporary view of the etiologic processes in AD, it is particularly beneficial for the further identification of the mechanisms of neurodegenerative disorders.