Alzheimer's Disease: Possible Hypotheses and Symptom Relief Treatments

By: Aitana Zamora Varela, Janet Nganga

Alzheimer’s Disease is a neurodegenerative disorder that has a profound cognitive impact, impairing memory, executive and motor functioning, and behavior. It accounts for 60% to 80% of all dementia cases. The progression of Alzheimer’s is typically categorized into four stages: preclinical, mild, moderate, and severe. Symptoms of Alzheimer’s disease (AD) vary based on several factors, including gender differences, and diagnoses of AD can depend on socioeconomic factors. For example, AD is more prevalent in females than in males, with women representing approximately two thirds of all cases. Women may experience more pronounced memory loss and emotional symptoms as opposed to men who  are more likely to exhibit behavioral changes.  Individuals from lower socioeconomic backgrounds often have limited access to healthcare resources leading to a delayed diagnosis and treatment of Alzheimer's. This is detrimental to these patients as Alzheimer's needs to be treated as soon as possible, preferably in the preclinical stage. But why? And what exactly is the cause of Alzheimer's? 

Alzheimer’s Disease is characterized by a complex set of pathological features, including the accumulation of amyloid-β (Aβ) plaques, the formation of neurofibrillary tangles (NFTs), early synaptic loss, and the presence of hippocampal and vascular lesions such as granulovacuolar degeneration. These abnormalities contribute to widespread neurodegeneration and cognitive decline. Two major hypotheses have been proposed to explain the molecular mechanisms underlying these pathological changes: the amyloid hypothesis and the tau hypothesis. The amyloid hypothesis suggests that the accumulation of Aβ plaques, derived from the cleavage of amyloid precursor protein by β-secretase and γ-secretase, is the initial trigger of AD. These extracellular plaques disrupt synaptic function, initiate inflammatory responses, and promote neuronal apoptosis. Aβ oligomers, smaller soluble aggregates of the protein, may be even more neurotoxic than the plaques themselves. Therapeutic strategies have largely focused on reducing Aβ levels or preventing plaque formation; however, repeated clinical failures have cast doubt on the sufficiency of this hypothesis, suggesting it may oversimplify AD pathology. In contrast, the tau hypothesis centers on the role of hyperphosphorylated tau protein, which aggregates into intracellular neurofibrillary tangles. Unlike Aβ, tau pathology more directly correlates with the severity of cognitive impairment and progresses through the brain in a predictable pattern, reflecting disease advancement. In a healthy brain, tau stabilizes microtubules, but in AD, abnormal phosphorylation causes it to detach, disrupt transport functions, and accumulate into toxic filaments. The precise molecular trigger for tau’s transformation remains unclear, but its role in synaptic dysfunction and cell death has been heavily researched. Therapeutic interest is shifting toward tau targeting interventions, such as inhibitors of tau phosphorylation or agents that promote tau clearance, though this area remains underfunded relative to Aβ research. Taken together, while Aβ plaques may initiate the degenerative process, tau pathology appears to drive clinical progression, indicating that a multifaceted therapeutic approach may be necessary to effectively address the disease.

Unfortunately though, conclusive treatments for the disease are still undergoing research. No new drug effective in curing AD has been approved since 2003. Only symptom relief treatments are available to slow down the progression of AD. There are a number of FDA approved drugs that can be administered depending on the severity of AD including AChEI’s, Donepenzil, Galantamine, Rivastigimine and the NDMA antagonist memantine. If one has been diagnosed in the preclinical stage, the likely recommendation of medication would be AChEIs. But what are AChEIs and what is their function? 

Acetylecholine is a neurotransmitter in the brain associated with numerous bodily functions but is important for memory, thinking and other cognitive functions when released between synapses. Acetylcholinesterase Inhibitors (AChEIs) work slowly by slowing down the breakdown of acetylcholine done by acetylecholinesterase. By preventing this breakdown, AChEIs enhance the communication done by neurons and this slows down cognitive degeneration to some degree. While this has shown effectiveness, it is also contingent on when this drug is administered and consistency. This drug is most effective when administered early (typically upon diagnosis granted the disease is still within the preclinical stage). Studies have shown patients who take AChEIs 6 months after diagnosis rapidly decline cognitive function as opposed to patients who started prior. Simply beginning early is not enough for this drug to be effective though. Once administered, it is imperative that treatment continues. Even temporary discontinuation of this drug results in rapid decline in cognitive function and increases the risk of needing care.  

As for the Amyloid Hypothesis, current treatments targeting Aβ have failed in clinical trials, emphasizing the disease’s multifactorial nature. Future strategies should focus on multi-target approaches addressing the complex network of pathways. The peripheral and central immune response, mitochondrial health, vascular integrity, and protein homeostasis are promising therapeutic measures.

Alzheimer's Disease is a multifactorial disease involving genetic predisposition, neurological complications, protein misfoldings, and more. These interrelated biological processes contribute to commonly known symptoms of AD some of which were mentioned like amyloid-β plaque accumulation, tau-mediated neurofibrillary tangles, and early synaptic loss. While current treatments like AChEIs offer temporary symptomatic relief by slowing down cognitive decline, they do not stop or reverse the symptoms of AD. Moreover, despite the research being conducted to find a cure, none have been successful. Advancing our knowledge of these mechanisms, particularly how molecular theories such as amyloid and tau pathologies integrate with broader cellular and systemic processes, is essential for the development of effective treatments. 

Citations:

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Yiannopoulou, K. G., & Papageorgiou, S. G. (2020, February 29). Current and future treatments in alzheimer disease: An update. Journal of central nervous system disease. https://pmc.ncbi.nlm.nih.gov/articles/PMC7050025/

Zhang, J., Zhang, Y., Wang, J., Xia, Y., Zhang, J., & Chen, L. (2024, August 23). Recent advances in alzheimer’s disease: Mechanisms, clinical trials and New Drug Development Strategies. Nature News. https://www.nature.com/articles/s41392-024-01911-3