Bowdoin Science Journal

Alzheimer's Disease

A novel therapeutic strategy for treating Alzheimer’s disease

by

Context

As of 2021, over 57 million people worldwide were living with dementia (World Health Organization, 2025). Alzheimer’s disease (AD) is the most common cause of dementia, representing 60–70% of its cases (World Health Organization, 2025). Most people develop AD in their sixties, and the disease is mostly characterized by a person’s difficulty in remembering recent events, yet symptoms also include problems with mood swings and language (National Institute on Aging, 2022). However, the causes of AD remain poorly understood (Knopman et al., 2021); although significant progress has been made in finding genetic factors, the environmental factors are not as clear. One biological definition of AD underlines the presence of malformed protein deposits in the brain, called amyloid-beta plaques and neurofibrillary tangles (“waste proteins”), which accumulate and damage neurons (Knopman et al., 2021).

No treatments are publicly available to stop or reverse the progression of AD. General advice, such as maintaining a healthy diet and physical activity, may temporarily improve symptoms. It has only been a few years since it has been shown for the first time that medications like lecanemab and donanemab can slow the progression of AD, yet these drugs are controversial due to their potentially dangerous side effects, such as brain swelling (Bitar et al., 2025).

Recent research

However, recent research focusing on the blood-brain barrier (BBB) has revealed that it might, after all, be possible to stop and reverse AD. The BBB, a highly selective permeability barrier that protects the central nervous system (CNS) from harmful substances and regulates the transport of essential molecules like glucose, helps move things in and out of the brain (Abbott, 2010). Dysfunction of the BBB is increasingly being seen as a factor in development of AD, as poor performance of the BBB means that it clears out the amyloid-beta plaques at a slower rate. Chen et al. present a novel therapeutic strategy that targets one specific receptor, the low-density lipoprotein receptor-related protein 1 (LRP1), in the BBB. LRP1 is a protein that helps clear amyloid-beta from the brain by facilitating its transport (Shinohara et al., 2017). It also influences amyloid-beta production by regulating certain enzymes (Shinohara et al., 2017). It is known that LRP1 levels are low in AD patients and low levels correlate with cognitive decline.

Methods

Polymersome design

The researchers engineered nanoscale vesicles (polymersomes) that bind LRP1 receptors. They synthesized four different versions carrying 0, 1, 40, and 200 peptides (ligands) to test how multivalency influences BBB transport. Multivalency increases the binding strength with the receptor. However, when binding is too strong, the LRP1 receptors degrade. Even though LRP1 levels are lower in AD patients, the goal of this method is to take advantage of what’s available by having these nanoparticles (vesicles) display just the right number of ligands to promote LRP1-mediated endocytosis (when the cell membrane engulfs substances to take them in) of the polymersome. This is why four different versions with varying amounts of peptides were tested; the ideal number of peptides was unknown. (Ultimately, the 40-peptide version performed the best.)

Post-binding

Once the polymersome binds to the LRP1 receptor, the receptor induces endocytosis and transports the polymersome inside the cell. Therefore, because the nanoparticle (polymersome) increases the number of LRP1 transport cycles per receptor, amyloid-beta also get to move via the LRP1-induced endocytosis (for example, soluble amyloid-beta may attach to the polymersome). This can solve the problem of having insufficient levels of LRP1 receptors (which leads to slower amyloid-beta removal, which can lead to AD).

Evaluation

  • In vitro (outside a living organism) BBB models: the authors compared multivalent and monovalent constructs and found that multivalent ligands (molecules that bind to receptors) bound the LRP1 receptor more effectively.
  • In vivo (inside a living organism) AD mouse models: after the administration of the treatment, biochemical assays confirmed that brain amyloid-beta plaque levels decreased. Imaging confirmed reduced brain amyloid-beta signals, and cognitive testing showed learning and memory improvements.

Results

The results in this study are significant. In AD model mice, this strategy reduced the level of brain amyloid plaques by nearly 45% and increased soluble plasma amyloid plaques 8 times in two hours (measured by ELISA, a laboratory blood test). This increase means that the plaque material is being “exported” out of the brain into the blood rather than accumulating in the brain. The imaging techniques used confirmed that brain amyloid-β signals had reduced after the intervention. Also, cognitive assessments showed that these AD model mice had improved in spatial learning and memory for up to 6 months post-treatment.

It is important to remember that the BBB of mice is not nearly as complex as the BBB of humans. Therefore, this intervention does not necessarily apply to humans. The study does not explore the off-target uptake in organs like the liver. The next steps for this research may be to repeat it in different AD models, perhaps even with ex vivo human brain microvessels, or to explore the effects of the intervention in different parts of the organism.

Recent research in Alzheimer’s disease has shown that slowing the progression of the disease may indeed be possible. This paper outlines just one of the methodologies that try to slow down the progression of AD. However, slowing down the progression of AD is not the same as reversing the effects of it. This research paper, as well as most research in AD, does not focus on reversing cognitive decline caused by AD; this is because to reverse such effects, we must first understand how to slow down the progression of the disease.

References

Abbott, N. J., Patabendige, A. A. K., Dolman, D. E. M., Yusof, S. R., & Begley, D. J. (2010). Structure and function of the blood–brain barrier. Neurobiology of Disease, 37(1), 13–25. https://doi.org/10.1016/j.nbd.2009.07.030

Bitar, I., Alabdalrazzak, M., Zamzam, M., Desai, Y., & Abushaban, K. (2025). Clinically silent amyloid-related imaging abnormality with edema following lecanemab therapy: A case report. Cureus, 17(8). https://doi.org/10.7759/cureus.91230

Knopman, D. S., Amieva, H., Petersen, R. C., Chételat, G., Holtzman, D. M., Hyman, B. T., Nixon, R. A., & Jones, D. T. (2021). Alzheimer disease. Nature Reviews Disease Primers, 7, 33. https://doi.org/10.1038/s41572-021-00269-y

National Institute on Aging. (2022, October 18). What Are the Signs of Alzheimer’s Disease? https://www.nia.nih.gov/health/alzheimers-symptoms-and-diagnosis/what-are-signs-alzheimers-disease

Shinohara, M., Tachibana, M., Kanekiyo, T., & Bu, G. (2017). Role of LRP1 in the pathogenesis of Alzheimer’s disease: evidence from clinical and preclinical studies. Journal of Lipid Research, 58(7), 1267–1281. https://doi.org/10.1194/jlr.R075796

World Health Organization. (2025, March 31). Dementia. https://www.who.int/news-room/fact-sheets/detail/dementia

Cover image by Robina Weermeijer on Unsplash. https://unsplash.com/photos/brown-brain-decor-in-selective-focus-photography-3KGF9R_0oHs

An Overview of Alzhimer’s Disease Pathogenesis

by

Keywords: pathogenesis, cholinergic changes, oxidative stress, amyloid plaque, Tau protein, mutation

Introduction

As people get older, many health complications begin to arise, many of which are cognitive. One such health complication is Alzheimer’s Disease (AD), which is one of the most common cause of dementia. AD is a disease that impacts fifty-five million people worldwide and one in three people over the age of eighty five experience advanced symptoms and signs of AD (Twarowski and Herbet 2023). AD is incurable and often leads to death, and currently a lot about how this disease works and about how it can be treated is unknown. AD is a complex multifactorial disease, and scientist are looking at many different causes (Twarowski and Herbet 2023). I will be covering the current understanding of AD pathogenesis (the process by which a disease is formed) through multiple lenses and discuss current treatments for AD. 

AD Pathogenesis Overview 

Cholinergic changes: 

One of the major neurotransmitters that allows for muscle movement, regulating heartbeat and blood pressure, and certain brain functions, is acetylcholine. Acetylcholine is active in the cerebral cortex, the basal ganglia, and the forebrain, and one of the first hypotheses for AD was cholinergic changes (Twarowski and Herbet 2023). A cholinergic change refers to the changes in the cholinergic system which is a neurotransmitter (acetylcholine) system that plays a role in memory, digestion, control of heartbeat, and movement (Sam and Bordoni 2023). When the nucleus basalis degenerates, there is a loss of synaptic connections that result in the deficiency of neurotransmission  (Twarowski and Herbet 2023). This can thus impact memory and movement, which are some of the most common symptoms of AD. The initial stages of AD are related to cholinergic changes and as the disease progresses, the cholinergic system loses its function until it all function is lost, resulting in death  (Twarowski and Herbet 2023).  

Figure 1. Demonstration of the cholinergic system in a neuron (Hall 2020 Mar 13).

Amyloid plaques and Tau proteins:

Amyloid plaques and the malfunction of Tau proteins are suspected to be two of the causes of AD that both lead to disease progression. Beta amyloids are small water-soluble peptides, and plaques will form if the beta amyloids do not have a stable structure (Twarowski and Herbet 2023). This lack of structure is thought of to be a cause of mutations. These plaques exhibit toxic properties to neuronal cells which causes neurons to degenerate (Twarowski and Herbet 2023). A Tau protein is a protein that promotes the assembly of tubulin which is a protein that is involved in cell division and cell movement. A Tau protein that is not functioning due to neurotoxins will bind to other Tau proteins and create tangles inside a neuron that lead to apoptosis of the neuron (Twarowski and Herbet 2023). This accumulation of plaques can cause the Tau proteins to form together and lead to tangles, revealing how there is a link between the two cause of AD (What Happens to the Brain in Alzheimer’s Disease? 2024 Jan 19). This process usually occurs in the final stages of AD pathogenesis.  

Figure 2. Amyloid beta plaques and Tau protein tangles impact on Neuron (McLoughlin).

 

Oxidative Stress: 

Another cause of AD is increased oxidative stress, which has many implications on people with AD. Oxygen is particularly important to the brain as the brain uses around twenty percent more oxygen than other organs in the body (Twarowski and Herbet 2023). Changes related to oxidative stress, which is an imbalance of free radicals and antioxidants in the body that leads to cell damage, are often seen in people with AD. This damage is caused by lipid oxidation as a result of oxidative stress breaks bonds in DNA molecules which increases the aging and death of neurons. These changes can also influence the mutation of Tau protein into advanced glycoxidation end products (AGEs) which are toxic to neurons and also lead to the progression of AD (Twarowski and Herbet 2023).  

Figure 3. Cell undergoing oxidative stress (Moore 2022 May 17).

Mutations:

One of the main and most significant factors that is related to the pathogenesis of AD and ties all of the previous factors together is genetic mutations as mutations are related to both cholinergic changes and oxidative stress. However, mutations in the genes that encode for the amyloid precursor protein have been identified as the most dangerous genetic risk factor associated with the development of AD (Twarowski and Herbet 2023). These are mutations in the 34 allele which is the allele of apolipoprotein E have been found to occur within one and five Alzheimer’s patients, and the risk of developing AD increases threefold with this mutation. Furthermore, this mutation may lead to the amyloid beta plaques and thus cause AD (Twarowski and Herbet 2023). Mutations are thus the largest contributing cause to AD because they can have so many implications that lead to the pathogenesis of AD. 

Figure 4. DNA that has undergone a mutation (Scoville 2019).

Conclusion

AD is a disease that impacts many people and causes many deaths annually, so being able to find a cure is incredibly important. AD pathogenesis is extremely complex, and as of today, scientists do not fully understand its pathogenesis, but we are getting closer. Understanding how the processes that lead to AD pathogenesis is the first step to being able to help find treatments that will help millions of people. Thus, scientists are still working diligently to understand how this disease works and how our current understanding can be improved. 

 

 

Literature Cited

Hall A. 2020 Mar 13. ChAT in 3D: Understanding the central cholinergic system. LifeCanvas Technologies. https://lifecanvastech.com/whole-brain-imaging-of-the-central-cholinergic-system-through-immunolabeling-chat/.

McLoughlin L. A Guide To Tau Proteins & Tauopathies. Assay Genie. https://www.assaygenie.com/blog/protein-tau-and-tauopathies.

Moore M. 2022 May 17. Effects of Oxidative stress | HHC. Life Science product | Helvetica Health Care. https://www.h-h-c.com/what-is-oxidative-stress-and-how-does-it-affect-your-health/.

Sam C, Bordoni B. 2023. Physiology, Acetylcholine. PubMed. https://www.ncbi.nlm.nih.gov/books/NBK557825/.

Scoville H. 2019. 4 Types of DNA Mutations and Examples. ThoughtCo. https://www.thoughtco.com/dna-mutations-1224595.

Twarowski B, Herbet M. 2023. Inflammatory Processes in Alzheimer’s Disease—Pathomechanism, Diagnosis and Treatment: A Review. International Journal of Molecular Sciences. 24(7):6518. doi:https://doi.org/10.3390/ijms24076518.

What Happens to the Brain in Alzheimer’s Disease? 2024 Jan 19. National Institute on Aging. https://www.nia.nih.gov/health/alzheimers-causes-and-risk-factors/what-happens-brain-alzheimers-disease.

 

The Solution to Alzheimer’s May Lie in Depression

by

Despite being discovered by Alois Alzheimer almost 120 years ago, Alzheimer’s Disease (AD) still remains incurable (Hippius & Neundörfer, 2003). AD causes the brain to break down over time, which is also known as neurodegeneration. AD begins by deterioration of the hippocampus, which is the part of the brain responsible for memory and emotion. It then slowly spreads to other parts of the brain, eventually breaking apart the brain stem, which is responsible for involuntary movements such as breathing and swallowing (Lee et al., 2015). Given that around 39 million people have Alzheimer’s worldwide and that this disease has a 100% fatality rate, scientists across the world have tried to find a cure to this ravaging disease (World Health Organization, 2023). While there is yet to be a cure, recent developments by Stephanie Langella could help with mitigating one of the earliest signs of Alzheimer’s: depressive symptoms.

In this study, Langella and her team studied Presenilin-1 (PSEN1) gene mutations, a major cause of early-onset Alzheimer’s Disease. The PSEN1 gene provides instructions for making the presenilin-1 protein. This protein is an essential part of a protein complex known as gamma-secretase. This complex cleaves toxic proteins such as the amyloid precursor protein (APP) to create nontoxic proteins. When the PSEN1 gene mutates, gamma-secretase struggles to form and break down these toxic proteins, causing APP molecules to join together to create amyloid-beta (also known as amyloid-ꞵ or A-ꞵ), the protein responsible for the neurodegeneration seen in Alzheimer’s Disease (Bagaria et al., 2022). 

A figure of gamma-secretase, APP processing, and generation of Amyloid-β (Aβ). Cleavages of C99 by gamma secretase (ε/ζ/γ) release sAPPβ, a type of APP which is beneficial to cells. When the PSEN1 gene mutates, gamma secretase (γ) produces AICD, a harmful type of APP, into a cell’s liquid (cytosol) and amyloid-β 37-43 into cell organelles. Aβ42 is the form of amyloid-β responsible for neurodegeneration in AD patients. (Steiner et al., 2018).

In particular, they studied its relationship to the neurodegeneration of the hippocampus and depressive symptoms (Langella et al., 2023). They began by creating two groups:  the first group consisted of carriers of the PSEN1 mutation but that had not yet been diagnosed with AD, and the second group consisted of the family members of the respective PSEN1 carriers that did not have the mutation and were not diagnosed with Alzheimer’s. Then, two structural MRIs – a method of neuroimaging which models the brain structures of a patient– with a one-year gap in between the two images were taken of the participants’ hippocampuses to measure the change in the volume of the hippocampus over a year. Participants also took the Geriatric Depression Scale, a 15-item survey that measures depressive symptoms, such as the subjects’ feelings of hopelessness and rating their interest in hobbies, to measure depressive symptoms over one year. 

Once the study was concluded, Langella found that there was no significant difference in the severity of the depressive symptoms between those carrying the PSEN1 mutation and those that did not. However, within the group carrying the PSEN1 mutation, those with smaller hippocampal volumes experienced more depressive symptoms. This association remained even after accounting for the age differences in the participants. This same association was not present in the non-PSEN1 carriers (Langella et al., 2023). Since the volume of the hippocampus did not have any relationship with depressive symptoms with non-PSEN1 carriers, there is likely some relationship between Alzheimer’s and depressive symptoms caused by hippocampal neurodegeneration. 

A).  Structural MRI of the hippocampus from the back of the head (shown in yellow)

C). Top-down structural MRI of the hippocampus (shown in yellow)  (Sato et al., 2021)

There are several important implications of this research. To start, if there is indeed a relationship between the severity of depressive symptoms and the size of the hippocampus in someone with AD, there is a chance that trying to mitigate these depressive symptoms through therapy and antidepressant medication could slow down the deterioration of the hippocampus. By keeping the hippocampus intact for a longer time, people with AD could have better emotional control and memory later in life, which would greatly improve their quality-of-life (Langella et al., 2023). Also, since AD first deteriorates the hippocampus, it is possible that the onset of depressive symptoms in people with the PSEN1 mutation could be used as an indicator to doctors on the severity of the neurodegeneration. For instance, if someone with the PSEN1 gene mutation suddenly begins displaying depressive symptoms, it is possible that AD has just recently started decaying the hippocampus. Doctors can then try to intervene and slow the decay of the hippocampus through administering antidepressants and therapy, but also through encouraging lifestyle changes such as increased exercise. This way, those with Alzheimer’s can live a longer time before their hippocampus fully degrades, letting them keep their memories for a longer time. 

Since this is one of the first studies relating depression and hippocampal decay in people with PSEN1 mutations, there is no theorized mechanism behind why this relationship exists in people with the PSEN1 mutation but not in those without. However, Langella et al. did find a particularly strong association between hippocampal decay in those with the PSEN1 mutation and displaying apathy, one of the measured depressive symptoms in the study (2023). More research should be done on the potential role of certain depressive symptoms on hippocampal decay, along with more research on the neural underpinnings relating the PSEN1 mutation, depression symptoms, and hippocampal decay. There is some evidence linking the formation of amyloid-ꞵ to depression in late-life major depression, but further research into the mechanism underlying this relationship is required (Pomara et al., 2022). 

However, there is a pressing issue with this study; it had a fairly small sample size, with the PSEN1 carrier group having 27 participants and the non-PSEN1 group having 26. Since AD is a disease that affects everyone slightly differently, having such a small sample size makes the results unreliable and hard to generalize to everyone with AD. Regardless of the issues in the study, developments such as the ones created by this study serve to improve the quality of life and life expectancy of people with AD, which promises to improve the lives of almost 39 million people and their families. With every passing discovery into Alzheimer’s, scientists are also getting more information on the mechanisms behind the disease, which could eventually lead humanity to curing the disease altogether. 

 

Citations

Bagaria, J., Bagyinszky, E., & An, S. S. A. (2022). Genetics, Functions, and Clinical Impact of Presenilin-1 (PSEN1) Gene. International journal of molecular sciences, 23(18), 10970. https://doi.org/10.3390/ijms231810970

 

Hippius, H., & Neundörfer, G. (2003). The discovery of Alzheimer’s disease. Dialogues in clinical neuroscience, 5(1), 101–108. https://doi.org/10.31887/DCNS.2003.5.1/hhippius

 

Langella S,  Lopera F,  Baena A, et al.  Depressive symptoms and hippocampal volume in autosomal dominant Alzheimer’s disease. Alzheimer’s Dement.  14 Oct. 2023, 986–994. https://doi.org/10.1002/alz.13501

 

Lee, J. H., Ryan, J., Andreescu, C., Aizenstein, H., & Lim, H. K. (2015). Brainstem morphological changes in Alzheimer’s disease. Neuroreport, 26(7), 411–415. https://doi.org/10.1097/WNR.0000000000000362

 

Pomara, N., Bruno, D., Plaska, C.R. et al. Plasma Amyloid-β dynamics in late-life major depression: a longitudinal study. Transl Psychiatry 12, 301 (2022). https://doi.org/10.1038/s41398-022-02077-8

 

Sato, Jinya, et al. “Lower Hippocampal Volume in Patients with Schizophrenia and Bipolar  Disorder: A Quantitative MRI Study.” Journal of Personalized Medicine, vol. 11, no. 2, 13 Feb. 2021, p. 121, https://doi.org/10.3390/jpm11020121.

 

Steiner, H., Fukumori, A., Tagami, S., & Okochi, M. (2018, October 28). Making the final cut: Pathogenic amyloid-β peptide generation by γ-secretase. The Journal of Cellular Pathology. https://www.cell-stress.com/researcharticles/making-the-final-cut-pathogenic-amyloid-%ce%b2-peptide-generation-by-%ce%b3-secretase

 

World Health Organization. “Dementia.” Dementia, 2023, www.who.int/news-room/fact-sheets/detail/dementia.