Our scientific question: Is there a gene associated with both regulation of thyroid hormones and Alzheimer’s Disease?

Hypothesis: We hypothesize that there is a gene that affects the regulation of thyroid hormones and can also contribute to the likelihood of getting Alzheimer's.

Note: This is not an experimental project, so we don’t have concrete materials. This is just how we researched our topic.

We’re using bioinformatic tools, namely OMIM and NCBI for our research. Here’s the outline of how we are going to do it:

1. Identifying the gene we want to study by searching keywords on OMIM (e.g. “thyroid +alzheimer+amyloid) and recording the gene name, entry number, and other information in a table. 
2. Narrowing down all the different genes to the most relevant and recurring gene. This was determined by how many keywords the entry includes, and how often we see this gene across many entries. 
3. Conduct a literature review using PubMed to collect supporting evidence that connects the identified mutation to thyroid hormone activity and its role in Alzheimer’s disease.
4. Finally, record our findings in our logbook for future reference.

We used OMIM by searching up keywords that were relevant to our topic. We then wrote the details from most relevant results into our logbook.

Oct 11, 2024 - Searched OMIM database using the keywords “thyroid + Alzheimer + amyloid”. The only result that matched all 3 keywords was:

Entry #	Location	Phenotype	Inheritance	Gene
105210	18q12.1	Hereditary amyloidosis	Autosomal Dominant	TTR

Nov 25, 2024 - Searched OMIM database using the keywords “thyroid +alzheimer”

Entry #	Location	Phenotype	Inheritance	Gene
607822	14q24.2	Alzheimer's disease, type 3, with or without spastic paraparesis	Autosomal Dominant	PSEN1

 

 

Nov 29, 2024- Searched OMIM database using the words “+Alzheimer’s disease + thyroid”

 

Entry #	Location	Phenotype	Inheritance	Gene
104310	19q13.32	Alzheimer Disease 2	Autosomal Dominant	APOE

 

Dec 2, 2024- Searched OMIM database using the keywords “+Thyroid Disorders+ amyloid+Alzheimer’s” 

 

Entry #	Location	Phenotype	Inheritance	Gene
218700	2q14.1	Hypothyroidism, congenital, due to thyroid dysgenesis or hypoplasia	Autosomal Dominant	PAX8

Dec 6- Searched OMIM database using the keywords “Alzheimer’s thyroid”

Entry #	Location	Phenotype	Inheritance	Gene
104300	7q36.1	Alzheimer's disease, late-onset, susceptibility to	Autosomal Dominant	NOS3
104300	10q22.2	Alzheimer's disease, late-onset, susceptibility to	Autosomal Dominant	PLAU
104300	17q22	Alzheimer's disease, susceptibility to	Autosomal Dominant	MPO
104300	21q21.3	Alzheimer disease	Autosomal Dominant	APP

Dec 6 - Searched OMIM database using the keywords “Alzheimer +hypothyroidism”

Entry #	Location	Phenotype	Inheritance	Gene
218700	2q14.1	Hypothyroidism, congenital, due to thyroid dysgenesis or hypoplasia	Autosomal Dominant	PAX8
275200	14q31.1	Hypothyroidism, congenital, non goitrous, 1	Autosomal Recessive	TSHR

 

Pubmed is a resource supporting the search and retrieval of biomedical and life sciences literature to improve health. So on Pubmed, we searched for some important keywords including the genes we chose (TTR, PAX8). We chose TTR. After all, it was consistently the first search result on OMIM, and PAX8 because it showed up multiple times in our searches. 

• in vitro means done in a lab environment like a petri dish or test tube, while in vivo means done on an actual living organism like a lab rat

TTR(transthyretin) related articles

“Hyperparathyroidism (HPT) could be a risk factor for the development and progression of Alzheimer's disease (AD). Progressive neurodegeneration in AD may affect the metabolism of thyroid hormones (THs) in the brain causing local brain HPT. HPT promotes the progression of AD by inducing the production of amyloid beta (Aβ) and tau protein phosphorylation with the development of synaptic plasticity and memory dysfunction. Besides, the metabolism of THs is dysregulated in AD due to the accumulation of Aβ and tau protein phosphorylation leading to local brain HPT.” - (Primary Hypothyroidism and Alzheimer’s Disease: A Tale of Two - PubMed, 2023)

Additional research about HPT: Hyperparathyroidism also known as (HPT) is when the parathyroid glands create high amounts of parathyroid hormone in the bloodstream.  The parathyroid is a gland situated below the thyroid. It secretes parathyroid hormone, which controls calcium in the body and is not directly related to the thyroid in function.

Takeaways: Hyperparathyroidism could potentially be linked to AD. Neurodegeneration may affect the metabolism of thyroid hormones causing HPT in the brain, which causes AD by inducing the production of amyloids. The accumulation of amyloid and tau protein also can make the metabolism of thyroid hormones dysregulated.

“TTR is an interesting therapeutic target for neurodegenerative diseases due to its recognized neuroprotective properties in the cognitive impairment context and interestingly in Alzheimer's disease (AD). Much evidence has been collected regarding the neuroprotective effects in AD, including through in vitro and in vivo studies as well as a wide range of clinical series. Despite this supported hypothesis of neuroprotection for TTR, the mechanisms are still not completely clear.” - (Transthyretin Stabilization: An Emerging Strategy for the Treatment of Alzheimer’s Disease? - PubMed, 2020)

Takeaways: There is some scientific evidence that TTR helps protect the nervous system from neurodegenerative diseases like Alzheimer’s. This has been shown in in vitro and in vivo studies, as well as in many clinical cases. However, we are not certain that this is true.

“Despite in vitro and in vivo evidence of the interaction between TTR and Aβ, genomewide association studies including large numbers of sporadic Alzheimer's disease patients have failed to show significant association between variation in the TTR gene and disease prevalence. Early clinical studies suggested an inverse relationship between CSF TTR levels and AD and the possibility of using the reduced CSF TTR concentration as a biomarker. Later, more extensive analyses indicated that CSF TTR concentrations may be increased in some patients with AD.” - (Buxbaum, 2023)

Takeaways: Tests in the lab and on live animals have shown that TTR interacts with amyloid beta, which is linked to AD. However, when scientists looked at lots of cases, they didn’t find a strong link between differences in TTR and AD. Even though early research said that people with AD had lower levels of TTR in their cerebrospinal fluid. But more detailed research later showed that in some cases, AD patients have higher TTR levels. This means that there currently is no clear link between TTR and AD.

“TTR transports the thyroid hormone thyroxine and the retinol-binding protein (RBP) bound to retinol (vitamin A). Mutations in TTR are associated with inherited transthyretin amyloidosis (ATTRv), a progressive, debilitating disease that is ultimately fatal and is characterized by misfolding of TTR and aggregation as amyloid fibrils, predominantly leading to cardiomyopathy or polyneuropathy depending on the particular TTR mutation.” - (Liz et al., 2020)

Takeaways: Mutations in the TTR gene are associated with transthyretin amyloidosis, which affects the nervous system. It’s characterized by misfolding of TTR and amyloid aggregation. This is relevant to this project because amyloid buildup leads to Alzheimer's and amyloidosis is linked to Alzheimer’s.

“Studies of human diseases have demonstrated that TTR in the cerebrospinal fluid can form amyloid, but more recently there has been recognition of the roles of TTR in depression and Alzheimer's disease. Furthermore, amyloid mutations in human TTR that are the normal residues in other species result in cardiac deposition of TTR amyloid in humans. Finally, a revised model for TTR-thyroxine entry into the cerebrospinal fluid via the choroid plexus, based on data from studies in TTR null mice, is presented.” - (Cell and Molecular Biology of Transthyretin and Thyroid Hormones, n.d.)

Takeaways: Mutations in amyloids in human TTR act differently than in most organisms. 

PAX(paired box) related articles 

“As an inhibitory transcription factor of IDH3β, the elevated PAX6 inhibited the expression of IDH3β, leading to tau hyperphosphorylation, synapse impairment, and learning and memory deficits resembling those seen in AD. Our data suggest that impaired oxidative phosphorylation accelerates AD progression via a positive feedback inhibition loop of IDH3β-lactate-PAX6-IDH3β. Breaking this loop by upregulating IDH3β or downregulating PAX6 attenuates AD neurodegeneration and cognitive impairments.” - (A Positive Feedback Inhibition of Isocitrate Dehydrogenase 3β on Paired-box Gene 6 Promotes Alzheimer-like Pathology, 2024)

Takeaways: Too much PAX6 means less IDH3β, which leads to less tau protein hyperphosphorylation, synapse impairment, and Alzheimer-like symptoms. It’s shown that AD progression could be accelerated with a positive feedback inhibition loop of IDH3β, lactate, PAX-6, and then back to IDH3β. Breaking this cycle by increasing IDH3β or decreasing PAX-6 would make the effects of related AD progression less severe.

“Genome-wide association analyses identified four suggestive loci (PAX3, CCRN4L, PIGQ, and ADAM19) at p < 1E-05. Our data suggest that short-term clinical disease progression in AD has a genetic basis.” - (Genetic Determinants of Disease Progression in Alzheimer’s Disease, n.d.)

Takeaways: The study has identified 4 locations on genomes that might play a role in the progression of AD in the short term: PAX3, CCRN4L, PIGQ, and ADAM19. These locations were identified through a wide association of analysis, which shows that genetic factors could influence the pace of progression of Alzheimer’s Disease. This supports our hypothesis that Alzheimer’s has some sort of genetic cause.

“Type 2 diabetes mellitus (T2DM) has been shown to increase the risks of cognitive decline and dementia. Paired box gene 4 (PAX4), a transcription factor for beta cell development and function has recently been implicated in pathways intersecting Alzheimer's disease and T2DM. Ethnic-specific R192H variation in PAX4 is associated with attention-specific cognitive impairment in Chinese with T2DM. Pending further validation studies, determining PAX4 R192H genotype may be helpful for early risk assessment of early-onset T2DM and cognitive impairment to improve diabetes care.”

Takeaways: Recent studies suggest PAX4 might influence brain function. A specific PAX4 variant has been linked to cognitive decline, particularly in attention. Since cognitive impairment is a feature of Alzheimer’s, this suggests that PAX4 could be involved in contributing to the disease.

Both in vitro and in vivo proof suggests TTR could protect the nervous system from Alzheimer's by binding to amyloids to prevent clumping. Despite this evidence, the details of how this works are unclear. When scientists analyzed a lot of cases, they didn’t find a strong link between TTR levels and the risk/severity of neurodegenerative diseases like Alzheimer’s. Later research even showed that AD patients had higher levels of TTR in their cerebrospinal fluid than normal, which contradicts previous cases that said that AD patients had lower levels. Mutations in the TTR gene have been linked to transthyretin amyloidosis, which is characterized by misfolding of TTR and amyloid clumps. It should also be noted that TTR levels which are normal/harmless in most animals result in cardiac disposition for humans. To summarize, even though there is proof that lower levels of TTR could result in Alzheimer’s, it’s still not entirely clear if this is true or how it works.

As for the paired-box gene, too much PAX6 inhibits the production of IDH3β, which leads to less tau protein hyperphosphorylation, synapse impairment, and Alzheimer-like symptoms. It’s possible that AD progression could be accelerated with a positive feedback inhibition loop of IDH3β, lactate, PAX-6, and then back to IDH3β. Breaking this cycle by increasing IDH3β or decreasing PAX-6 would make the effects of related AD progression less severe. Recent studies suggest that PAX4 might influence brain function. A specific PAX4 variant has been linked to cognitive decline, particularly in attention. Since cognitive impairment is a feature of Alzheimer’s, this suggests that PAX4 could be involved in contributing to the disease.

Some other genes that could be associated with Alzheimer’s are PAX3, CCRN4L, PIGQ, and ADAM19. 

On hyperparathyroidism: There is a possible link between hyperparathyroidism and Alzheimer’s. Specifically, neurodegeneration could affect the usual metabolism of thyroid hormones. In Alzheimer’s, brain cells get damaged, which disrupts how thyroid hormone usually works in the brain.  This could lead to problems with how brain cells process calcium, which could send the brain into a local hyperparathyroidism state and increase signs of amyloid aggregation and tau tangles. (We gave the hyperparathyroidism article a separate because the thyroid and parathyroid operate separately. Parathyroid hormones mainly control calcium, while T3 and T4 control functions like metabolism and protein production.)

After finding our results, we understand which genes impact Alzheimer’s Disease much better now. However, there are always improvements we can make. We can further understand how a mutation changes the structure of a protein and how it affects the protein's function. There are existing tools that can help visualize the structure of proteins based on the mutation, like the AI bioinformatic tool AlphaFold.  Besides that, we also could’ve used more of a variety of databases including BLAST and NCBI to get more widespread data from multiple perspectives.

Alzheimer’s disease - Symptoms and causes. (n.d.). Mayo Clinic. 

 

What is Alzheimer’s? (n.d.). Alzheimer’s Association.

 

The role of genes in your Alzheimer’s risk. (n.d.-b). Mayo Clinic.

 

Is Alzheimer’s hereditary/genetic? | Alzheimer’s Association. (n.d.-b). Alzheimer’s Association.

 

Hyperthyroidism vs. Hypothyroidism: Here’s How to Tell The Difference | Hartford HealthCare | CT. (n.d.).

 

Dellwo, A. (2024, November 25). How to tell the difference between hyperthyroidism and hypothyroidism. Verywell Health.

 

Goiter - Symptoms & causes - Mayo Clinic. (2021, November 6). Mayo Clinic. 

 

Thyroid nodules - Symptoms & causes - Mayo Clinic. (2022, February 11). Mayo Clinic. 

 

What is Alzheimer’s? (n.d.). Alzheimer’s Association. https://www.alz.org/alzheimers-dementia/what-is-alzheimers

 

Wikipedia contributors. (2025, January 27). Alzheimer’s disease. Wikipedia. https://en.wikipedia.org/wiki/Alzheimer%27s_disease

 

 Alzheimer’s disease - Symptoms and causes. (n.d.). Mayo Clinic. https://www.mayoclinic.org/diseases-conditions/alzheimers-disease/symptoms-causes/syc-20350447#:~:text=Alzheimer%27s%20disease%20is%20the%20most,and%20the%20brain%20to%20shrink.

 

Alzheimer’s Disease Fact Sheet. (n.d.). In National Institute on Aging.

Treatments for Alzheimer’s & Dementia | Alzheimer’s Association. (n.d.). Alzheimer’s Association. https://www.alz.org/alzheimers-dementia/treatments

What is Alzheimer’s? (n.d.-a). Alzheimer’s Association. https://www.alz.org/alzheimers-dementia/what-is-alzheimers

What is Alzheimer’s? (n.d.-b). Alzheimer’s Association. https://www.alz.org/alzheimers-dementia/what-is-alzheimers#:~:text=Research-,Understanding%20Alzheimer%27s%20and%20dementia,%2D80%25%20of%20dementia%20cases.&text=Alzheimer%27s%20is%20not%20a%20normal%20part%20of%20aging.

Wikipedia contributors. (2025, January 27). Alzheimer’s disease. Wikipedia. https://en.wikipedia.org/wiki/Alzheimer%27s_disease

A positive feedback inhibition of isocitrate dehydrogenase 3β on paired-box gene 6 promotes Alzheimer-like pathology. (2024, April 29). PubMEd. https://pubmed.ncbi.nlm.nih.gov/38679634/

Alzheimer’s disease - Symptoms and causes. (n.d.). Mayo Clinic. https://www.mayoclinic.org/diseases-conditions/alzheimers-disease/symptoms-causes/syc-20350447#:~:text=Alzheimer%27s%20disease%20is%20the%20most,and%20the%20brain%20to%20shrink.

Alzheimer’s Disease Fact Sheet. (n.d.). In National Institute on Aging.

Buxbaum, J. N. (2023, November 6). The Role of CSF Transthyretin in Human Alzheimer’s Disease: Offense, Defense, or not so Innocent Bystander. https://pubmed.ncbi.nlm.nih.gov/38176942/

Cell and molecular biology of transthyretin and thyroid hormones. (n.d.). PubMed. Retrieved December 20, 2024, from https://pubmed.ncbi.nlm.nih.gov/17338921/

Genetic determinants of disease progression in Alzheimer’s disease. (n.d.). PubMed. Retrieved December 27, 2024, from https://pubmed.ncbi.nlm.nih.gov/25114068/

Liz, M. A., Coelho, T., & Belloti, V. (2020, October 1). A Narrative Review of the Role of Transthyretin in Health and Disease. PubMed. https://pubmed.ncbi.nlm.nih.gov/33001386/

Primary Hypothyroidism and Alzheimer’s Disease: A Tale of Two - PubMed. (2023, August 4). https://pubmed.ncbi.nlm.nih.gov/37540395/

Transthyretin Stabilization: An Emerging Strategy for the Treatment of Alzheimer’s Disease? - PubMed. (2020, November 17). https://pubmed.ncbi.nlm.nih.gov/33212973/

Treatments for Alzheimer’s & Dementia | Alzheimer’s Association. (n.d.). Alzheimer’s Association. https://www.alz.org/alzheimers-dementia/treatments

What is Alzheimer’s? (n.d.-a). Alzheimer’s Association. https://www.alz.org/alzheimers-dementia/what-is-alzheimers

What is Alzheimer’s? (n.d.-b). Alzheimer’s Association. https://www.alz.org/alzheimers-dementia/what-is-alzheimers#:~:text=Research-,Understanding%20Alzheimer%27s%20and%20dementia,%2D80%25%20of%20dementia%20cases.&text=Alzheimer%27s%20is%20not%20a%20normal%20part%20of%20aging.

What is Alzheimer’s? (n.d.-c). Alzheimer’s Association. https://www.alz.org/alzheimers-dementia/what-is-alzheimers

Wikipedia contributors. (2025, January 27). Alzheimer’s disease. Wikipedia. https://en.wikipedia.org/wiki/Alzheimer%27s_disease

We would like to thank our parents, who have helped us on our science journey! We are also extremely grateful for our amazing teachers, Ms. Lai and Mr. Earle. They have always come to our aid whenever we were confused on a specific part.