Alzheimer’s at the Genetic Level

One of the big hallmarks of medical progress over time has been specificity. When we are sick with a cold, many home remedies are systemic. Systemic treatments have effects on your whole body, the whole system. Rest, mom’s home-cooked soup, and water are all systemic remedies that help the whole body fight an acute illness. But sitting in bed all day eating soup isn’t really healthy long-term, and all that salt isn’t great for the heart. For many diseases, the whole body isn’t failing, only a specific part is. If a problem originates in a particularly finicky organ - like the brain - specificity of treatments can become the most important part.

Alzheimer’s dementia is a brain disorder that affects our ability to make and recall memories and our cognitive processing (things like learning, language, and problem-solving). What exactly happens to the brain during Alzheimer’s dementia isn’t fully understood, but one of the major theories is the Amyloid Hypothesis. The Amyloid Hypothesis states that amyloid β (beta), a small protein, accumulates between neurons in the brain in plaques and causes Alzheimer’s ^[1]. Many clinical trials have targeted the amyloid β plaques with limited success, though a couple of recent FDA approvals give hope ^[2]. Two new treatment options are currently being investigated which attack Alzheimer’s at the most specific level we have, the level of genetics.

The pathway for genetics is that DNA is translated into mRNA, which is then transcribed into a protein. There are a lot of other pieces to each step, but that’s the general outline. Proteins are the end result. Proteins can have many functions, including releasing or sensing chemicals, moving food, waste, or materials, providing the structure of cells or organs, and so on. Effective and specific treatments for Alzheimer’s might change the speed and amount of protein produced from DNA.

Amyloid β needs an extra step. It is made from another protein, amyloid precursor protein (APP) ^{[3, 4]}. APP is a useful protein in the brain, and levels of APP are thought to be influenced by iron levels ^{[1, 5]}. When there is too much of it (perhaps from too much iron in the brain) the brain breaks it into pieces, some of which are dangerous ^{[1, 3, 4, 5, 6]}. Buntanetap, also called posiphen, is a potential treatment medication undergoing clinical trials to lower the concentration of APP in participants at risk of Alzheimer’s ^{[3, 4]}. Buntanetap limits the ability of iron to recruit more APP, and will hopefully balance APP levels (and therefore amyloid β levels) during clinical trials ^{[1, 3, 4]}.

Beyond amyloid β, there are clinical trials targeting cognitive decline itself. To make memories, the brain has to make physical changes ^{[7, 8]}. These changes involve proteins, which means they also involve genetics. Our genetic code isn’t constant over time; enzymes and chemicals change what code is read and what code is inaccessible in a process called epigenetics ^[7]. One enzyme that plays a role in memory and cognitive function is called KDM5. This enzyme makes parts of the DNA code less accessible ^[9]. At normal concentrations, KDM5 regulates proteins that control memory and energy in the brain, but when there is too much KDM5, our memory and cognition decline ^{[9, 10]}. The brains of Alzheimer’s patients are found to have much higher levels of KDM5 than the brains of healthy individuals ^[11]. Clinical trials are underway to test KDM5 inhibitors that have the potential to keep KDM5 levels healthy and may help reduce cognitive decline at a fundamental level ^[9].

These two approaches expose the diverse and exciting avenues scientists are pursuing for Alzheimer’s treatment. Targeting Alzheimer’s dementia by getting genetic regulators in check is some of the most futuristic stuff I’ve ever heard of. And it’s way more specific than a bowl of soup!

Creative Director Benton Lowey-Ball, BS, BFA

References:

[1] Bandyopadhyay, S., & Rogers, J. T. (2014). Alzheimer's disease therapeutics targeted to the control of amyloid precursor protein translation: maintenance of brain iron homeostasis. Biochemical pharmacology, 88(4), 486-494. https://pmc.ncbi.nlm.nih.gov/articles/PMC4064675/

[2] Kim, C. K., Lee, Y. R., Ong, L., Gold, M., Kalali, A., & Sarkar, J. (2022). Alzheimer’s disease: key insights from two decades of clinical trial failures. Journal of Alzheimer's Disease, 87(1), 83-100. https://content.iospress.com/articles/journal-of-alzheimers-disease/jad215699

[3] Maccecchini, M. L., Chang, M. Y., Pan, C., John, V., Zetterberg, H., & Greig, N. H. (2012). Posiphen as a candidate drug to lower CSF amyloid precursor protein, amyloid-β peptide and τ levels: target engagement, tolerability and pharmacokinetics in humans. Journal of Neurology, Neurosurgery & Psychiatry, 83(9), 894-902. https://jnnp.bmj.com/content/83/9/894.short

[4] Delport, A., & Hewer, R. (2022). The amyloid precursor protein: A converging point in Alzheimer’s disease. Molecular Neurobiology, 59(7), 4501-4516. https://link.springer.com/article/10.1007/s12035-022-02863-x

[5] Cahill, C. M., Lahiri, D. K., Huang, X., & Rogers, J. T. (2009). Amyloid precursor protein and alpha synuclein translation, implications for iron and inflammation in neurodegenerative diseases. Biochimica et Biophysica Acta (BBA)-General Subjects, 1790(7), 615-628. https://pmc.ncbi.nlm.nih.gov/articles/PMC3981543/

[6] Kisby, B., Jarrell, J. T., Agar, M. E., Cohen, D. S., Rosin, E. R., Cahill, C. M., ... & Huang, X. (2019). Alzheimer’s disease and its potential alternative therapeutics. Journal of Alzheimer's disease & Parkinsonism, 9(5). https://pmc.ncbi.nlm.nih.gov/articles/PMC6777730/

[7] Collins, B. E., Sweatt, J. D., & Greer, C. B. (2019). Broad domains of histone 3 lysine 4 trimethylation are associated with transcriptional activation in CA1 neurons of the hippocampus during memory formation. Neurobiology of learning and memory, 161, 149-157. https://pmc.ncbi.nlm.nih.gov/articles/PMC6541021/

[8] Kandel, E. R., Schwartz, J. H., Jessell, T. M., Siegelbaum, S., Hudspeth, A. J., & Mack, S. (Eds.). (2000). Principles of neural science (Vol. 4). New York: McGraw-hill.

[9] Gehling, V. S., Bellon, S. F., Harmange, J. C., LeBlanc, Y., Poy, F., Odate, S., ... & Albrecht, B. K. (2016). Identification of potent, selective KDM5 inhibitors. Bioorganic & medicinal chemistry letters, 26(17), 4350-4354. https://www.sciencedirect.com/science/article/abs/pii/S0960894X16307399

[10] Liu, X., & Secombe, J. (2015). The histone demethylase KDM5 activates gene expression by recognizing chromatin context through its PHD reader motif. Cell reports, 13(10), 2219-2231. https://pmc.ncbi.nlm.nih.gov/articles/PMC4684901/