Factors that Contribute to Alzheimer’s Disease

There are a number of contributing factors to the onset of Alzheimer’s Disease. In this note, I'll be detailing 10 of the biggest factors (according to current research), as well as how/why it is impacting your risk for developing Alzheimer's Disease.

Intrinsic Vulnerabilities

(1) Old Age -

As you may have guessed, the biggest factor for developing Alzheimer's Disease is old age, with the probability of getting Alzheimer’s disease increasing as you get older. This is why we have been seeing the increase in the way we have in previous years. There are more people who are living longer and our brains just can’t keep up.

(2) ApoE4 -

ApoE4 is a gene variant that codes for apolipoprotein E. This gene variant is worse at clearing amyloid-β and performing synaptic repair. These both are characteristics of Alzheimer's, as described in this post.

Inflammatory and Immune Dysregulation

(3) Neuroinflammation -

When inflammation becomes chronic, the immune cells in your brain, called microglia, stay active for too long. Instead of helping with repair, they release chemicals that damage neurons and accelerate plaque and tangle buildup.

(4) Obesity -

Carrying too much body fat increases inflammation throughout the body. Fat tissue releases molecules that make insulin resistance worse and put extra stress on the brain, both of which raise the risk of Alzheimer’s.

(5) Traumatic Brain Injury and Stroke -

A single head injury or stroke can cause long-lasting damage. The brain responds with inflammation and scar-like changes, and over time this increases amyloid and tau buildup while lowering your brain’s resilience.

Vascular and Metabolic Dysfunction

(6) Vascular Insufficiency -

When blood flow to the brain is reduced, the brain does not get enough oxygen or nutrients. This also makes it harder to clear amyloid-β, creating an environment where Alzheimer’s pathology develops faster.

(7) Type 2 Diabetes Mellitus -

Type 2 diabetes disrupts how your body regulates blood sugar and insulin. Since the brain depends on insulin to help with energy use and memory processes, this disruption makes it harder for neurons to communicate. Over time, this raises amyloid buildup and tau changes, making diabetes one of the strongest lifestyle-related risk factors for Alzheimer’s.

Cellular Energy and Redox Balance

(8) Mitochondrial Impairment

Your mitochondria are the energy powerhouses of your cells. When they start breaking down, neurons cannot produce enough energy to function properly, and the increase in byproducts like free radicals damages brain tissue.

(9) Oxidative Stress

Oxidative stress is when unstable molecules called reactive oxygen species build up and damage DNA, proteins, and fats in the brain. Because the brain uses so much oxygen, it is especially vulnerable to this process, which accelerates neurodegeneration.

Environmental and Toxic Exposures

(10) Heavy Metals

Exposure to heavy metals such as lead or mercury increases oxidative stress and makes it easier for proteins like amyloid-β to misfold and clump together. While not the most common risk factor, it still contributes to Alzheimer’s disease in exposed populations.

References:

1. Hou, Y., Dan, X., Babbar, M., Wei, Y., Hasselbalch, S. G., Croteau, D. L., & Bohr, V. A. (2019). Ageing as a risk factor for neurodegenerative disease. Nature Reviews Neurology, 15(10), 565–581. https://doi.org/10.1038/s41582-019-0244-7

2. Liu, C. C., Kanekiyo, T., Xu, H., & Bu, G. (2013). Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy. Nature Reviews Neurology, 9(2), 106–118. https://doi.org/10.1038/nrneurol.2012.263

3. Heppner, F. L., Ransohoff, R. M., & Becher, B. (2015). Immune attack: the role of inflammation in Alzheimer disease. Nature Reviews Neuroscience, 16(6), 358–372. https://doi.org/10.1038/nrn3880

4. Profenno, L. A., Porsteinsson, A. P., & Faraone, S. V. (2010). Meta-analysis of Alzheimer’s disease risk with obesity, diabetes, and related disorders. Biological Psychiatry, 67(6), 505–512. https://doi.org/10.1016/j.biopsych.2009.02.013

5. Johnson, V. E., Stewart, W., & Smith, D. H. (2010). Traumatic brain injury and amyloid-β pathology: a link to Alzheimer’s disease? Nature Reviews Neuroscience, 11(5), 361–370. https://doi.org/10.1038/nrn2808

6. Iadecola, C. (2013). The pathobiology of vascular dementia. Neuron, 80(4), 844–866. https://doi.org/10.1016/j.neuron.2013.10.008

7. Chatterjee, S., & Mudher, A. (2018). Alzheimer’s Disease and Type 2 Diabetes: A Critical Assessment of the Shared Pathological Traits. Frontiers in Neuroscience, 12, 383. https://doi.org/10.3389/fnins.2018.00383

8. Wang, W., Zhao, F., Ma, X., Perry, G., & Zhu, X. (2020). Mitochondria dysfunction in the pathogenesis of Alzheimer’s disease: recent advances. Molecular Neurodegeneration, 15(1), 30. https://doi.org/10.1186/s13024-020-00376-6

9. Butterfield, D. A., & Halliwell, B. (2019). Oxidative stress, dysfunctional glucose metabolism and Alzheimer disease. Nature Reviews Neuroscience, 20(3), 148–160. https://doi.org/10.1038/s41583-019-0132-6

10. Xu, J., & Jia, Z. (2021). Heavy metals in Alzheimer’s disease: Mechanisms and targeted therapy. Frontiers in Aging Neuroscience, 13, 652032. https://doi.org/10.3389/fnagi.2021.652032