The Role of the Apolipoprotein E4 (APOE4) Gene in Triggering Alzheimer’s

Alzheimer’s is a degenerative condition characterized by irreversible damage to one’s ability to think, recall memories, and perform cognitive abilities like learning and problem-solving. Alzheimer’s progresses slowly over time and can become so severe that affected persons have difficulty completing daily tasks, such as remembering to take medication. It is the most common cause of dementia, a general term used to describe the loss of cognitive ability and memory, responsible for roughly 60 to 80 percent of dementia diagnoses.

Scientists have discovered a connection between the development of Alzheimer’s disease and specific gene variant called the APOE4 gene. However, they have also discovered a relationship between klotho protein and the APOE4 gene that looks promising in the prevention or treatment of Alzheimer’s.

What is Klotho Protein?

Klotho protein is a naturally occurring protein that is the focus of numerous research initiatives around the world for its known regulation in aging. Scientists are currently working to develop a treatment therapy using klotho protein that may be able to prevent dementia in high-risk individuals, like those with the APOE4 gene. Research has shown that under-expression of klotho protein is associated with an increased risk of developing Alzheimer’s and that overexpression of klotho protein can prevent or slow the progress of cognitive decline.

What is the Apolipoprotein E (APOE) Gene?

The apolipoprotein E (APOE) gene is responsible for the production of a protein, called apolipoprotein E, that carries cholesterols and fats through the bloodstream. One variant or form of the APOE gene, called e4, has been linked to an increased risk of developing Alzheimer’s disease. It is also associated with early onset of symptoms of aging.1

How is the APOE4 Gene Related to the Development of Alzheimer’s?

The exact mechanism of how the e4 variant of the APOE gene leads to the onset of Alzheimer’s is unknown. However, researchers have seen that individuals with the e4 variant of the APOE gene possess clusters of proteins, called amyloid plaques, in their brain tissue. Amyloid plaques can be toxic and, when they accumulate, can cause the death of nerve cells in the brain that can then lead to signs and symptoms of Alzheimer’s.2 Furthermore, inheritance of the APOE4 gene is associated with a known structural change, called cortical thinning, in the brains of individuals diagnosed with Alzheimer’s disease.3,4

It’s important to distinguish that inheriting this variation of the APOE gene does not mean that you will definitely develop Alzheimer’s disease. This genetic variation only increases an individual’s risk of developing Alzheimer’s.

How Does Klotho Protein Interact with the APOE4 Gene?

A study observing the interaction between APOE4 gene and klotho protein showed promising results for a potential new therapy using klotho protein. Results from the study showed that individuals who possessed the APOE4 gene variant and a variant of the klotho gene that led to increased klotho protein production were less affected by cortical thinning associated with the APOE4 gene, compared to individuals who did not possess the klotho gene variant.5

How do I know if I Have a Genetic Variant That Puts Me at Risk for Developing Alzheimer’s?

If you have a family member that has been diagnosed with Alzheimer’s disease, you may have inherited a genetic variant associated with the condition. If you’re interested in knowing whether you have received a copy of this gene, talk to your doctor about genetic testing. If you test positive for this variant, there is hope for future Alzheimer’s treatments. Scientists are currently working on a preventative treatment and cure for Alzheimer's disease using klotho protein.


  1. Alzheimer's Disease Genetics Fact Sheet. National Institute of Aging. Publication date unavailable. Updated August 30, 2015. Accessed August 08, 2018.
  2. APOE Gene. US National Library of Medicine - Genetics Home Reference. Published December 2008. Updated August 07, 2018. Accessed August 08, 2018.
  3. Fennema-Notestine C, Panizzon M, Thompson W, Chen CH, Eyler L, Fischl B, Franz C, Grant M, Jak A, Jernigan T, Lyons M, Neale, M, Seidman L, Tsuang M, Xian H, Dale A, Kremen W. Presence of ApoE ε4 Allele Associated with Thinner Frontal Cortex in Middle Age. Journal of Alzheimer’s Disease. 2011; 26(Suppl 3): 49–60.
  4. Dickerson B, Bakkour A, Salat D, Feczko E, Pacheco J, Greve D, Grodstein F, Wright C, Blacker D, Rosas HD, Sperling R, Atri A, Growdon J, Hyman B, Morris J, Fischl B, Buckner B. The Cortical Signature of Alzheimer's Disease: Regionally Specific Cortical Thinning Relates to Symptom Severity in Very Mild to Mild AD Dementia and is Detectable in Asymptomatic Amyloid-Positive Individuals. Cerebral Cortex. 2009 Mar; 19(3): 497–510.
  5. Schultz S, Boots E, oh J, Darst B, Koscik R, Gallagher C, Carlsson C, Rowley H, Bendlin B, Asthana S, Sager M, Hogan K, Hermann B, Engelman C, Johnson S, Dubal D, Okonkwo O. Longevity Gene Klotho Alters APOE4-Related Cortical Thinning: Findings From the Wisconsin Registry for Alzheimer’s Prevention. Alzheimer's & Dementia. 2016 July; 12(7): 56.