APOE4 genotype and risk of developing Alzheimer’s disease

Apolipoprotein E gene allele 4 (APOE4) is a major genetic risk factor for late-onset Alzheimer’s disease (AD). Individuals carrying one copy of the APOE4 allele are known to be at 3-4-fold increased risk of developing AD compared with those carrying the more common APOE3 allele. The risk of developing AD is increased by 8-15-fold if an individual is carrying two copies of the APOE4 gene. The proportion of APOE genotypes and alleles differ between populations of different ethnic groups and gender [1]. A meta-analysis of clinical and autopsy-based studies on five ethnic groups (Caucasian, African American, Hispanic, and Japanese) revealed that the risk of developing AD was increased among Caucasian subjects with one APOE4 copy compared to individuals homozygous for APOE3 [1]. With regards to the gender, evidence indicate that the APOE4 risk for AD is greater in women, especially in heterozygous individuals carrying one APOE4 allele [2].

What is the role of APOE in brain?
Like other apolipoproteins, APOE is involved in lipid binding, and it is the predominant cholesterol transporter in the brain. While it is mainly generated by astrocytes, during stress, it has also shown to secrete by other cell types such as microglia and neurons. This multicellular expression and transport between cells often complicate our understanding of APOE4-mediated pathogenesis. To investigate this complexity, it is important to investigate cell-type-specific molecular processes influenced by APOE4.

APOE works to reduce lipid and cholesterol levels by binding to the low-density lipoprotein receptor allowing for cellular lipid uptake. The APOE isoforms impact how lipoproteins are cleared and the extent in which it is accomplished. APOE3 is considered as the control phenotype when comparing the function of APOE2 and APOE4 alleles. APOE2 has a decreased affinity to the receptor and decreases the risk of late-onset AD compared with APOE3 through both amyloid-β (Aβ)-dependent and independent mechanisms [3]. However, APOE2 carriers could develop type III hyperlipoproteinemia and exhibit increased risk of cerebrovascular diseases and neurological disorders.

APOE4 has an increased lipid binding ability and shows increased cellular accumulation of cholesterol and cholesterol esters. Recent work by Blanchard et al. showed that aberrant cholesterol deposition in APOE4 oligodendrocytes affects cellular functions including myelination [4]. This observation agrees with reduced myelination found in APOE4 brains. By facilitating cholesterol transport pharmacologically, Blanchard et al. observed improved axonal myelination and learning and memory in APOE4 mice. This work highlighted possible therapeutic opportunities for AD by modulating cholesterol transport.

Are there any non-pharmacological interventions?
Around 40% of dementia is suggested to attribute to a combination of twelve risk factors: education to a maximum of age 11–12 years, midlife hypertension, midlife obesity, hearing loss, late life depression, diabetes, physical inactivity, smoking, social isolation, excessive alcohol consumption, head injury, and air pollution [5]. These highlight the importance of managing lifestyle factors in preventing or delaying dementia. Fernandez-Matarrubia showed an active lifestyle favorably associated with improving cognitive function among APOE4 non-carriers but not with APOE4 carriers [6]. The authors suggest low number of APOE4 carriers is one of the limitations for this study, which may be overcome with a bigger sample size. There is still a lot of work to be done to better understand how environmental factors interact with genetics to help individuals prevent or delay cognitive decline at an early stage.

APOE also known to interact with Aβ, tau tangles, and pathogenic molecules such as lipopolysaccharides. Hence, APOE is believed to facilitate the clearance of inflammatory and pathogenic molecules suggesting its role in neuroinflammation. Prolonged neuroinflammation could induce neuronal damage and cell death by activating reactive oxygen species that can directly damage neurons or by sustaining chronic stress to induce a battery of inflammatory pathways that can damage or kill neurons. Carotenoids, antioxidant micronutrients that could accumulate in APOE containing lipid particles, have been suggested as another approach to reduce neuroinflammation [7]. Future research would benefit from understanding the relationship between APOE genotype and how we could use micronutrients to accumulate in brain to help relive oxidative stress. Such research could help clinicians to decide on precision medicine.

However, this opens new sets of questions. Should we test for the APOE4 gene? What information is out there for the public if they find out they carry one or two alleles of APOE4 genotype? What should they do?

[1] Husain MA, Laurent B, Plourde M (2021) APOE and Alzheimer’s disease: from lipid transport to physiopathology and therapeutics. Front Neurosci 15, 630502.
[2] Riedel BC, Thompson PM, Brinton RD (2016) Age, APOE and sex: Triad of risk of Alzheimer's disease. J Steroid Biochem Mol Biol 160, 134-147.
[3] Kloske CM, Wilcock DM (2020) The important interface between Apolipoprotein E and neuroinflammation in Alzheimer's disease. Front Immunol 11, 754.
[4] Blanchard JW, Akay LA, Davila-Velderrain J, von Maydell D, Mathys H, Davidson SM, Effenberger A, Chen CY, Maner-Smith K, Hajjar I, Ortlund EA, Bula M, Agbas E, Ng A, Jiang X, Kahn M, Blanco-Duque C, Lavoie N, Liu L, Reyes R, Lin YT, Ko T, R'Bibo L, Ralvenius WT, Bennett DA, Cam HP, Kellis M, Tsai LH (2022) APOE4 impairs myelination via cholesterol dysregulation in oligodendrocytes. Nature 611, 769–779.
[5] Livingston G, Huntley J, Sommerlad A, Ames D, Ballard C, Banerjee S, Brayne C, Burns A, Cohen-Mansfield J, Cooper C, Costafreda SG, Dias A, Fox N, Gitlin LN, Howard R, Kales HC, Kivimaki M, Larson EB, Ogunniyi A, Orgeta V, Ritchie K, Rockwood K, Sampson EL, Samus Q, Schneider LS, Selbæk G, Teri L, Mukadam N (2020) Dementia prevention, intervention, and care. Lancet 396, 413-446.
[6] Fernández-Matarrubia M, Goni L, Rognoni T, Razquin C, Fernández-Lázaro CI, Bes-Rastrollo M, Martínez-González MÁ, Toledo E (2021) An active lifestyle is associated with better cognitive function over time in APOE ɛ4 non-carriers. J Alzheimers Dis 79, 1257-1268.
[7] Dias IH, Polidori MC, Li L, Weber D, Stahl W, Nelles G, Grune T, Griffiths HR (2014) Plasma levels of HDL and carotenoids are lower in dementia patients with vascular comorbidities. J Alzheimers Dis 40, 399-408.

Last comment on 11 September 2023 by Lawrence Broxmeyer, MD





APOE has 299 amino acids and three variants E2, E3, 4E that differ by two amino acids, cysteine C and arginine R, in positions  

         122 158

E2     C.   C

E3.    C.   R

E4.    R    R


APOE4 increases the risk, lowers the age of onset, and enhances the development and progression of Alzheimer dementia (AD)


% Frequency   AD

E2     8.4.         3.3

E3.    77.9        59.4

E4     13.7.       36.7                 


 % Frequency   AD      Risk

E2/2   0.706      0.152  0.2

E2/3   6.54.       2.32   0.35

E2/4   1.15        1.43    1.6

E3/3 60.68      35.28    0.6

E3/4  10.67     21.80    2

E4/4    1.88     13.47    7


Among people with one APOE4 gene, there are 2-times more people with than without AD. Among people with two APOE4 genes, there are 7-times more people with than without AD.

Among people with two APOE2 genes, there are 5-times more people without than with AD.


Two APOE4 genes increase AD risk 12-fold compared to two APOE3, and 35-fold compared to two APOE2  


Q: how is it possible that AD risk increases 35-fold when APOE2 becomes APOE4, that is, C112R + C158R, how about doing it the other way.




Raulin et al. (2022). ApoE in Alzheimer's disease: pathophysiology and therapeutic strategies.Mol Neurodegener 17:72

Apolipoprotein E gene allele 4 (APOE4) is not only “genetic”. APOE-ε4 alleles are known to show a distinct increase in tuberculosis [Taghi Naserpour Farivar., et al. “Apolipoprotein E Polymorphism in Tuberculosis Patients”. Journal of Applied Sciences 8.4 (2008): 719-722], Thank you.