Synonyms: Apolipoprotein E, LPG, LDLCQ5, AD2


Back to the Top

Apolipoprotein E is a secreted apolipoprotein involved in lipid metabolism. It complexes with lipids to form lipoprotein particles that transport cholesterol and triglycerides via the bloodstream and facilitate the transfer of cholesterol and phospholipids between cells in the brain. In the periphery, ApoE is expressed by hepatocytes and macrophages. In the brain, it is produced and secreted primarily by astrocytes and activated microglia.

ApoE has three isoforms—ApoE2, E3, and E4—with unique cysteine/arginine combinations at positions 130 and 176. Every person has an APOE genotype determined by homozygous or heterozygous pairs of the alleles encoding these isoforms—for example, APOE3/E3 or APOE3/E4. The APOE4 allele is thought to be the ancestral form of the APOE gene which gave rise to APOE2 and APOE3.

While APOE4 increases the risk for late-onset Alzheimer’s disease, APOE2 reduces it. The largest datasets from studies of Caucasian populations show APOE4 increasing AD risk in a dose-dependent manner with one allele raising risk about threefold, and two alleles elevating it 10- to 15-fold relative to APOE3. In contrast, one APOE2 allele cuts AD risk down to about half of that of carriers of two APOE3 alleles, and two alleles reduce it to 13 percent.

Overall, the population risk that can be attributed to APOE4 is approximately 20 percent, although its effects vary between populations of different ancestries. APOE4 also modifies the age of AD onset, with carriers’ symptoms emerging about five years earlier than those of non-carriers. Whether and under what circumstances APOE4 affects disease progression remains uncertain, although most studies suggest it accelerates it.

ApoE4 initiates a cascade of early alterations which can lead to later pathological changes associated with AD, including both gain- and loss-of-function effects relative to ApoE3. It appears to contribute to both hallmark AD pathologies, amyloid plaques and neurofibrillary tangles. In addition, it has been blamed for altering lipid transport and metabolism in brain cells and fueling neuroinflammation, abnormal cellular stress responses, and blood-brain barrier breakdown. ApoE4 has also been reported to reduce neurogenesis, disrupt endocytosis and intracellular trafficking, impair mitochondrial function and energy metabolism, as well as modify transcription. At a tissue level, it appears to alter brain glucose metabolism and cause neural network dysfunction.

Multiple approaches to therapeutically counter the harmful effects of ApoE4 are being examined, ranging from directly targeting the protein to mitigating its downstream effects.

In addition to the three common APOE alleles—APOE2, E3, and E4—genetic variants in other positions, many of them rare, have also been studied (see APOE genetic variant dataset). Some have been tied to AD or to other neurological disorders, and/or to peripheral conditions including alterations of lipid metabolism, cardiovascular health, and kidney function.


Mutations Citations

  1. APOE R176C (ApoE2)
  2. APOE C130R (ApoE4)

Mutation Interactive Images Citations

  1. APOE

Further Reading


  1. . Apolipoprotein E and Alzheimer disease: pathobiology and targeting strategies. Nat Rev Neurol. 2019 Sep;15(9):501-518. Epub 2019 Jul 31 PubMed.
  2. . A Quarter Century of APOE and Alzheimer's Disease: Progress to Date and the Path Forward. Neuron. 2019 Mar 6;101(5):820-838. PubMed.
  3. . APOE and Alzheimer's disease: advances in genetics, pathophysiology, and therapeutic approaches. Lancet Neurol. 2021 Jan;20(1):68-80. PubMed.
  4. . Apolipoprotein E and Alzheimer's Disease: Findings, Hypotheses, and Potential Mechanisms. Annu Rev Pathol. 2022 Jan 24;17:73-99. Epub 2021 Aug 30 PubMed.
  5. . ApoE Cascade Hypothesis in the pathogenesis of Alzheimer's disease and related dementias. Neuron. 2022 Apr 20;110(8):1304-1317. Epub 2022 Mar 16 PubMed.
  6. . Lipoproteins in the Central Nervous System: From Biology to Pathobiology. Annu Rev Biochem. 2022 Jun 21;91:731-759. Epub 2022 Mar 18 PubMed.
  7. . A multi-hit hypothesis for an APOE4-dependent pathophysiological state. Eur J Neurosci. 2022 May 5; PubMed.