Antibodies are proteins produced by the immune system that can be engineered to target specific molecules involved in disease. Apolipoprotein E (APOE) is a protein involved in fat metabolism throughout the body and brain. Scientists are exploring antibodies that specifically target the APOE protein as a potential therapeutic approach for Alzheimer’s disease.
The APOE Gene’s Link to Alzheimer’s Disease
The APOE gene makes the apolipoprotein E protein, which has three common forms: APOE2, APOE3, and APOE4. APOE3 is the most common allele. In the brain, APOE transports cholesterol and lipids, essential for maintaining and repairing nerve cells. It is primarily produced by astrocytes, with some secretion by microglia and neurons during stress.
The APOE4 allele is a major genetic risk factor for late-onset Alzheimer’s disease. Individuals with one copy of APOE4 have an increased risk of developing Alzheimer’s by approximately two to four times compared to those with two APOE3 copies. Carrying two copies of APOE4 further increases this risk, potentially by eight to fifteen times. While APOE4 elevates risk and is associated with an earlier age of disease onset, it does not guarantee Alzheimer’s disease.
Therapeutic Mechanism of APOE Antibodies
APOE antibodies interact with the APOE protein in the brain to influence Alzheimer’s pathology. Their primary goal is to reduce or neutralize the effects of APOE protein, especially the APOE4 form, which promotes the buildup of amyloid plaques and tau tangles. APOE4 alters amyloid-beta (Aβ) clearance, aggregation, and metabolism, encouraging Aβ aggregation.
These antibodies may work by binding to specific APOE protein conformations, particularly those in amyloid-beta plaques. This binding is proposed to help clear amyloid-beta from the brain or prevent its aggregation. Studies in mouse models have shown that anti-APOE antibodies can decrease amyloid-beta burden, similar to anti-amyloid-beta antibodies. This approach aims to disrupt the interaction between APOE and amyloid-beta, which contributes to the disease process.
Clinical Trials and Development
Research into APOE antibodies for Alzheimer’s disease is an active area of investigation. This includes studies exploring various strategies to target APOE, such as antisense oligonucleotides and monoclonal antibodies. Early preclinical studies have shown that anti-APOE monoclonal antibodies can reduce amyloid-beta plaque load and may improve cognitive abilities in mouse models. One specific anti-human APOE antibody, HAE-4, has demonstrated reductions in amyloid-beta plaques and amyloid-beta-driven tau seeding and spreading in mouse models expressing human APOE4.
Clinical trials typically proceed through different phases, evaluating safety, dosage, and efficacy. While direct APOE antibody therapies are still in early stages, some gene therapy programs designed to modulate APOE expression are advancing, with one such program aiming to reduce APOE4 while increasing APOE2 levels. Such programs anticipate presenting early data in 2025.
Known Risks and Safety Concerns
Antibody-based therapies for Alzheimer’s disease, including those targeting amyloid-beta, have been associated with specific safety concerns, primarily Amyloid-Related Imaging Abnormalities (ARIA). ARIA can manifest in two forms: ARIA-E, which involves edema or swelling in the brain, and ARIA-H, which refers to microhemorrhages or small bleeds. These abnormalities are detected through magnetic resonance imaging (MRI) scans, which are typically scheduled at regular intervals during treatment.
The risk of experiencing ARIA can be higher in individuals who carry the APOE4 gene allele. For instance, individuals with one copy of APOE4 may have a three-fold increased risk of ARIA compared to non-carriers, while those with two copies could face a six-fold higher risk, potentially reaching up to a 33% chance. This elevated risk is thought to be linked to APOE4’s influence on cerebrovascular integrity, increased neuroinflammation, and higher levels of cerebral amyloid angiopathy (CAA), where amyloid deposits occur in blood vessel walls. While many ARIA cases are asymptomatic, some individuals may experience symptoms such as headache, confusion, or dizziness.
Distinction from Other Alzheimer’s Treatments
Many current Alzheimer’s therapies, such as lecanemab and donanemab, directly target amyloid-beta plaques, aiming to remove these protein aggregates from the brain. Other treatments in development focus on tau tangles, which are abnormal accumulations of tau protein inside neurons.
Targeting APOE with antibodies represents a different strategy because APOE is a genetic risk factor influencing both amyloid and tau pathology. Instead of directly removing plaques or tangles, APOE antibodies aim to modulate the APOE protein itself, particularly the APOE4 isoform, to prevent or reduce the formation of these downstream pathologies. This is considered an “upstream” approach, addressing a factor that contributes to the disease process at an earlier stage.