Advancements in Alzheimer's Treatment Unveil New Diagnostic Applications

Alzheimer’s disease is a growing public health concern, affecting over 6 million people in the United States and standing as the seventh leading cause of death in the nation¹. By 2050, it is expected that nearly 13 million individuals will be affected². These statistics raise concerns about the future and the need to address Alzheimer’s disease. Significant progress has been made in both the diagnosis and treatment of Alzheimer's disease since its initial description in the early 1900s. As more Alzheimer’s disease treatment options become available, the field of diagnostics is rapidly evolving to adapt to new demands. The use of apolipoprotein E (APOE) genotyping as a screening tool prior to therapy, rather than for diagnostic purposes, serves as an example of the changing dynamics of the diagnostics field in response to the availability of new Alzheimer’s treatments.

Alzheimer's Disease Approved Treatment

Two classes of Alzheimer’s disease drugs have been approved by the Federal Drug Administration (FDA): those that treat symptoms and those that delay disease progression in those with early-stage Alzheimer's disease.

Drugs that target symptoms are most effective when given early in the course of the disease and can slow the progression of mild to moderate symptoms, improving the quality of life for Alzheimer’s disease patients. To date, seven drugs in this class have been approved by the FDA³. The second class of drugs, disease-modifying therapies (DMTs), alter the clinical progression of the disease, and only two drugs have been approved to date³. Each targets beta-amyloid at various stages of plaque development, and both mitigate cognitive decline by effectively eliminating beta-amyloid plaque from the brain. Furthermore, there are currently a total of 70 clinical trials evaluating multiple physiological targets including anti-beta-amyloid drugs³. 

Aducanumab (Aduhelm) was the first drug approved in 2021 under the accelerated approval pathway by the FDA⁴. Lecanemab (Leqembi) received traditional approval from the FDA in July of 2023 to treat early Alzheimer's disease, including in people living with mild cognitive impairment (MCI) or mild dementia due to Alzheimer's disease who have confirmation of elevated beta-amyloid in the brain⁵. Other drugs targeting amyloid beta plaques, such as donanemab, are in clinical trials with expected approval by the end of 2023⁶.

Based on the clinical study results, anti-amyloid treatments have side effects including amyloid-related imaging abnormalities (ARIA)⁷. Depending on the drug therapy and the dose, ARIA can develop within the first few weeks or months of treatment, thereby limiting the optimal dose⁸. There are two forms of ARIA, ARIA-E which is characterized by edema, and ARIA-H which is characterized by hemorrhagic changes⁹. Although ARIA is typically asymptomatic and is only diagnosed by a brain PET scan, it might cause additional symptoms such as headache, worsening disorientation, dizziness, visual abnormalities, nausea, vomiting, and seizures. Additionally, ARIA-E with aducanumab has been linked to one death, and ARIA-H with donanemab has been linked to one death⁸. ARIA can be treated by suspending medication until symptoms or radiographic signals improve or permanently discontinuing treatment¹⁰.

APOE e4: More Than a Genetic Predisposition Marker for Alzheimer’s Disease

The ApoE protein has been demonstrated to have a role in Alzheimer’s disease pathology and functions as a lipid transporter for the delivery of cholesterol and phospholipids ¹¹. In humans, there are three APOE alleles — APOE e2, APOE e3, and APOE e4 (see Table 1) — that result in three different isoforms of the ApoE protein (e2, e3, and e4).  APOE e3 is the most common allele and is predicted to have minimal effect on Alzheimer’s disease, and the APOE e2 allele has been shown to be neuroprotective against Alzheimer’s disease but could present an increased risk for cardiovascular disease in homozygous individuals^11-13. The APOE e4 allele is the strongest genetic risk factor and is present in up to 25 percent of the US population, and homozygotes (up to 5 percent of the population) have up to a 15-fold increased risk of developing Alzheimer’s disease^{12, 14, 15}. Carriers of  APOE e4 alleles have been shown to be at an increased risk for ARIA after anti-amyloid treatment¹⁶. ARIA may potentially be more likely to be recurrent, severe, or serious in individuals homozygous for the APOE e4 allele^17-20.

Given the potential for negative outcomes in APOE carriers after anti-amyloid treatment, the recommendation prior to the prescription of Leqembi is to screen patients for APOE genotypes to allow for discussions regarding the risks for ARIA^{9, 21}. The Leqembi label states, “Prescribers should inform patients that if genotype testing is not performed, they can still be treated with LEQEMBI; however, it cannot be determined if they are APOE e4 homozygotes and at a higher risk for ARIA.”

APOE Genotyping Holds New Clinical Utility

The APOE e4 allele of the APOE gene is demonstrated to be a significant genetic risk factor for negative consequences after administration of currently available Alzheimer’s disease treatment as explained above and, while some US clinical labs offer APOE genotyping, there is currently no FDA-approved solution^22-26. To date, the use of APOE genotyping in predictive testing has been shown to be limited in a clinical capacity as APOE e4 carriers do not always develop Alzheimer’s disease. Approximately 35 to 42 percent of individuals diagnosed with Alzheimer's disease are not APOE e4 carriers^27-29.

However, with the new FDA-approved anti-beta amyloid drugs, APOE genotyping can be helpful in determining genetic status prior to beginning these disease-modifying treatments in mild to moderate Alzheimer’s disease cases. This will aid in identifying patients who might be at risk from potentially life-threatening consequences of anti-amyloid treatment while affording non-carriers access to medication that can reduce cognitive decline.

A Look Toward the Future

To date, there are no FDA-approved tests to determine genetic status prior to beginning treatment targeting amyloid plaques in Alzheimer’s disease patients. This situation may change as more drugs in this class are approved by the FDA which could lead to a requirement for an APOE genetic screen in Alzheimer’s disease patients.

Furthermore, APOE genotyping can be used for patient stratification to determine inclusion criteria for clinical trials as more treatments are developed and additional biomarkers are identified. APOE genotyping may offer potential benefits in enhancing the efficacy of other therapeutic interventions focusing on ApoE levels, functions, structure, lipidation status, and other related factors¹¹. APOE genetic screening could be also used to limit the pool of individuals undergoing broad biomarker screens in blood or CSF or as a pre-screen prior to amyloid imaging studies³⁰. The recent advances in Alzheimer’s disease treatment are promising and it is clear that ApoE is an important player in this field.

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Tables

Table 1 APOE Gene Characteristics^{31, 32}

References

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