Nithya Mathai, DNP and Robert Colton, MD
Alzheimer’s disease is a complex progressive neurodegenerative disorder characterized by cognitive decline and memory impairment. Currently, this disease affects over 5 million Americans. While the exact etiology remains unknown to a degree, genetic factors can play a significant role in its pathogenesis and risk. The most commonly identified genetic variant was apolipoprotein E (APOE).
APOE exists in three isoforms: ε2, ε3, and ε4, with APOE ε4 allele being strongly associated with increased AD risk and earlier age of onset. About 25% percent of the population carries at least one copy of APOE4 and 2 to 3% carry 2 copies (homozygous for APO E4). The APOE ε2 allele is rare and appears to confer more of a protective effect, reducing the risk and delaying the onset of AD.
People with one copy of E4 (heterozygous) have about 3 times higher lifetime risk of Alzheimer’s disease (AD) and those with 2 copies have about 12 times higher lifetime risk. These genetic variants are not determinative. They are just risk factors, and the risk can be mitigated through aggressive lifestyle interventions.
The Science: APOE in Alzheimer’s Disease
APOE is involved in lipid metabolism, neuronal repair, and synaptic plasticity, suggesting its potential role in AD pathophysiology. Strong evidence from clinical and basic research suggests that a major pathway by which APOE4 increases the risk of AD is by driving earlier and more abundant amyloid pathology in the brains of APOE*ε4 carriers (Yu Yamazaki et.al, 2019).
Could the answer for Alzheimer’s be in one’s DNA, are there benefits to test for APOE?
1. Early Detection and Diagnosis: APOE testing allows for health care providers to identify those who are an increased genetic component to developing Alzheimers. Early detection of APOE ε4 carriers can facilitate timely intervention and personalized management strategies, including lifestyle modifications and preventive measures.
2. Health Care Prognostic Outcomes: APOE genotype has allowed for improved prognostic implications, influencing the age of onset, disease progression, and cognitive decline in AD patients. APOE ε4 carriers may exhibit a more rapid decline in cognitive function and are more likely to develop severe forms of the disease compared to non-carriers.
3. Clinical Trial Enrollment: APOE testing can aid in patient risk stratification and selection for clinical trials evaluating potential disease-modifying therapies for AD. In order to find a cure to Alzheimer’s, it is imperative to continue genetic research to allow for researchers and providers to target Alzheimer’s. Could the answer be within one’s genes? Consistent and immersive research is imperative for this disease. Targeting APOE ε4 carriers in clinical trials may enhance therapeutic efficacy and improve outcomes by selecting individuals most likely to benefit from treatment.
4. Personalized and targeted treatment approach: Knowledge of APOE status enables the development of personalized treatment plans tailored to individual genetic risk profiles. This includes optimizing pharmacological interventions, such as the use of cholinesterase inhibitors(ex: Aricept) and memantine (ex: Namenda), and exploring emerging targeted therapies aimed at modulating specific APOE-related pathways.
Ethical Considerations of Genetic Testing:
APOE testing has certain limitations and ethical considerations. The predictive value of APOE testing for individual risk assessment is modest, as many APOE ε4 carriers do not develop AD, and conversely, many AD patients do not carry the APOE ε4 allele. This can lead to increased anxiety and depression between patients, family members and friends. Additionally, APOE testing raises concerns regarding patient autonomy, privacy, and the psychological impact of receiving genetic risk information. Testing also opens the conversation of overall familial risk.
How is this test completed:
Our providers at Thema Brain Health order your genetic test to the nearest lab to you. The specimen can be collected via blood samples or with a buccal swab (cheek swab). Results usually take around 4-7 days to result. It is imperative to consult with your provider about the results of your genetic test. Genetic test results can be complicated. It is important to have all your questions answered by the providers while going through the results.
In the field of Alzheimer’s’ APOE testing is a promising tool in the management of Alzheimer’s disease, offering insights into disease risk (fam, prognosis, and personalized treatment approaches. While further research is needed to fully elucidate the clinical utility and implications of APOE testing, integrating genetic testing into clinical practice represents a crucial step towards targeted and personalized medicine in AD care.
References:
1. Reiman, E. M., et al. (2001). Functional brain abnormalities in young adults at genetic risk for late-onset Alzheimer’s dementia. Proceedings of the National Academy of Sciences, 98(19), 11830-11835.
2.. Livingston, G., et al. (2020). Dementia prevention, intervention, and care: 2020 report of the Lancet Commission. The Lancet, 396(10248), 413-446.
3. Yamazaki, Y., Zhao, N., Caulfield, T.R. et al. Apolipoprotein E and Alzheimer disease: pathobiology and targeting strategies. Nat Rev Neurol 15, 501–518 (2019). https://doi.org/10.1038/s41582-019-0228-7