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Two Copies, One Condition? Understanding APOE Allele State in over 14,000 Symptomatic Patients  

Clinical Genetics and Therapeutics
  • Primary Categories:
    • Clinical-Adult
  • Secondary Categories:
    • Clinical-Adult & Pediatric
Introduction:
Recent attention on Alzheimer’s disease (AD) due to new treatments and articles has sparked discussion on the risk factors associated with AD. While AD is genetically heterogeneous, APOE is the strongest known risk factor. The 3 major alleles of APOE (APOE2, APOE3, and APOE4) are associated with varying risks of AD and cardiovascular disease. A recent article suggested that these individuals have a separate genetic condition with increased risk for AD and cognitive impairment. APOE4 heterozygotes also have an increased risk for AD and cardiovascular disease. In contrast, APOE 3,2 carriers have a decreased risk of cardiovascular disease. Individuals with homozygous APOE2 alleles have a decreased risk for AD and cardiovascular disease. Herein, we present the largest cohort of symptomatic individuals undergoing APOE testing and compare phenotypes presented in individuals with homozygous APOE4 alleles. 

Methods:
We retrospectively reviewed consecutive results and provider-included clinical information from 14,629 adults who had APOE symptomatic testing for AD at a CLIA-certified diagnostic laboratory. Specimens were received from the United States and its territories. APOE genotyping was performed by restriction endonuclease digestion of PCR amplified genomic DNA. Statistical analysis was performed using a two tailed Fisher’s exact test. The study was found to be exempt under 45 CFR § 46.104(d)(4). 

Results:
Of the 14,629 individuals undergoing testing, APOE alleles states were as follows: 4/4-1,329, (9.1%), 4/3-5,212, (35.6%), 4/2-412, (2.8%), 3/3-6,566, (44.9%), 3/2-1,061, (7.3%), 2/2-49, (0.3%). The average age of testing is 65.7, and did not correlate with allele state.  



This cohort presented with the following phenotypes:1,790, (12.2%) individuals had a reported diagnosis of AD, 4,772, (32.6%) had cerebellar degeneration (CD), 4,058, (27.7%) had memory loss (ML) ,1,846, (12.6%) had dementia (D), 1,024, (7.0) had cognitive impairment (CI), 409, (2.8%) had cardiovascular disease (CVD) and 70, (0.5%) had a reported family history (FH). Individuals often had more than one phenotype reported. 



Clinical phenotypes with allele states were as follows:  

  • 4/4- AD 13.9%, CD 34.8%, ML 26.1%, D 13.2%, CI 7.7%, CVD 1.6% and FH 0.2%. 




  • 4/3- AD 13.4%, CD 34.8%, ML 26.7%, D 12.4%, CI 7.3%, CVD 2.6% and FH 0.4%. 




  • 4/2 - AD 11.9%, CD 34.8%, ML 29.4%, D 11.2%, CI 5.6%, CVD 3.2% and FH 1.5%. 




  • 3/3 - AD 11.5%, CD 34.8%, ML 28.6%, D 12.0%, CI 7.1%, CVD 3.2% and FH 0.5%. 




  • 3/2 - AD 9.0%, CD 34.8%, ML 28.7%, D 17.7%, CI 5.3%, CVD 2.5% and FH 0.2%. 




  • 2/2- AD 6.1%, CD 34.8%, ML 264.5%, D 10.2%, CI 0.0%, CVD 6.1% and FH 2.0%. 


No statistically significant differences in allele states were observed among individuals with these phenotypes.   

Conclusion:
Our results do not reflect an increased risk of cognitive impairment nor cardiovascular disease in individuals with homozygous APOE4 alleles. Since an increased risk for cardiovascular disease has been consistently demonstrated in previous studies, it is possible that providers who test patients for AD related features are either unaware of this risk or did not provide these features. It is uncertain whether the increased risk for cognitive impairment in individuals with homozygous APOE4 does not exist or just was not present in this cohort. Further studies are needed to evaluate this finding, additional clinical and demographic information, and potential modifiers. 



Due to recent studies, there has been considerable discussion on whether individuals with homozygous APOE4 alleles have a distinct genetic condition, which may indicate certain testing procedures and treatment practices. We suggest that much is still to be learned regarding APOE and risks, and that further studies should be undertaken to further elucidate risks. With current treatments possible for individuals, these studies are necessary to aid in patient care, counseling, and prognosis. 

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