Apolipoprotein E Genotype and Aβ Accumulation: Protective Effect of ε2 Allele

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While the most common recent approach in Alzheimer disease drug discovery is to directly target the β-amyloid pathway, the high prevalence of apolipoprotein E ε4 in Alzheimer disease and the ease of identifying ε4 carriers make the APOE genotype and its corresponding protein an appealing therapeutic target to slow Aβ accumulation.

Study data published in JAMA Neurology suggest that the apolipoprotein E (APOE) ε2 allele may be protective against amyloid-β (Aβ) accumulation in the presence of the APOE ε4 allele. In this retrospective neuroimaging study, APOE ε2 was associated with significant reductions in both overall and age-dependent levels of Aβ in the presence of ε4. These data may be significant in the development of novel Alzheimer disease treatments.

Along with age, APOE genotype is one of the strongest risk factors for Aβ accumulation. Compared with APOE ε3-only carriers, rates of early Aβ accumulation are highest in ε4 carriers and lowest in ε2 carriers. This study sought to evaluate the protective effects of ε2 in patients also carrying the ε4 allele.

Investigators conducted a cross-sectional study using screening data from the Anti-Amyloid Treatment in Asymptomatic Alzheimer Disease Study, conducted between 2014 and 2017. The present study used data from adults aged 65-85 years without cognitive impairment who underwent a fluorine 18–labeled (18F)-florbetapir positron emission tomography scan and had available APOE genotype information.

Participants who were taking a prescription Alzheimer medication, had a Clinical Dementia Rating >0, or had a current serious illness were excluded. The primary outcome of interest was Aβ pathology, measured by 18F-florbetapir standardized uptake value ratio (SUVR). Cognition was measured by the Preclinical Alzheimer Cognitive Composite (PACC).

The analytic cohort comprised 4432 participants of mean age 71.3 ± 4.7 years, among whom 2634 (59.3%) were women. Overall, 1512 (34.1%) had a positive Aβ level. APOE genotype was significantly associated with 18F-florbetapir SUVR (P <.001 for trend). Patients with an ε2 and ε3 allele (ε23 genotype) had significantly lower mean 18-F florbetapir SUVR compared with the ε33 group (1.02 vs 1.05; P =.01).

The ε24 group also had significantly lower mean 18F-florbetapir SUVR compared to the ε34 group (1.11 vs 1.18; P <.001). A significant interaction was detected between APOE genotype and age to predict 18-florbetapir SUVR (P <.001). SUVR increased with age, with more dramatic increases observed in groups with the ε4 allele. Compared to the ε33 group, SUVR in the ε22 and ε23 group increased much more slowly over time (0.006 vs 0.002 SUVR per year; P =.01).

By contrast, the ε34 group had approximately twice the rate of the ε33 group (0.012 vs 0.006 SUVR per year; P <.001). The association between 18F-florbetapir SUVR and poorer PACC scores did not differ by APOE genotype. While APOE ε4 carriers displayed worse performance on the PACC compared to the ε33 group, this difference was completed mediated by Aβ. After adjusting for Aβ levels, composite PACC scores were similar between APOE genotypes. These results suggest that carrying an ε2 allele in the presence of an ε4 allele may protect against Aβ accumulation.

The primary study limitation was the exclusion of participants with cognitive impairment; results may only apply to those with Aβ pathology in the absence of cognitive dysfunction. Even so, “[the findings are] important for potential treatments that attempt to biochemically mimic the function of the ε2 allele in order to facilitate Aβ clearance in ε4 carriers,” the investigators wrote. “Such a treatment strategy is appealing, as ε4 carriers make up approximately two-thirds of patients with Alzheimer disease dementia.”

Disclosure: One study author declared affiliations with the pharmaceutical industry. Please see the original reference for a full list of authors’ disclosures.


Insel PS, Hansson O, Mattsson-Carlgren N. Association between apolipoprotein E ε2 vs ε4, age, and β-amyloid in adults without cognitive impairment [published online October 12, 2020]. JAMA Neurol. doi: 10.1001/jamaneurol.2020.3780