Assistant Professor of Neuroscience and Neurology, Feil Family Brain and Mind Research Institute, Department of Neurology, Weill Cornell Medical College

Dr. Ishii reports no financial relationships relevant to this field of study.

SYNOPSIS: Using a genetic risk score of 23 common genetic variants and apolipoprotein E genotype could help stratify individuals into those very likely to those very unlikely to develop late-onset Alzheimer’s disease and dementia.

SOURCE: van der Lee SJ, Wolters FJ, Ikram MK, et al. The effect of APOE and other common genetic variants on the onset of Alzheimer’s disease and dementia: A community-based cohort study. Lancet Neurol 2018;17:434-444.

Despite the recent advances in understanding the determinants of late-onset Alzheimer’s disease (AD), accurately predicting an individual’s risk for developing AD remains challenging. Large genetic screens have discovered several important genes in sporadic forms of AD, but the individual contribution of each gene, including apolipoprotein E (APOE), remains relatively small. Therefore, van der Lee et al set out to determine whether combining APOE genotype and 23 other common genetic variants could help predict an individual’s likelihood of developing AD and dementia.

Study participants were part of the Rotterdam Study, a large prospective community-based cohort study enrolling residents aged 55 years and older in a district of Rotterdam, Netherlands. Dementia was screened at baseline and subsequent visits with the Mini-Mental State Examination and the Geriatric Mental Schedule organic level. Subjects were excluded if there was no follow-up time beyond age 60 years. Additionally, the entire cohort was monitored continuously for dementia through electronic linkage with outpatient medical records. A consensus panel made the final diagnosis of AD or dementia according to standardized criteria. DNA for genotyping was obtained from baseline blood samples. The investigators included 23 genetic variants that showed genome-wide significant evidence of association with AD to generate a weighted genetic risk score (GRS) using reported effect estimates as weights. Subjects were categorized into tertiles of the GRS. Mortality was accounted as a competing event.

A total of 12,255 of 14,926 participants met study criteria. Follow-up was completed for 92% of 144,738 potential person-years, with median follow-up of 11.0 years. APOE genotype was imputed for 3% of subjects, which had a greater than 98% concordance with direct genotyping. Directly genotyped or imputed APOE genotype data were available for 11,375 out of 12,255 subjects.

As expected, APOE genotype had a strong effect, with E4/E4 having 48.3% (95% confidence interval [CI], 40.1-57.3) and heterozygous for E4 having 18.4% (95% CI, 16.5-20.4) risk for developing AD by age 85 years. By comparison, the risk was 8.6% (95% CI, 7.7-9.6) for E3/E3 and 5.5% (95% CI, 4.1-7.4) for E2/E2 or E2/E3 genotypes. For all, the risk of dementia was higher than AD but showed similar overall patterns. When stratified by tertiles of GRS, the risk for developing AD by age 85 years was 15.8% (95% CI, 14.1-17.6) for the high-risk, 11.8% (95% CI, 10.3-13.5) for the middle-risk, and 7.7% (95% CI, 6.5-9.1) for the low-risk.

When accounting for both the APOE genotype and the GRS, the risk for developing AD or dementia by age 85 years was the lowest in individuals with E2/E2 or E2/E3 genotypes and in the GRS low-risk tertile at 4.1% (95% CI, 2.1-7.7%) for AD and 7.2% (95% CI, 4.5-11.5%) for dementia. By comparison, individuals with E4/E4 genotypes and in the GRS high-risk tertile had the highest risk with 62.7% (95% CI, 47.2-78.2%) for AD and 77.5% (95% CI, 63.1-89.3%) for dementia. Within the same APOE genotype, risks of both AD and dementia were higher in the GRS high-risk tertile than the low-risk tertile.

When examining the percent risk by age, individuals with E4/E4 and GRS high-risk tertile attained 5% risk of AD at age 67 years and 12.5% at age 71 years. By comparison, individuals with E2/E3 or E2/E2 and GRS low-risk tertile had a 5% risk of AD at age 85 years and 12.5% by age 100 years. Furthermore, E4/E4 with GRS high-risk tertile attained a 40% risk of AD 10 years earlier than those in the low-risk tertile. Similar patterns were seen with risk for developing dementia. Finally, when parental history of dementia was considered, the risk for developing dementia was further increased in individuals with a positive parental history of dementia in the highest risk group (APOE E4/E4 and GRS high-risk tertile) compared to those in the same risk group who did not have a parental history of dementia.

COMMENTARY

There are significant strengths to this study, including using a large community-based setting, prospective determination of AD and dementia, high follow-up completion (92%), length of study (up to 25 years), and adjustments made for competing risk of mortality. However, notable limitations exist. All study participants are of native Dutch descent, possibly leading to cohort-specific effects requiring validation in other populations. Additionally, GRS was comprised of genetic data obtained from other studies in different cohorts. Therefore, it is not clear if the reported effect estimates of these genetic variations accurately predict those in this or other populations. Nevertheless, van der Lee et al demonstrated that stratifying an individual’s risk for developing AD or dementia could be accomplished using noninvasive genetic screenings that are becoming increasingly more common in clinical practice. Furthermore, accurately predicting an individual’s risk for developing AD would be extremely useful in prevention trials, where investigators can recruit subjects with the highest risk of AD without being confounded by those with very low risk. Alternatively, studies on subjects with the lowest risk could yield new insight regarding protective factors against dementia. Finally, since individuals with APOE E4/E4 genotype and high-risk tertile for GRS have a risk for developing AD of 62.7% and not 100%, non-genetic determinants, such as environmental and lifestyle factors, likely contribute to an individual’s risk despite significant genetic risk factors. Although significant work needs to be done, additional research building on this important study could help move the field from prediction to prevention and ultimately treatment.