A study published in Lancet Neurology found that a weighted genetic risk score (GRS) composed of 23 different genetic variants associated with Alzheimer disease (AD) provides greater cumulative risk assessment of AD than APOE alone among cognitively normal individuals aged ≥55 years.

Participants from the Rotterdam Study who were free from dementia and were ≥55 years old were included in this analysis (n=12,255). Investigators calculated incidence curves for AD and dementia up to age 100 years. The GRS evaluated in this study included 23 genetic variants, including ABCA7, MS4A6A/MS4A4E, EPHA1, CD33, CD2AP, and TREM2 variants, among others. Analyses were stratified by GRS tertiles (low-risk, n=3402; middle-risk, n=3292; and high-risk, n=3317 tertiles) and APOE genotypes (APOE ε3/ε3, n=6662; APOE ε4/ε4, n=261; APOE ε3/ε4, n=2608; APOE ε2/ε4, n=312; APOE ε2/ε3, n=1453; and APOE ε2/ε2, n=79).

Among the 1609 participants who developed dementia during a median follow-up period of 11.0 years (interquartile range, 4.9-15.9; 133,123 person years), a total of 1262 (78%) had AD. Investigators observed interactions between APOE genotypes and the GRS for the relationship with dementia (P =.04) and AD (P =.03). The difference between the high-risk and low-risk tertiles by 85 years of age was 37.2% for dementia (P =2.2×10−4) and 27.0% for AD (P =8.5×10−3), represented by a 7- to 10-year difference in terms of onset age. The GRS primarily modified the risk for and onset of dementia and AD among homozygous carriers for APOE ε4.

The difference in risk by age 85 years between carriers who were homozygous for APOE ε2 or heterozygous with only 1 copy of the ε2 and ε3 alleles in the low-risk tertile vs homozygous APOE ε4 carriers in the high-risk tertile was 70.3% (7.2% vs 77.5%; P =3.0×10−23) for dementia and 58.6% (4.1% vs 62.7%; P =6.2×1013) for AD. This risk difference was represented by an 18- to 29-year age difference at dementia onset and was particularly noticeable when investigators included parental history of dementia (difference in risk, 83.8%; P =1.1×10−20).

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Nonresponse bias as a result of nonparticipation represents a potential limitation of this study. In addition, risk estimates were unstable because of the small number of participants in the stratified subgroups.

Including these 23 genetic variants in addition to “APOE could contribute towards better risk stratification in the community, facilitating planning of feasible and efficient preventive and curative clinical trials.”


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(5):434-444.