Background Recent genome-wide association studies (GWAS) for Alzheimer’s Disease and related dementias (ADRD) have increased statistical power via larger analysis datasets from biobanks by 1) including non-age-matched controls and prevalent cases, and/or 2) including individuals who report a family history of ADRD as proxy cases. However, these methods have the potential to increase noise and distort genetic associations which are important for genomic-informed prevention and treatment of ADRD. Here, we sought to understand how the effect sizes of genetic associations in ADRD could be sensitive to these methodological choices, using APOE genotypes as an example.

Methods Participants in the All of Us Research Program over the age of 49 at enrollment (n=258,693) were assigned one of four categories: incident ADRD (developed after enrollment in All of Us), prevalent ADRD (present on enrollment), proxy ADRD (participant noted a family history of ADRD), and control (no history or diagnosis of ADRD). Dementia diagnoses were determined using available Electronic Health Records (EHR) and APOE genotype was determined using whole-genome sequencing. Effect sizes for the associations between APOE risk alleles and ADRD diagnoses were compared using polychotomous logistic regression.

Results The mean age of the cohort was 67±10 years, and it was 58% female; 63% clustered predominantly with European genetic reference populations. Among the participants, 3,107 (1.2%) had prevalent ADRD, 301 (0.1%) had incident ADRD, and 19,910 (7.7%) reported a family history of ADRD (proxy ADRD). Both prevalent and proxy ADRD had attenuated associations with APOE genotype compared to incident ADRD. The adjusted generalized ratio (95% CI) (AGR) for incident ADRD for APOE ε4 heterozygotes was 2.95 (2.31-3.74) compared to 2.10 (1.96-2.24) and 1.42 (1.32-1.55) for proxy and prevalent ADRD, respectively. For APOE ε4 homozygotes, the effect sizes were even more different. Furthermore, APOE association effect sizes increased when restricting the control (no ADRD) group to older age brackets.

Conclusions Our study highlights how genetic associations with ADRD can be sensitive to how cases are defined in biobanks like All of Us, with effect sizes downwardly biased when using prevalent or by-proxy cases compared to incident cases.

The authors have declared no competing interest.

This work was performed with funding from NIH P30 AG072973 (CM, JDM) and T32 AG078114 (CM); NIH P20 GM130423 (OJV), 5UL1TR002366 (OJV), and P30 AG035982 (OJV, JDM & RHS). JHK is funded by the NIHs Office of the Director under awards 1OT2OD026549 and OT2OD036485 and the National Heart, Lung, and Blood Institute (NHLBI) under awards R21HL172036, R01 HL156993, and R01 HL158686. This work was also supported by the NHGRI Intramural Research Program ZIA HG200417 (JCD).

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The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

Informed consent for all participants is conducted in person or through an eConsent platform that includes primary consent, HIPAA Authorization for Research use of EHRs and other external health data, and Consent for Return of Genomic Results. The protocol was reviewed by the Institutional Review Board (IRB) of the All of Us Research Program. The All of Us IRB follows the regulations and guidance of the NIH Office for Human Research Protections for all studies, ensuring that the rights and welfare of research participants are overseen and protected uniformly

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