Estimating age at Aβ onset in the 1946 British birth cohort: exploring the influence of APOE ɛ4 carriership and sex

Abstract Background Cerebral Aβ accumulates decades before symptom onset in AD. Sampled iterative local approximation (SILA, Betthauser et al. 2022) is a technique for estimating time from Aβ positivity (Aβ+) using Aβ‐PET. Here we explore the influence of APOE‐ɛ4 carriership and sex on estimated age of Aβ+ (EAAβ) in primarily cognitively normal individuals from the longest‐running British birth cohort. Method Participants in Insight 46 were drawn from the 1946 British birth cohort and underwent combined PET/MR scanning with [18F]florbetapir at two timepoints. Centiloid (CL) values were calculated using a whole cerebellum reference region and partial volume correction. We used Gaussian mixture modelling (99 th percentile of lower distribution) to define an Aβ+ threshold of 12 CL. We constructed a CL vs Aβ time curve with SILA from available longitudinal Aβ‐PET scans (n=324, interval=2.4+/‐0.2yrs), which was applied to the whole sample (n=463) to calculate EAAβ. Some scans were below the CL range that could be modelled, and the estimated EAAβ was truncated to the furthest time before onset on the CL vs time curve. Kaplan‐Meyer plots and Cox regression were used to investigate EAAβ and risk of estimated Aβ+ by APOE‐ɛ4 and sex, right censoring participants where EAAβ was truncated. Result Mean (SD) chronological age was 70.6+/‐0.7yrs at baseline and 73.0+/‐0.6yrs at follow‐up scan and 30.5% were Aβ+ve by follow‐up (n=141, 55.3% APOE‐ɛ4, 51.8% female). SILA results and distribution of EAAβ are shown in Figures 1 and 2. EAAβ were truncated due to low Aβ binding in 35.7% (n=166, 15.7% APOE‐ɛ4, 50% female). APOE ɛ4 carriers reached median EAAβ 8.6 years earlier than non‐carriers (Figure 3A). Median EAAβ for females was marginally earlier than males with overlapping CIs (Figure 3B). APOE‐ɛ4 was strongly associated with risk of estimated Aβ+ (HR[95%CI] = 2.4[1.9,3.0]), adjusted for sex. Female sex (1.1[0.8,1.3]) and the interaction between APOE‐ɛ4 and sex (1.2[0.8,1.9]) were non‐significant. Conclusion Estimated Aβ positivity was reached on average 8.6 years earlier for APOE ɛ4 carriers. Consistent with results from other cohorts, APOE‐ɛ4, not sex, significantly heightened the risk of estimated Aβ positivity. Future research will explore life course and downstream events related to Aβ timing.