Biomarkers

We investigated sex differences in a machine learning-derived imaging signature of AD brain atrophy (i.e., SPARE-AD⁵), in relation to age, genetic factors (APOE ε4 allele), and multi-organ biological age gap (BAG^2,3).

Data from the iSTAGING and MULTI consortia included 53,622 participants without diagnosed cognitive impairment (mean age: 61.8 ± 12.6 years; 54% women). The SPARE-AD model uses a support vector machine with a linear kernel to distinguish between cognitively normal individuals and those with AD⁵. Generalized linear models assessed sex differences and nine BAG associations with SPARE-AD, adjusting for age, sex, APOE ε4, and interactions, and analysis of covariance (ANCOVA) with Tukey's test to assess differences in SPARE-AD scores between APOE ε4 allele carrier groups.

Overall, SPARE-AD increased with age (β = 0.018, p < 2e-16). Women had higher SPARE-AD scores than men (β = -0.393, p < 2e-16). Women had higher SPARE-AD scores at younger ages but lower values at older ages (β = 0.006, p < 2e-16 for the age-sex interaction term) when compared to males (Figure 1a). Furthermore, SPARE-AD was positively associated with the number of APOE ε4 alleles (β = 0.018, p =  1.06e-6). Non-carriers and heterozygous carriers of the APOE ε4 allele exhibited lower SPARE-AD scores compared to homozygous carriers in analyses of both combined sexes and in men alone; this pattern was not observed in women (Figure 1b-d). Among the nine BAGs, the brain BAG was most strongly associated with SPARE-AD in both sexes combined (β = 0.018, p =  1.09e-302) (Figure 2a) and separately (women: β = 0.017, p =  5.08e-128; men: β = 0.019, p =  4.24e-175) (Figure 2b-c). Other significant BAG associations were observed in men and not in women, including musculoskeletal (β = 0.004, p =  0.02), immune (β = 0.004, p =  0.02), and metabolic BAGs (β = 0.005, p =  0.02) (Figure 2b-d).

SPARE-AD scores increased with age and were higher in women at younger ages but lower than men at older ages, with a significant age*sex interaction, and were positively associated with the number of the APOE ε4 allele, particularly in men.