3.1 Characteristics of participants
A total of 707 non-demented individuals were included in CABLE. The mean (SD) age of the study sample was 62.5 (SD = 10.5) years old and female accounted for roughly 59%. Participants who have higher plasma SHBG levels tend to be older (p < 0.0005) and achieved less MMSE scores (p < 0.05). As for ADNI, 450 non-demented individuals were included at baseline. The study sample was older (74.8 ± 7.2 years) and comprised less female (37%). Participants who have higher plasma SHBG levels tend to be older (p = 0.03) and female (p < 0.0001) (Table 1)
3.2 Correlation analysis of SHBG levels in plasma and CSF
Data of SHBG levels both in plasma and in CSF were available for 188 subjects from ADNI-1. The correlation analysis showed that SHBG levels in plasma and CSF were highly related for both sexes (p = 2.12 × 10 -10, r = 0.44) (Figure 1A).
3.3 Plasma SHBG was associated with lower CSF Aβ42
CSF biomarker abnormality is deemed as the earliest change during the AD course. The cross-sectional analyses revealed that plasma SHBG was negatively correlated with CSF levels of CSF Aβ42 (r = -0.17, p = 0.0001). After adjusting age, gender, education, APOE4 status, and MMSE at baseline, significant associations were found between plasma SHBG and CSF Aβ42 (p < 0.005) (Figure 1B). No interactions with gender or APOE4 status were found, though the subgroup analyses indicated that the association was only significant in APOE4 non-carriers (p < 0.005). Longitudinally, higher plasma SHBG was associated with faster decline of CSF Aβ42 (Figure 1C), after adjusting for age, gender, education, APOE4 status, and clinical diagnosis. No significant associations were revealed for CSF tau proteins (Table e-1) though potential interactions with APOE4 status were found (Table e-2).
3.4 Plasma SHBG accelerates hippocampus atrophy and brain metabolism decline
In the prodromal stage of AD, CSF biomarker change was followed by the structural atrophy as well as brain metabolic decline. We found individuals with higher plasma SHBG showed faster hippocampus atrophy (p = 0.028, Figure 2A) and brain metabolism decline (p = 0.025, Figure 2B). No significant interaction terms were found and sensitivity analyses barely change the results.
3.5 Plasma SHBG contributes to cognitive decline
With the accumulation of biomarker and imaging abnormalities, cognitive impairments become the core manifestations with the disease progress. We identified that higher plasma SHBG levels conferred faster decline in general cognition (Figure 2C and 2D), memory function (Figure 2E), and executive function (Figure 2F). Sensitivity analyses excluding those who developed AD within one year since baseline or adding TT and FTI as covariates barely influenced the results.
3.6 Plasma SHBG increases AD dementia risk
In the cohort for incident AD dementia, 199 subjects were lost and 237 were finally included (with a follow-up duration of 3.2 ± 2.4 years), among whom 164 subjects (36%) developed AD dementia. No significant differences in age, sex, education, and plasma SHBG at baseline were found between those who completed the follow-up and those who were lost. Compared with the lowest tertile (T1), subjects with higher plasma SHBG were associated with an average of 50% (T2) and 60% (T3) increased risk of developing AD dementia, independent of age, sex, education, APOE genotype, and diagnosis. The significance barely changed after further adjusting lifestyle factors and vascular risk factors. (Figure 3) Stratified analyses indicated that the influences of plasma SHBG levels on the risk of incident AD dementia were stronger in the male group and those with advanced age. (Table 2) Sensitivity analyses excluding those who developed AD dementia within one year since baseline or adding TT and FTI as covariates did not change the results.