None of the AD genetic risk indices (i.e., ADPRS, APOE, ADPRS−APOE, ADPRS−APOE x APOE) were significantly associated with any non-imaging or imaging phenotype after either Bonferoni or FDR multiple testing correction (non-imaging: all |B| < 2.42; all p > 0.00118; all pfdr > 0.23, Fig. 1, Supplemental Tables 4; imaging: all |B| < 0.03; all p > 0.003; all pfdr > 0.22, Supplemental Tables 5–7). After conducting a monte-carlo based simulation power analysis using SIMR (Green and MacLeod 2016) our most significant effect only had 58% power.
Psychosocial And Behavioral Phenotypes
No psychosocial and behavioral phenotypes, within any domain (n = 8; i.e., cognition, screen time, demographics, substance, culture/environment, physical health, family mental health, and child mental health) were significantly associated with any index of AD genetic risk after either Bonferoni or FDR multiple testing correction. Across the four indices of genetic risk for AD: ADPRS, APOE, ADPRS−APOE, ADPRS−APOE x APOE genotype six of the eight assessed domains had nominally significant associations (P < 0.01). There were no nominally significant associations in either the Demographic or Screen Time domain. In total, across six domains (i.e., Child Mental Health, Family Mental Health, Physical Health/Development, Culture/Environment, Substances, Cognition) the fourth indices of genetic risk for AD: ADPRS, APOE, and ADPRS−APOE, ADPRS−APOE x APOE genotype there were 18, 12, 10, and 15 nominally significant associations, respectively (nominal significance considered as p < 0.01 due to the large number of phenotypes investigated). Specifically, the following number of nominally significant associations were observed for each AD genetic risk by domain: Child Mental Health (ADPRS= 10, APOE = 4, ADPRS−APOE= 4, ADPRS−APOE x APOE genotype = 7), Family Mental Health (ADPRS= 4, APOE = 4, ADPRS−APOE= 5, ADPRS−APOE x APOE genotype = 3), Physical Health/Development (ADPRS= 4, APOE = 3, ADPRS−APOE= 3, ADPRS−APOE x APOE genotype = 5), Culture/Environment (ADPRS= 0, APOE = 1, ADPRS−APOE= 0, ADPRS−APOE x APOE genotype = 0) Substances (ADPRS= 1, APOE = 1, ADPRS−APOE= 0, ADPRS−APOE x APOE genotype = 0), Cognition (ADPRS= 0, APOE = 1, ADPRS−APOE= 0, ADPRS−APOE x APOE genotype = 0. Below we briefly summarize the directionality of associations that were below an uncorrected p value threshold of 0.01 within each of these domains for ADPRS, APOE, ADPRS−APOE. Nominally significant ADPRS−APOE x APOE interactions are not described below as no post-hoc tests were conducted to characterize the directionality of these moderation effects due to the lack of significant interactions when accounting for multiple testing.
Cognition. APOE risk alleles were associated with reduced performance on the Rey Auditory Verbal Learning Test, a neuropsychological assessment of auditory-verbal attention, memory, and learning (Total score: B = -0.04, p = 0.0061, pfdr = 0.70). No other associations p < 0.01 were observed for any AD genetic risk index. No other cognition phenotypes were associated with any AD genetic index at even nominal p < 0.05 levels of significance (all ps > 0.05).
Screen Time. No associations < 0.01 were observed for any AD genetic risk index.
Demographics. No associations < 0.01 were observed for any AD genetic risk index.
Substances. Higher ADPRS was associated with greater substance accessibility (i.e., “If your child wanted to get a drug like cocaine, LSD, or amphetamines, how easy would it be for them to get some?”; B = 0.04, p = 0.008, pfdr = 0.64). No other associations < 0.01 were observed for any AD genetic risk index.
Culture/Environment. The presence of APOE risk alleles were associated with talking more often to one’s parent/guardian about daily plans (B = 0.04, p = 0.001, pfdr = 0.43). No other associations < 0.01 were observed for any AD genetic risk index.
Physical Health (inclusive of development). Both higher ADPRS and APOE risk alleles were associated with a later age (in months) when being able to sit up by oneself as an infant/toddler (both Bs > 0.04, ps < 0.002, psfdr > 0.23) and being evaluated by a medical professional for a sprain (both Bs > 0.12, ps < 0.002, psfdr > 0.23). Higher ADPRS was associated with greater pubertal development among males (B = 0.05, p = 0.006, pfdr = 0.57) and APOE risk alleles were associated with more hospitalizations (B = 0.10, p = 0.005, pfdr = 0.66). Finally, ADPRS−APOE was associated with receiving stitches from a medical practitioner and birth complications as well as a reduced number of broken bones (all |B|s > 0.08, all ps < 0.008, all psfdr > 0.77). No other associations < 0.01 were observed for any AD genetic risk index.
Family Mental Health. The caregivers (predominantly mothers) of individuals with high ADPRS reported increased bragging, being less mean, and increased intrusive thoughts (all |B|s > 0.02, all ps < 0.01, all psfdr > 0.23). Among those with more APOE risk alleles, caregivers reported more bragging and talking too much as well as being less mean to others and that their behavior is less changeable (all |B|s > 0.02, all ps < 0.01, all psfdr > 0.43). Caregivers of those with elevated ADPRS−APOE reported lower emotional disturbance (e.g., less anhedonia, not crying a lot), dependence on others, and difficulty making decision (all Bs < -0.03, all ps < 0.01, all psfdr > 0.82). No other associations < 0.01 were observed for any AD genetic risk index.
Child Mental Health. Greater ADPRS was associated with reduced anxiety (e.g., difficulty controlling worries) and manic symptoms (e.g., racing thoughts) and impairment (e.g., clinically significant distress due to worry) as well as increased impairment due to compulsions (all |B|s > 0.14, all ps < 0.009, all psfdr > 0.23). APOE risk alleles were associated with greater compulsive symptoms (e.g., past compulsions) and impairment (e.g., past impairment in function due to compulsions) and reduced anxiety symptoms (i.e., difficulty controlling worries) (all |B|s > 0.17, all ps < 0.007, all psfdr > 0.43). Finally, greater ADPRS−APOE was associated with less clinging to adults/dependence and receipt of special services at school as well as greater sleep problems and insomnia (all |B|s > 0.04, all ps < 0.009, all psfdr > 0.77). No other associations < 0.01 were observed for any AD genetic risk index. All corrected and uncorrected non-imaging phenotype results are in Supplemental Table 4.
Neuroimaging Phenotypes
No brain phenotype, either global or regional, was significantly associated with any index of AD genetic risk, when adjusting for multiple testing using FDR or Bonferroni correction (all |B|s < 0.03; all ps > 0.003; all psfdr > 0.22; Supplemental Tables 5–7). The association between ADPRS−APOE and increased cerebellum volume and white matter approached significance with FDR correction (volume: right & left: both Bs > 0.26, both ps < 0.007, both psfdr=0.074; white matter volume: B = 0.01, p = 0.0058, pfdr=0.074). The hippocampus, which was been previously associated with AD genetic risk in healthy samples, was not associated with any index of AD genetic risk (all |B| <0.02; all ps > 0.14, all psfdr >0.68; Supplemental Table 5–7). Across the four indices of genetic risk for AD: ADPRS, APOE, ADPRS−APOE, ADPRS−APOE x APOE genotype all eight imaging domains had nominally significant associations (P < 0.05). There were no nominally significant associations in the Whole Brain imaging modality. In total, across the seven imaging domains (i.e., Whole Brain, Regional Subcortical Volume, Regional Cortical Thickness, Cortical Surface Area, Regional Mean Diffusivity Regional Fractional Anisotropy, and RSFC) the four indices of genetic risk for AD (ADPRS, APOE, and ADPRS−APOE, ADPRS−APOE x APOE genotype) had 16, 20, 27, and 25 nominally significant associations, respectively. Specifically, the following number of nominally significant associations were observed for each AD genetic risk by imaging modality: Whole Brain (ADPRS= 0, APOE = 0, ADPRS−APOE= 3, ADPRS−APOE x APOE genotype = 0) Regional Subcortical Volume (ADPRS= 3, APOE = 4, ADPRS−APOE= 5, ADPRS−APOE x APOE genotype = 1), Regional Cortical Volume (ADPRS= 3, APOE = 2 ADPRS−APOE= 4, ADPRS−APOE x APOE genotype = 4), Regional Cortical Thickness (ADPRS= 4, APOE = 4, ADPRS−APOE= 5, ADPRS−APOE x APOE genotype = 4), Cortical Surface Area (ADPRS= 3, APOE = 3, ADPRS−APOE= 4, ADPRS−APOE x APOE genotype = 7), Regional Mean Diffusivity (ADPRS= 1, APOE = 3, ADPRS−APOE= 2, ADPRS−APOE x APOE genotype = 2), Regional Fractional Anisotropy (ADPRS= 0, APOE = 0, ADPRS−APOE= 1, ADPRS−APOE x APOE genotype = 2), and RSFC (ADPRS= 2, APOE = 4, ADPRS−APOE= 3, ADPRS−APOE x APOE genotype = 5). Below, we briefly summarize associations that were nominally significant, i.e., p < 0.05 uncorrected for multiple testing for ADPRS, APOE risk alleles, ADPRS−APOE. The ADPRS−APOE x APOE interactions are not described here as no post-hoc tests to characterize these interactions were conducted due to the lack of significance when accounting for multiple testing.
Whole Brain
ADPRS−APOE was associated with greater total, right, and left cortical volumes at nominal levels of significance (all Bs > 0.023, all ps < 0.04, all psfdr = 0.22). No other nominally significant associations were observed for any AD genetic risk index. All whole brain results are in Supplemental Table 6.
Regional
Volume. Subcortical. Overall, AD genetic risk (i.e., ADPRS, APOE risk alleles, ADPRS−APOE) was associated with greater left and right Nucleus Accumbens volumes at nominal levels of significance (all Bs > 0.02; all ps < 0.05, all psfdr > 0.10). ADPRS was also associated with increased right putamen volume, as well as decreased right thalamic volume (all |Bs| > 0.01; all ps < 0.05, all psfdr > 0.18). APOE genotype was associated with decreased brain stem volume, cerebellar cortical volume, and right thalamic volume (all Bs > 0.01; all ps < 0.04, all psfdr > 0.20). Finally, ADPRS−APOE was associated with increased cerebellar cortex and cerebellar white matter volume (all Bs > 0.02; all ps < 0.02, all psfdr > 0.07). Cortical. ADPRS was associated with increased volume in the right precentral gyrus, left superior temporal sulcus, and right lingual gyrus, as well as decreased volume in the right medial orbitofrontal cortex (all |Bs| > 0.019; all ps < 0.05, all psfdr > 0.48). APOE risk alleles were associated with increased volume in the right paracentral lobule and left superior temporal sulcus (all |Bs| > 0.029; all ps < 0.02, all psfdr = 0.52). Finally, ADPRS−APOE was associated with increased volume in the left precuneus, as well as decreased left caudal anterior cingulate, right inferior parietal, and left parahippocampal cortical volumes (all |Bs| > 0.02; all ps < 0.03, all psfdr = 0.10). All regional Volume results are in Supplemental Table 5.
Cortical Thickness. ADPRS was associated with decreased thickness in the left and right supramarginal regions as well as the right inferior temporal region and increased thickness in the left superior temporal sulcus region (all |B|s > 0.019, all ps < 0.04, all psfdr > 0.30). APOE risk alleles were associated with increased thickness in the both hemispheres of the cuneus and the left superior temporal sulcus, as well as decreased inferior temporal thickness (all |B|s > 0.02, all ps < 0.03, all psfdr > 0.13). ADPRS−APOE4 was associated with increased left middle temporal and right isthmus cingulate thickness, as well as decreased left and right parahippocampal and right precuneus thickness (all |B|s > 0.018, all ps < 0.05, all psfdr > 0.42). All regional Cortical thickness results are in Supplemental Table 5.
Cortical Surface Area. ADPRS was associated with increased right paracentral and right inferior temporal surface area, as well as decreased left caudal middle frontal surface area (all |B|s > 0.018, all ps < 0.04, all psfdr = 0.73). APOE risk alleles were associated with increased surface area in the right paracentral and left superior temporal sulcus, as well as decreased left rostral anterior cingulate surface area (all |B|s > 0.02, all ps < 0.04, all psfdr = 0.81). ADPRS−APOE was associated with increased left precuneus and right inferior temporal surface area, as well as decreased left caudal anterior cingulate and right inferior parietal surface area (all |B|s > 0.019, all ps < 0.03, all psfdr > 0.19). All Cortical Surface Area results are in Supplemental Table 5.
Mean Diffusivity. ADPRS was associated with increased mean diffusivity (MD) within the right anterior thalamic radiations (B = 0.02, p = 0.006, psfdr = 0.23). APOE risk alleles were associated with increased MD within the right anterior thalamic radiations and the left striatal inferior frontal cortex, as well as decreased MD within the right parahippocampal cingulum (all |B|s > 0.02, all ps < 0.03, all psfdr = 0.27). ADPRS−APOE4 was associated with increased MD within the left parietal superior longitudinal fasciculus and the right inferior-fronto-occipital fasciculus (B > 0.01, all ps < 0.05, all psfdr = 0.39). All regional mean diffusivity results are in Supplemental Table 5.
Fractional Anisotropy. ADPRS−APOE was associated with decreased FA within the right inferior-fronto-occipital fasciculus (B = -0.01, p = 0.037, psfdr = 0.61). No other nominally significant associations were observed for any AD genetic risk index. All regional Fractional Anisotropy results are in Supplemental Table 5.
Rating state functional connectivity. ADPRS was associated with less functional coupling within the cingulo-opercular network and between the salience network and ventral attention network (B < -0.02, all ps < 0.05, all psfdr = 0.95). APOE risk alleles were associated with increased correlated activity between the retrosplenial temporal network and both the "none" network and the default network and negative correlations between the retrosplenial temporal network and both the visual network and the dorsal attention network (all |B|s > 0.03, all ps < 0.02, all psfdr = 0.97). ADPRS−APOE4 was associated with increased correlation between the dorsal attention network and sensorimotor hand network, between the fronto-parietal network and salience network, and between the auditory network and cingulo-parietal network (B > 0.02, all ps < 0.04, all psfdr > 0.33). All RSFC results are in Supplemental Table 7.