Alzheimer’s disease polygenic risk score and neuroimaging biomarkers in the FINGER multidomain lifestyle randomized controlled trial

GAZI SAADMAAN HOSSAIN; RAMIREZ, A; DALMASSO, MARÍA C.; HITUNEN, M; KEMPPAINEN, N; LEHTISALO, J; NGANDU, T; RINNE, J; SOININEN, H; STEPHEN, S; KIVIPELTO, M; SOLOMON, A

Amsterdam

Congreso; AAIC2023; 2023

Alzheimer's Association

Background: A comprehensive polygenic risk score for Alzheimer’s disease (AD-PRS) was recently developed based on 83 genome-wide significant variants (Bellenguez et al. 2022), excluding APOE. This study investigated AD-PRS and APOE4 in relation to neuroimaging biomarkers in the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER). Method: FINGER included at-risk individuals without dementia from the general population, aged 60-77 years. Participants were randomized to either 2-year multidomain lifestyle-based intervention or regular health advice. N=132 participants underwent MRI scans, and N=48 underwent PET scans (PiB, FDG) at baseline; N=112 and N=39 had repeated scans at 2 years. MRI measures included hippocampus, total gray matter and white matter lesion volumes, and cortical thickness. Composite indices were calculated for PiB and FDG uptake values. We report preliminary results from linear regressions (standardized β-coefficients, p-values).Result: At baseline, higher AD-PRS tended to relate to lower hippocampus volume (β=-0.15, p=0.07) and FDG-PET index (β =-0.23, p=0.08); this remained after APOE adjustment. APOE4 was associated with lower hippocampus volume (β =-0.27, p=0.001) and higher PiB-PET index (β =0.48, p=0.001). Overall, AD-PRS was not related to 2-year change in neuroimaging measures, while APOE4 was related to decreasing hippocampus (β=-0.27, p=0.01) and total gray matter (β=-0.25, p=0.01) volumes, and cortical thickness (β=-0.28, p=0.003). There were no significant interactions of AD-PRS or APOE4 with randomization group in relation to neuroimaging changes. However, in analyses stratified by AD-PRS (below vs above median), there was less PIB index increase in intervention vs control in the higher AD-PRS group (β=-0.60, p=0.03); no intervention control-difference was found in the lower AD-PRS group (β=0.04, p=0.86). In analyses stratified by APOE4, PIB index tended to increase less in intervention vs control in non-carriers (β=-0.38, p=0.078), with no intervention-control difference in carriers (β=0.05, p=0.89).Conclusion: Unlike APOE4, AD-PRS was not related to 2-year change in AD-related neuroimaging measures. AD-PRS and APOE4 may also have very different impact on potential intervention effects on amyloid, i.e. less accumulation in the higher-risk group (AD-PRS) vs lower-risk group (APOE). However, these exploratory findings need to be verified in larger studies.