Alzheimer’s disease Genetic Pathways Impact on Imaging Endophenotypes In Non-Demented Individuals
Poster No:
867
Submission Type:
Abstract Submission
Authors:
Luigi Lorenzini1, Lyduine Collij1, Niccoló Tesi1, Natalia Vilor-Tejedor2, Silvia Ingala1, Betty Tijms1, Andre Altmann3, Frederik Barkhof4
Institutions:
1Amsterdam UMC, Amsterdam, Netherlands, 2BarcelonaBeta Brain Research Center, Barcelona, CT, 3UCL, London, I am not in the U.S. or Canada, 4Amsterdam University Medical Centre, Amsterdam, Noord-Holland
First Author:
Co-Author(s):
Introduction:
Little is known about the genetic factors and the downstream molecular pathways determining individual variability in imaging biomarkers associated with Alzheimer's disease (AD). We studied polygenic risk scores (PRS) and pathway-specific PRS in relationship with AD fluid and imaging biomarkers, in non-demented individuals from the European Prevention of Alzheimer's Dementia (EPAD) cohort.
Methods:
EPAD inclusion criteria were age>50 and Clinical Dementia Rating≤0.5. AD-PRS was determined based on 85 previously identified loci, including and excluding APOE (PRSAPOE, PRSnoAPOE). Using gene-variant and variant-pathway mapping, six pathway-specific PRSnoAPOE were identified, representative of 1) immune-activation, 2) signal-transduction, 3) inflammatory-response, 4) migration, 5) amyloid-production, and 6) clearance (Figure 1). Linear models were used to assess the relationship of the global and pathway PRS with fluid AD biomarkers, including Aβ1-42, p-Tau181, and t-tau; and several imaging biomarkers, including hippocampal volume, global and lobar white matter hyperintensities (WMH) volumes, fractional anisotropy (FA) in 14 regions of interest from diffusion tensor imaging, and 10 resting-state network connectivity from functional MRI. Models were adjusted for age, sex, site, and multiple comparisons.
·Figure 1. Results of the pathway analysis.
Results:
1738 participants met the inclusion criteria for this study. Mean age was 65.72 + 7.31 years, and 767 were males. Overall, participants were cognitively unimpaired, and only the 27.4% had a CDR=0.5 (very mild impairment). All pathway-PRSs were associated with CSF Aβ1-42 (all FDR adjusted p<0.05), except for the migration pathway that showed a trend-level association only (FDR adjusted p=0.08). All pathway-PRSs were also significantly associated with CSF p-Tau181 even when correcting for CSF Aβ1-42 (all FDR adjusted p<0.05), except for the inflammation pathway that showed a trend-level association (FDR adjusted p=0.08).
Association of pathway-PRS with quantitative imaging biomarkers are shown in Figure 2. Lower hippocampal volumes showed a mild association with higher pathway-PRSs of migration and clearance, which did not survive multiple testing corrections. For white matter hyperintensities (WMH) volumes, higher clearance pathway-PRS was associated with higher WMH volumes in most regions. The effect was most pronounced in global, frontal, and temporal periventricular, and parietal deep white matter. Only the migration pathway was related to increases in FA in the splenium, body, and genu of the corpus callosum. Lower FC within the ventral default mode network (DMN) was associated with higher scores in the pathway-PRS of signal transduction.
Association of pathway-PRS with quantitative imaging biomarkers are shown in Figure 2. Lower hippocampal volumes showed a mild association with higher pathway-PRSs of migration and clearance, which did not survive multiple testing corrections. For white matter hyperintensities (WMH) volumes, higher clearance pathway-PRS was associated with higher WMH volumes in most regions. The effect was most pronounced in global, frontal, and temporal periventricular, and parietal deep white matter. Only the migration pathway was related to increases in FA in the splenium, body, and genu of the corpus callosum. Lower FC within the ventral default mode network (DMN) was associated with higher scores in the pathway-PRS of signal transduction.
·Figure 2. Association of pathways with quantitative multimodal imaging-derived phenotypes.
Conclusions:
We show that genetic risk beyond APOE facilitates the manifestation of AD related pathologies, and that risk in distinct pathways may contribute to differential neuropathological fingerprints. We demonstrate that clearance and migration pathways were associated with neuroimaging measures of white matter integrity, while FC alterations were mostly determined by genetic risk in variants related to synaptic communication and plasticity.
Disorders of the Nervous System:
Neurodegenerative/ Late Life (eg. Parkinson’s, Alzheimer’s) 2
Genetics:
Genetic Association Studies
Genetic Modeling and Analysis Methods 1
Modeling and Analysis Methods:
Connectivity (eg. functional, effective, structural)
Keywords:
Cerebrovascular Disease
FUNCTIONAL MRI
STRUCTURAL MRI
WHITE MATTER IMAGING - DTI, HARDI, DSI, ETC
1|2Indicates the priority used for review