Document Type
Journal Article
Publication Title
Brain Communications
Volume
6
Issue
5
Publisher
Oxford Academic
School
Centre for Precision Health
Funders
National Institutes of Health (RF1-AG059869, U19-AG033655, P01-AG026276, RF1-AG027161, P30-AG066507, P30-AG066444, P01-AG003991, U19-AG032438, U19-AG024904, P30-AG062715, P20-AG068082) / Australian Commonwealth Scientific Industrial Research Organisation / National Institute on Aging Intramural Program
Abstract
Reduced brain volumes and more prominent white matter hyperintensities on MRI scans are commonly observed among older adults without cognitive impairment. However, it remains unclear whether rates of change in these measures among cognitively normal adults differ as a function of genetic risk for late-onset Alzheimer's disease, including APOE- ε4, APOE-ε2 and Alzheimer's disease polygenic risk scores (AD-PRS), and whether these relationships are influenced by other variables. This longitudinal study examined the trajectories of regional brain volumes and white matter hyperintensities in relationship to APOE genotypes (N = 1541) and AD-PRS (N = 1093) in a harmonized dataset of middle-aged and older individuals with normal cognition at baseline (mean baseline age = 66 years, SD = 9.6) and an average of 5.3 years of MRI follow-up (max = 24 years). Atrophy on volumetric MRI scans was quantified in three ways: (i) a composite score of regions vulnerable to Alzheimer's disease (SPARE-AD); (ii) hippocampal volume; and (iii) a composite score of regions indexing advanced non-Alzheimer's disease-related brain aging (SPARE-BA). Global white matter hyperintensity volumes were derived from fluid attenuated inversion recovery (FLAIR) MRI. Using linear mixed effects models, there was an APOE-ε4 gene-dose effect on atrophy in the SPARE-AD composite and hippocampus, with greatest atrophy among ε4/ε4 carriers, followed by ε4 heterozygouts, and lowest among ε3 homozygouts and ε2/ε2 and ε2/ε3 carriers, who did not differ from one another. The negative associations of APOE-ε4 with atrophy were reduced among those with higher education (P < 0.04) and younger baseline ages (P < 0.03). Higher AD-PRS were also associated with greater atrophy in SPARE-AD (P = 0.035) and the hippocampus (P = 0.014), independent of APOE-ε4 status. APOE-ε2 status (ε2/ε2 and ε2/ε3 combined) was not related to baseline levels or atrophy in SPARE-AD, SPARE-BA or the hippocampus, but was related to greater increases in white matter hyperintensities (P = 0.014). Additionally, there was an APOE-ε4 × AD-PRS interaction in relation to white matter hyperintensities (P = 0.038), with greater increases in white matter hyperintensities among APOE-ε4 carriers with higher AD-PRS. APOE and AD-PRS associations with MRI measures did not differ by sex. These results suggest that APOE-ε4 and AD-PRS independently and additively influence longitudinal declines in brain volumes sensitive to Alzheimer's disease and synergistically increase white matter hyperintensity accumulation among cognitively normal individuals. Conversely, APOE-ε2 primarily influences white matter hyperintensity accumulation, not brain atrophy. Results are consistent with the view that genetic factors for Alzheimer's disease influence atrophy in a regionally specific manner, likely reflecting preclinical neurodegeneration, and that Alzheimer's disease risk genes contribute to white matter hyperintensity formation.
DOI
10.1093/braincomms/fcae276
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.
Comments
Soldan, A., Wang, J., Pettigrew, C., Davatzikos, C., Erus, G., Hohman, T. J., ... & Albert, M. S. (2024). Alzheimer’s disease genetic risk and changes in brain atrophy and white matter hyperintensities in cognitively unimpaired adults. Brain Communications, 6(5). https://doi.org/10.1093/braincomms/fcae276