Fig. 1: The manifestation of the R1 and R2 dimensions of brain atrophy in the MCI/AD population.

A Brain association studies reveal two dominant brain atrophy dimensions. A linear regression model was fit to the 119 GM ROIs at baseline for the R1 and R2 dimensions. The −log₁₀(p value) of each significant ROI (Bonferroni correction for the number of 119 ROIs: −log₁₀(p value) >3.38) is shown. A negative value denotes brain atrophy with a negative coefficient in the linear regression model. All the statistics (r, Pearson’s correlation coefficient) are presented in Supplementary Table 1. The brain maps denote the signed p value, and the range of r for each dimension is also shown. Of note, the sample size (N) for R1 and R2 is the same for each ROI. B Genome-wide association studies demonstrate that the R2, but not R1, dimension is associated with variants related to APOE genes (genome-wide p value threshold with the red line: −log₁₀(p value) >7.30). We associated each common variant with R1 and R2 using the whole-genome sequencing data from ADNI. Gene annotations were performed via positional, expression quantitative trait loci, and chromatin interaction mappings using FUMA [58]. We then manually queried whether they were previously associated with AD-related traits in the GWAS Catalog [55]. Red-colored loci/genes indicate variants associated with AD-related traits in previous literature. C Clinical association studies show that the R2 dimension is associated to a larger extent with AD-specific biomarkers, including SPARE-AD [41], an imaging surrogate to AD atrophy patterns, and APOE ε4, the well-established risk allele in sporadic AD. The R1 dimension is associated to a larger extent with aging (e.g., SPARE-BA [42], an imaging surrogate for brain aging) and vascular-related biomarkers (e.g., WML white matter lesion). The same linear regression model was used to associate the R1 and R2 dimensions with the 45 clinical variables, including cognitive scores, modifiable risk factors, CSF biomarkers, disease/condition labels, demographic variables, and imaging-derived phenotypes. The radar plot shows representative clinical variables; results for all 45 clinical variables are presented in Supplementary eTable 3. The SPARE-AD and SPARE-BA scores are rescaled for visualization purposes. The gray-colored circle lines indicate the p value threshold in both directions (Bonferroni correction for the 45 variables: −log₁₀(p value) >2.95). A positive/negative −log₁₀(p value) value indicates a positive/negative correlation (beta). The transparent dots represent the associations that do not pass the Bonferroni correction; the blue-colored dots and red-colored dots indicate significant associations for the R1 and R2 dimensions, respectively.