  Late-life depression (LLD) is characterized by considerable heterogeneity in
clinical manifestation. Unraveling such heterogeneity would aid in elucidating
etiological mechanisms and pave the road to precision and individualized
medicine. We sought to delineate, cross-sectionally and longitudinally,
disease-related heterogeneity in LLD linked to neuroanatomy, cognitive
functioning, clinical symptomatology, and genetic profiles. Multimodal data
from a multicentre sample (N=996) were analyzed. A semi-supervised clustering
method (HYDRA) was applied to regional grey matter (GM) brain volumes to derive
dimensional representations. Two dimensions were identified, which accounted
for the LLD-related heterogeneity in voxel-wise GM maps, white matter (WM)
fractional anisotropy (FA), neurocognitive functioning, clinical phenotype, and
genetics. Dimension one (Dim1) demonstrated relatively preserved brain anatomy
without WM disruptions relative to healthy controls. In contrast, dimension two
(Dim2) showed widespread brain atrophy and WM integrity disruptions, along with
cognitive impairment and higher depression severity. Moreover, one de novo
independent genetic variant (rs13120336) was significantly associated with Dim
1 but not with Dim 2. Notably, the two dimensions demonstrated significant
SNP-based heritability of 18-27% within the general population (N=12,518 in
UKBB). Lastly, in a subset of individuals having longitudinal measurements,
Dim2 demonstrated a more rapid longitudinal decrease in GM and brain age, and
was more likely to progress to Alzheimers disease, compared to Dim1 (N=1,413
participants and 7,225 scans from ADNI, BLSA, and BIOCARD datasets).
