Gray matter structural and molecular signatures in Alzheimer's disease and late-life depression.

OBJECTIVE

We aimed to systematically compare alterations in gray matter volume alterations in patients with Alzheimer's disease (AD) and late-life depression (LLD), explore the underlying molecular mechanisms, and provide insights for early identification and targeted intervention strategies.

METHOD: We recruited 33 patients with AD and 38 patients with LLD, along with 40 age- and sex-matched healthy older adults as controls. All participants underwent high-resolution structural MRI at 3.0 Tesla. To analyze gray matter volume changes, we applied voxel-based morphometry (VBM). Furthermore, we used the JuSpace toolbox to perform cross-modal spatial correlation analysis of neurotransmitter profiles and cell surface markers associated with gray matter changes.

RESULTS

Structural MRI showed that, compared with both the HC and LLD groups, AD exhibited extensive gray-matter atrophy. Relative to HC, the atrophy predominantly involved the bilateral hippocampus, parahippocampal gyrus, cingulate cortex and precuneus; compared with LLD, the atrophy further extended into the temporo-parieto-fronto-occipital association cortex, encompassing the middle/inferior temporal gyrus, precuneus, insula, middle frontal gyrus, cingulate cortex, middle occipital gyrus and medial superior frontal gyrus. No significant gray-matter volume differences were detected between the LLD and HC groups. Cross-modal analyses indicated abnormal associations with the 5-HT system in both groups; in AD, gray-matter reductions were negatively correlated with cholinergic and dopaminergic receptors and SV2A distribution, whereas in LLD they were positively correlated with NMDA receptors and negatively correlated with DAT and cerebral blood flow. At the cellular level, AD gray-matter reductions were negatively correlated with the distribution of projection neurons and SST interneurons and positively correlated with PVALB; LLD was negatively correlated with the granule-cell layer and PVALB neuron distribution; both groups showed weakened associations with mitochondrial complex I/IV function.

CONCLUSION

AD and LLD exhibit a "partially overlapping yet markedly divergent" profile in gray-matter atrophy patterns, neurotransmitter signatures and cellular phenotypes, supporting the notion that the two disorders share common biological pathways but progress along distinct trajectories.