An MRI-based macro- and microstructural neuroimaging-wide association study of subsequent cognitive impairment.

Comprehensive Summary

Duran et al. examined 154 MRI-based brain markers across 103 brain regions to determine which structural changes most reliably precede cognitive impairment in cognitively normal (CN) older adults. The study analyzed 509 participants aged 51–95 years from the Baltimore Longitudinal Study of Aging (BLSA), using repeat 3T MRI scans and cognitive assessments collected between 2008 and 2019. Over an average follow-up of 4.7 years (SD: 2.4), 80 of the 509 participants (15.7%) developed cognitive impairment, classified as MCI (n=50), dementia (n=27), or otherwise impaired not meeting MCI/dementia criteria (n=3), while 429 remained cognitively stable. Longitudinally, those who developed impairment showed the greatest accelerated decline in white matter (WM) microstructural integrity, particularly in the corpus callosum, cingulum bundle, and inferior fronto-occipital fasciculus, compared to those who remained CN. Cortical thinning in temporal and occipital regions and increased Alzheimer's-related atrophy scores (SPARE-AD and R2 medial temporal lobe index) were also significantly elevated in participants who went on to develop impairment. These WM changes were most pronounced in male participants and in those who were amyloid-positive at baseline.

Outcomes and Implications

This study adds meaningful evidence that DTI-based WM microstructural measures are among the earliest and most sensitive MRI indicators of impending cognitive decline, potentially detectable years before clinical diagnosis. By benchmarking all 154 biomarkers on the same standardized scale within a single longitudinal cohort, the findings offer clinicians a clearer hierarchy of neuroimaging markers to prioritize when assessing preclinical dementia risk. The sex- and amyloid-stratified results are particularly relevant: males with subsequent impairment showed faster WM deterioration across a broader set of tracts, amyloid-positive individuals showed steeper decline in both WM integrity and Alzheimer's-related atrophy scores, and females showed accelerated occipital cortical thinning as a sex-specific signal, possibly reflecting postmenopausal neurobiological vulnerability. The authors caution that the BLSA sample skews toward highly educated, predominantly White participants, limiting generalizability, and that broader clinical implementation of DTI-based WM screening awaits validation in larger, more diverse cohorts.