Duran, Tugce; Bilgel, Murat S.; An, Yang; Kandala, Sri; Davatzikos, Christos A.; Landman, Bennett Allan; Erus, Guray; Moghekar, Abhay R.; Ferrucci, Luigi G.; Walker, Keenan A.; & Resnick, Susan M. (2026). An MRI-based macro- and microstructural neuroimaging-wide association study of subsequent cognitive impairment. Alzheimer’s and Dementia, 22(2), e71135. https://doi.org/10.1002/alz.71135
This study followed cognitively normal adults over time to determine which magnetic resonance imaging (MRI) biomarkers best predict future cognitive impairment. Researchers examined 154 different MRI-based measurements in 509 participants from the Baltimore Longitudinal Study of Aging who were age 50 or older and cognitively normal at the start of the study. Participants underwent repeated cognitive testing and 3 Tesla (3T) MRI scans, including T1- and T2-weighted imaging to assess brain structure and diffusion tensor imaging (DTI) to measure white matter microstructural integrity. The analyses accounted for factors such as age and other confounders and also examined differences by sex and amyloid beta (Aβ) status, a biological marker associated with Alzheimer’s disease.
Over an average follow-up of 4.6 years, individuals who later developed cognitive impairment showed greater declines in white matter integrity compared to those who remained cognitively stable. These changes were especially pronounced in major white matter tracts, including the corpus callosum, cingulum bundle, and inferior fronto-occipital fasciculus, which are pathways that connect different brain regions. To a lesser extent, thinning and atrophy in the temporal lobe were also linked to later impairment. The associations between brain changes and future cognitive decline were stronger in men and in individuals who were amyloid-positive.
Overall, the findings suggest that early changes in white matter microstructure, as measured by DTI, are particularly sensitive indicators of future mild cognitive impairment (MCI) and dementia. Certain MRI metrics may therefore be especially useful for identifying risk in people who are still cognitively normal.
FIGURE 1
Study overview. Participants were selected from the BLSA neuroimaging substudy based on cognitively normal (CN) status and age 50 or older at baseline. The study data included longitudinal cognitive assessments, clinical diagnoses (Dx), 3T magnetic resonance imaging scans, and baseline plasma biomarkers related to Alzheimer’s disease and related dementias, specifically amyloid beta 42/40, collected between 2008 and 2019. The subsequently impaired (SI) group (also CN at baseline) included individuals who later developed mild cognitive impairment (MCI) or dementia or were “Impaired, not MCI/dementia.” Impairment onset dates ranged from 2012 to 2019 (≈1- to 9-year interval).