Diffusion Changes in Hippocampal Cingulum in Early Biologically Defined Alzheimer’s Disease

Background: Diagnosis of Alzheimer’s disease (AD) was recently shifted from clinical to biological construct to reflect underlying neuropathological status, where amyloid deposition designated patients to the AD continuum, and additional tau positivity represented AD. Objective: To investigate white matter (WM) alteration in the brain of patients in the AD continuum. Methods: A total of 236 subjects across the clinical and biological spectra of AD were included and stratified by normal/abnormal (–/+) amyloid (A) and tau (T) status based on positron emission tomography results, yielding five groups: A–T–cognitively normal (CN), A+T–CN, A+T+ CN, A+T+ mild cognitive impairment, and A+T+ AD. WM alteration was measured by diffusion tensor imaging (DTI). Group differences, correlation of DTI measures with amyloid and tau, and diagnostic performance of such measures were evaluated. Results: Compared with A–T–CN, widespread WM alteration was observed in the AD continuum, including hippocampal cingulum (CGH), cingulum of the cingulate gyrus, and uncinate fasciculus. Diffusion changes measured by regional mean fractional anisotropy (FA) in the bilateral CGH were first detected in the A+T+ CN group and associated with tau burden in the AD continuum (p <  0.001). For discrimination between A+T+ CN and A–T–CN groups, CGH FA achieved accuracy, sensitivity, and specificity of 74%, 58%, and 78% for right CGH and 57%, 83%, and 47% respectively for left CGH. Conclusion: WM alteration is widespread in the AD continuum. Diffusion alteration in CGH occurred early and was correlated with tau pathology, thus may be a promising biomarker in preclinical AD.