Early axonal degeneration linked to clinical decline in Alzheimer’s disease progression revealed with diffusion MRI

BACKGROUNDAxonal degeneration is believed to be an early hallmark of Alzheimer's disease (AD). This study investigated the temporal trajectory of axonal loss and its association with cognitive and functional decline using a dMRI-derived axonal density index (ADI).METHODSLongitudinal dMRI, CSF, and PET data from the ADNI study were analyzed, including 117 subjects that were cognitively normal (CN) and 88 that were cognitively impaired (CI), consisting of 74 individuals with mild cognitive impairment (MCI) and 14 with AD. Linear mixed-effects models examined group differences and associations between baseline and longitudinal changes in ADI, CSF, or PET biomarkers and clinical outcomes. Results derived from larger CSF (n = 527) and PET (tau-PET: n = 870; amyloid-PET: n = 1,581) datasets are also presented.RESULTSCompared with the CN group, the CI group exhibited significantly lower baseline ADI values and steeper longitudinal decline (P < 10-6). Lower baseline ADI predicted faster cognitive and functional decline in the CI group (MMSE: P = 0.03; CDR-SB: P < 10-4), and longitudinal decreases in ADI were associated with worsening clinical outcomes (MMSE: P = 0.001; CDR-SB: P < 10-12). Compared with CSF and PET biomarkers, ADI demonstrated superior sensitivity in tracking disease progression and matched these biomarkers in predicting future cognitive and functional decline. Furthermore, decreases in ADI were significantly associated with declines in clinical outcomes; this association was observed only with amyloid-PET, but not CSF, biomarkers.CONCLUSIONAxonal degeneration is an early and clinically meaningful feature of AD. ADI is a promising noninvasive biomarker for early detection, prognosis, and disease monitoring.TRIAL REGISTRATIONClinicalTrials.gov NCT00106899.FUNDINGThis work was supported by the National Institute on Aging Intramural Research Program.