Verbal memory and hippocampal volume predict subsequent fornix microstructure in those at risk for Alzheimer's disease.

While strong cross-sectional evidence supported the use of fornix microstructure as a marker for detecting Alzheimer's disease (AD), longitudinal data remains inconclusive on the sequential nature of fornix microstructure abnormalities and AD progression. An unequivocal longitudinal relationship between fornix microstructure and markers of AD progression -memory impairment and hippocampal atrophy, must be established to validate fornix microstructure as a marker of AD progression. We included 115 participants from the Alzheimer's Disease Neuroimaging Initiative across the non-demented AD spectrum- defined as those who had at least one AD risk marker at baseline (e.g., mild cognitive impairment (MCI) due to AD diagnosis, amyloid or ApoE4 positivity) and/or 'cognitively normal individuals who converted to MCI due to AD or AD, with structural and diffusion tensor imaging scans at baseline and two years follow-up. Hippocampal volumes (HV), fractional anisotropy (FA) and mean diffusivity (MD) in the fornix were extracted. Memory was indexed via composite scores of verbal memory tests. Structural equation models tested the bidirectional cross-lagged effects of fornix microstructure, memory, and HV. Impaired memory and smaller HV at baseline significantly predicted worse fornix microstructure (decreased FA and increased MD) two years later. Baseline fornix microstructure was not associated with subsequent changes in memory and HV. Fornix microstructure is compromised likely at a later stage, where significant decline in memory and hippocampal atrophy have occurred. This limits the utility of fornix microstructure in the early detection of AD. Our findings inform the possible pathophysiology and refined the use of AD neural markers.