Brain microstructure mediates effects of tau on cognitive decline in early Alzheimer’s disease

Abstract

AbstractBackgroundTau propagation from medial temporal regions to neocortex correlates with cognitive decline and neurodegeneration. Microstructural damage to medial temporal gray matter and associated white matter predicts Alzheimer’s disease (AD)‐related cognitive impairment. However, whether brain cytoarchitectural injury mediates effects of tau on cognitive dysfunction, or promotes cognitive decline via convergent pathways, remains unresolved.MethodWe used restriction spectrum imaging (RSI) to identify microstructural brain abnormalities associated with total tau, and to determine whether they mediate tau‐related cognitive decline. RSI, cerebrospinal fluid total tau, global cognitive function and verbal episodic memory data were acquired on 34 participants ranging from cognitively normal to mild AD (21 normal controls, 13 cognitively impaired (mild cognitive impairment or early AD)). Longitudinal RSI and cognitive data were collected two and four years post‐baseline, respectively. Restricted isotropic diffusion (RI), neurite density (ND), and isotropic free water (IF) were computed in hippocampus, entorhinal cortex, and six white matter tracts. Partial correlations examined associations among tau, microstructure, and cognition and mediation analyses assessed whether microstructure mediates tau‐related cognitive decline. Linear regressions compared the sensitivity of tau, amyloid and microstructure to cognitive outcomes. Partial correlations tested whether tau predicts subsequent microstructural change.ResultTau most strongly correlated with reduced RI, a measure of intracellular integrity, in the hippocampus and fornix. Tau and microstructure in all examined regions correlated with baseline and longitudinal cognitive performance. Hippocampal and fornix RI mediated effects of tau on cross‐sectional memory and global cognitive function, but direct effects of tau on cognition were not significant. White matter and entorhinal microstructure better predicted baseline memory and global cognition, and hippocampal IF better predicted global cognitive decline, than did tau or amyloid. Tau predicted more rapid decline in white matter RI and ND.ConclusionMarkers of tau‐related neurodegeneration may reflect hippocampal and fornix injury that promotes memory impairment and dementia progression. However, medial temporal and white matter microstructure better predicts cognitive outcomes than tau and amyloid, implicating additional factors contributing to neural injury underlying cognitive decline. RSI may be useful for identifying microstructural brain abnormalities consequent to AD pathology or other risk factors, that signal early cognitive dysfunction.