The interplay between functional MRI measures of episodic memory and CSF measures of tau in healthy adults at risk of Alzheimer’s Disease

Abstract

AbstractBackgroundNeural changes occur early in Alzheimer’s disease (AD). Longitudinal data on the relationship between AD pathology and brain activity, however, are sparse. Using an established cohort of cognitively unimpaired older adults (PREVENT‐AD) at risk of AD (due to familial incidence), we assessed the relationship between functional magnetic resonance imaging (fMRI) activity during episodic memory retrieval and cerebrospinal fluid (CSF) markers of tau and β‐amyloid. We aimed to test whether baseline fMRI signal predicts changes in CSF markers and vice versa.MethodThree‐hundred and three participants (64.7±8.3yrs, 82 male) underwent task‐based fMRI of associative episodic memory retrieval at baseline, with longitudinal fMRI data for up to five timepoints with a 3, 12, 24, and 48‐month follow‐up. Region of Interest (ROI) analysis assessed retrieval activity (Fig.1A; t‐contrast differentiating hits for old stimuli from the correct rejection of new stimuli) in the bilateral precuneus and medial temporal lobe (MTL, Fig.1B‐1C). In a subset of participants (n = 117, 30 male), CSF was sampled to quantify t‐tau, p‐tau 181, and the ratio of β‐amyloid 1‐42 to p‐tau 181 (with another measurement 36‐months post‐baseline). Data were analyzed with random‐intercept linear mixed models, assessing changes in ROI activity and CSF markers over time. We tested whether baseline ROI activity predicted change in CSF markers and whether baseline CSF measures predicted change in ROI activity over time.ResultResults indicate a significant decrease in precuneus activity over time, but not MTL, and an increase in t‐tau and p‐tau 181 (Fig.2A‐2D). No change was observed for β‐amyloid/p‐tau 181 ratio. We also observed a significant time by baseline MTL activity interaction on t‐tau (Fig.3) with higher baseline activity being associated with lower t‐tau in CSF over time. We observed no relationship between baseline CSF markers and functional activity.ConclusionWhile preliminary, these results suggest that baseline MTL retrieval activity may predict t‐tau (a marker of neurodegeneration) accumulation in the CSF of healthy adults at risk of AD. Further analyses of whole‐brain episodic memory responses, episodic memory task‐performance over time, and of positron emission tomography (PET) measures of regional tau and β‐amyloid, are critical to extend these findings further.