The effect of local versus remote Beta‐Amyloid on functional connectivity mediated Tau‐Spread in Alzheimer’s Disease

Abstract

AbstractBackgroundIn Alzheimer’s disease (AD), Amyloid‐beta deposition (Ab) is associated with tau spreading from epicenters to connected regions. Yet, Ab and tau accumulate in strikingly different patterns, and it is unclear how Abdrives tau spreading. We envision two mechanisms, i.e. i) that cortical Ab exerts remote effects and “pulls” tau out of connected epicenters or ii) that tau is pushed out of epicenters, once Ab has reached the tau epicenters (Fig.1A). We tested both mechanisms in AD spectrum patients and determined the predominant mechanism by which Ab drives tau spreading.MethodsWe included 313 ADNI participants (n = 110 CN Ab‐, n = 98 CN‐Ab+, n = 70 MCI Ab+, n = 35 Dementia Ab+), with baseline amyloid‐ and longitudinal tau‐PET, based on which we calculated tau‐PET rates of change (ROC) for 200 cortical ROIs (Schaefer‐atlas; Fig.2). Using the same atlas, a resting‐state fMRI‐connectivity template was obtained in 42 healthy controls. For each subject, we determined tau epicenters as 5% of ROIs with highest baseline tau‐PET and assessed epicenter connectivity. Using ROI‐wise regression, we tested whether faster tau‐PET increase was explained by the simultaneous occurrence of i) higher tau‐PET in the epicenter, ii) stronger connectivity to the tau epicenter and iii) higher Ab in the target region (i.e. pull‐effect) or the tau epicenter (i.e. push‐effect). Lastly, we assessed ROI‐wise main effects of local Ab vs. Ab in the tau epicenter on tau‐PET changes, to determine which mechanism predominates.ResultsHigher tau and Ab in the epicenter explained faster tau‐PET increase in connected temporo‐parietal and frontal regions (Ab‐push‐effect, Fig.1B). In contrast, Ab‐pull‐effects were found also for late‐Braak regions (Fig.1C). Congruently, we found that Ab push effects dominated over Ab‐pull effects in temporo‐parietal brain regions, whereas Ab‐pull effects dominated in late‐Braak regions (Fig.1D‐F). Lastly, patients in which Ab and tau converged locally showed fastest subsequent tau accumulation (Fig.3).ConclusionAb exerts local and remote effects on tau spreading, yet local convergence of Ab and tau in the epicenter may predominantly drive tau spreading. Thus, local convergence of Ab and tau is a key event in AD that gives rise to accelerated tau spreading, previously referred to as cataustrophy.