Stage‐dependent amyloid beta‐ and tau‐associated longitudinal white matter degeneration in early stages of Alzheimer’s disease

Background Alzheimer’s disease(AD) is associated with pathological deposition of amyloid‐beta(Aβ) plaques and neurofibrillary tau tangles which have been shown to be related to poorer white‐matter(WM) integrity using diffusion‐MRI(dMRI) [Vipin et al.,2019;Jacobs et al.,2018]. However, possible interactive effects between Aβ and tau on microstructural WM changes remain unclear. Additionally, partial volume artefacts impact dMRI sensitivity but can be corrected through free‐water(FW) correction to provide FW and FW‐corrected tissue measures(FAt)[Pasternak et al.,2009]. Thus, we examined additive and interactive effects of Aβ and tau burden on temporal progression of FW‐corrected WM changes in temporoparietal WM fibres at baseline and over‐time in cognitively normal elderly(CN) and mild cognitive impairment(MCI). We hypothesize that MCI subjects would show more widespread Aβ and tau‐related temporoparietal WM alterations than CN. Additionally, based on prior evidence, Aβ and tau interactive effects would be more prevalent for FW than tissue‐based measures. Method We used dMRI data from 72 CN and 82 MCI subjects from the Alzheimer’s Disease Neuroimaging Initiative followed over 2‐4 time‐points(55‐90 years). Aβ burden was quantified using AV‐45 PET standardized uptake value and tau burden was quantified using cerebrospinal fluid phosphorylated‐tau(Ptau) levels. We derived subject‐specific FW and FAt fibre maps using the longitudinal TRActs‐Constrained‐by‐UnderLying‐Anatomy method[Yendiki et al.,2016]. Result CN with higher Aβ burden showed faster decline in RUNC FAt (uncorrected‐p=0.0055; Fig.1). However, in MCI, widespread Ptau effects were found(Fig.2) i.e. higher baseline Ptau burden was associated with lower fibre FAt in left superior longitudinal fasciculus parietal (SLFP; uncorrected‐p=0.039) and left(uncorrected‐p=0.0062) and right(uncorrected‐p=0.026) superior longitudinal fasciculus temporal(SLFT). Synergistic Aβ*Ptau effects were instead observed in right cingulum angular bundle(CAB) FW in CN at baseline and over‐time (FDR‐corrected:p<0.05; Fig.3). This effect was more widespread in MCI‐ higher Aβ combined with higher Ptau associated with higher FW in right CAB, SLFP, SLFT and uncinate fasciculus fibres at baseline(Fig.4). Conclusion Our findings provide insights into stage‐dependent differences in additive and synergistic influences of Aβ and Ptau between tissue‐based and FW‐based WM metrics. Thus, together with Aβ and Ptau burden, FW‐corrected WM measures likely provide more detailed insight regarding the regions showing alterations related to the interaction between neuropathological hallmarks of AD to collectively inform regarding disease progression.