AbstractBackgroundMyelin is the cholesterol‐rich layer ensheathing axons in the white matter (WM). The APOE ε4 allele has been associated with both reduced cholesterol transport to myelin layers in mice and with faster tau progression in individuals with AD. Here we asked the questions whether 1) APOE ε4 is associated with lower myelin and 2) any myelin decreases mediate the association between APOE ε4 and the rate of tau‐PET accumulation in Aβ+ individuals. To assess myelin, we repurposed florbetapir‐PET tracer binding, previously shown to be sensitive to myelin binding protein in the WM (Stankow et al. Annals Neurol 2011).MethodWe included 43 Aβ‐ cognitively normal (CN, global florbetapir SUVR < 1.11) and AD‐spectrum participants (56 CN Aβ+, 32 MCI Aβ+, and 20 AD Aβ+) from ADNI. To extract individual myelin levels, we averaged each participant’s florbetapir SUVR within individual T1‐MRI based WM masks (global myelin) or 58 fiber‐tracts generated from multishell DTI (fiber‐tract myelin). To control for a putative influence by grey‐matter florbetapir levels, we adjusted the individual WM‐florbetapir SUVRs for grey‐matter florbetapir SUVR via linear regression analysis and computed z‐scores of the adjusted WM‐florbetapir SUVRs across all participants (Moscoso et al. EJNNMI, 2022). For tau‐PET, flortaucipir SUVRs were extracted in Braak‐stage GM ROIs or in the tracts’ cortical projection zones, and mixed effect linear regression was used to estimate the rate of regional flortaucipir change.ResultHigher APOE ε4 score was associated with both lower WM‐florbetapir z‐score (β = ‐0.329, p<0.001) and faster tau‐PET increase in Braak stage 3+4 ROIs (β = 0.224, p = 0.01) in Aβ+ participants (Fig. 1A&B). Using bootstrapped mediation analysis, we found that the WM‐florbetapir z‐score mediated the effect of APOE dosage on the rate of tau‐PET accumulation in Braak 3+4 (b = 2´10‐4 [95% CI: 2´10‐5, 3´10‐4], p = 0.02, Fig 1C). At the fiber‐tract level, APOE ε4 dosage exacerbated the association between decreased fiber‐tract florbetapir and faster tau‐PET increase in the tracts’ projection zones (p<0.001).ConclusionAPOE ε4 may contribute to the accumulation of tau pathology in a myelin dependent manner. Myelin impairment is treatable by several known drugs and therefore an attractive therapeutic target in AD.
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