125 Tau PET and cognition in early- and late onset AD study population. Others point towards genetics explaining higher tau burden, since comparable results were found in autosomal dominant mutation carriers (e.g. presenilin-1)[66, 67]. The differential spatial patterns of tau pathology in early-onset AD might also be explained by genetic involvement, as early-onset AD patients are less frequently APOE4 allele carriers, and E4 genotype does influence spatial patterns of brain pathology[68-70]. In the present study, however, we did find slightly, but non-significantly lower E4 allele carriership in early-onset AD, which makes it unlikely that E4 genotype may have explained the findings. A strength of this study is usage of a single dynamic [18F]flortaucipir PET scan to derive measures of both tau pathology (BPND) and relative cerebral blood flow (R1). Furthermore, we repeated analyses with partial volume-corrected data. Although we did find some (test-specific) differences in the association between R1 and cognition, core results that led to our conclusions remained. Given that the implications of applying partial volume-correction to R1 data are currently not entirely understood, and that all other results remained essentially comparable, we feel atrophy does not bias our findings to a large extent. There were also several limitations. First, the late-onset AD patients in our study were relatively young, which might hamper generalizability of results to older study populations. Second, seven participants did not have sufficient neuropsychological data available for cognition analyses. Although results are not expected to be influenced to a large extent, it might be that results as described in this study are slightly underestimating the differential effect of age-at-onset, given that neuropsychological data were missing in the most severely progressed patients (mean MMSE score: 20±4). Third, the cross-sectional design did not allow investigating the temporal evolution of tau pathology, rCBF and cognitive impairment. Future studies with longitudinal data available could aid in elucidating the timely pathways of these three parameters. In conclusion, early-onset AD is characterized by higher levels of tau pathology and stronger associations between lateral temporal, and occipito-parietal tau pathology or lower rCBF and cognitive impairment. These findings may have important implications for clinical trials, since effects of potential tau- or blood flow targeting therapeutic interventions might exert larger effects in early-onset AD compared to late-onset AD patients. Furthermore, differences between early- and late-onset AD patients as described in the current study should be considered in any therapeutic intervention trial were either cognition is used as an outcome measure or where indirect effects on tau pathology or rCBF are expected, to ensure correct interpretation of results and aid in the formation of appropriate patient selection criteria. 5
RkJQdWJsaXNoZXIy MjY0ODMw