123 Tau PET and cognition in early- and late onset AD DISCUSSION The main findings of this study include higher levels of neocortical tau pathology in early-onset AD compared to late-onset AD, while late-onset AD showed reduced rCBF in the medial temporal lobe compared to early-onset AD. Moreover, we found that higher levels of tau pathology and lower cerebral blood flow in lateral temporal, and occipito-parietal regions were more strongly associated with cognitive impairment (mainly executive functioning domain) in early- vs late-onset AD. Previous studies demonstrated that, relative to late-onset AD, early-onset AD exhibits more extensive pathological and neurodegenerative changes with respect to (among others) amyloid, metabolic activity[7, 46], atrophy[47, 48], functional network changes[49-51] and tau[52, 53]. The current study extends on these previous studies not only showing greater tau load in early- vs late-onset AD, but also providing novel insights into age-dependent differences in cerebral blood flow, and demonstrates differential associations of both biomarkers with cognition. These findings contribute to our understanding of the differences between early- and late-onset AD patients and may support that younger AD patients are more suitable for inclusion in clinical trials, as the stronger link between pathology and cognitive decline suggests that a greater benefit may be achieved in this population when targeting tau pathology or cerebral blood flow compared to older AD patients, where this link is less strong. Besides, our results emphasize the importance of cerebrovascular health (and its potential treatment) in younger AD patients specifically. For tau pathology, associations with worse cognitive performance across non-memory domains were stronger in early-onset AD, apart from associations in the medial temporal lobe. The medial temporal region is predominantly involved in sporadic (late-onset) AD[16, 51, 54], and in line with this, associations with cognitive performance for this region were stronger in late-onset AD. For rCBF, we found that lower blood flow was associated with a higher degree of cognitive impairment in non-memory domains in early- vs late-onset AD. This indicates that higher levels of neocortical tau pathology and lower rCBF have a relatively stronger influence on cognitive (dys)functioning in early-onset AD. The main hypothesis for these findings is that co-pathologies (e.g. other proteinopathies such as TDP-43 or alpha-synuclein, or vascular damage) often developing at older age, may contribute to progressive cognitive impairment in late-onset AD[55-57]. However, a recent study showed that co-pathologies also play an important role in the clinical phenotype of early onset AD[26]. Another explanation could be that the brain regions most heavily affected in early-onset AD, are more important for broader cognitive functioning (other than memory-specific), and comprise specific neuronal networks crucial for specific cognitive functions. The parietal lobe contains a high pathologic burden in early-onset 5
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