The study had several limitations. First, neuropathological validation is important for this work, but currently no datasets with tau PET, 18F-FDG PET and autopsy were available to us. Analyses in symptomatic individuals were performed on one cohort (ADNI) which includes multiple sites but with well-established data harmonization methods. Given the ADNI inclusion/exclusion criteria, this sample may not be representative of the broader population of cognitively impaired patients that harbor more mixed pathology, particularly vascular disease. A more heterogeneous sample might show more phenotypes/groups. However, the HABS dataset offers corresponding evidence of T/NM dissociation patterns in cognitively normal older adults known to harbor significant regional relationships between tau and 18F-FDG PET42. Notably, these similar T/NM groups arose with use of two distinct processing methods (ANTs for ADNI data and FreeSurfer for HABS data), indicating robustness of clustering to specific processing pipelines. Despite this, the separation of susceptible groups by imaging and cognitive factors associated with copathology highlight the non-trivial amount of copathology in ADNI participants. To this point, autopsy study of an ADNI subset demonstrated that α-synuclein and TDP-43 polypathology are frequently present in ADNI patients and correlate with antemortem imaging markers16. The canonical group is a statistical designation and does not quantify the absolute amount of AD vs. non-AD pathology. However, the canonical group does provide a relative benchmark for the population. While there was not much available data to study resilience-related factors, our initial analysis of resilient and susceptible groups supports the continued search for genetic, epigenetic and pathophysiological features that influence these relationships. Note that resilient groups had significantly higher APOE2 carrier frequency and the susceptible groups trended toward higher APOE4 frequency, though these differences were not seen after adjusting for A status (Supplementary Fig. 9B). Investigations into additional AD-associated features, such as glial and immune cell-mediated inflammation as well as blood brain barrier dysfunction, may also be warranted4,43,44.
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