HAI Book 2025 - Flipbook - Page 253
Farrell, Michelle
The interaction of initial medial temporal lobe tauopathy and amyloid-beta
spatial extent in driving caTAUstrophe
Michelle Farrell1, Emma G. Thibault1, Grace Del Carmen Montenegro1, Jessie Fanglu Fu1, Elliott
Slade1, Michael J Properzi1, Julie C. Price1, Bernard Hanseeuw1,2, Rema Raman3, Michael
Donohue3, Paul Aisen3, Reisa A. Sperling1,4, Keith A. Johnson1,4
1
Massachusetts General Hospital, Boston, MA, US
Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels, BE
3
Keck School of Medicine, University of Southern California, Los Angeles, CA, US
4
Brigham & Women’s Hospital, Boston, MA, US
2
Background: The accelerated spread of medial temporal lobe (MTL)-tau into the neocortex in the presence of
amyloid-beta (A´) is a key event in Alzheimer9s disease (AD) pathogenesis, dubbed 8caTAUstrophe9. We sought to
assess whether the onset of caTAUstrophe varies based on initial MTL tauopathy level and the extent of A´ in the
neocortex and MTL.
Methods. 246 cognitively-unimpaired older adults were included (Table1) from the A4 trial (n=191, placebo) and the
LEARN study (n=55) with baseline A´-PET (florbetapir) and 1-4 tau-PET scans (flortaucipir) over up to 5.5 years.
Baseline A´ was quantified using neocortical spatial extent (EXT; %florbetapir+) and classified into stages: EXT-0
(A´-,
85%). MTL and neocortical temporal (NeoT) tau SUVR
were computed, and individuals were grouped by high/low baseline MTL-tau. Linear mixed models assessed the
time*baseline-A´-EXT stage*MTL-tau-group interaction on MTL and NeoT tau SUVR. Additional analyses
evaluated MTL-A´ and its association with changing MTL-tau.
Results. MTL and NeoT tau proliferation diverged based on initial MTL-tau level (Figure1). In MTL-low participants
(Figure2A), increased MTL and NeoT tau proliferation were not observed until the widespread Ab-EXT-stage2.
These accelerated tau changes were associated with baseline MTL-A´ elevations (Figure2B). Conversely, tau
proliferation started earlier in those with initially high MTL-tau (Figure2C), with accelerated MTL-tau change and
the onset of NeoT-tau with spreading A´ in EXT-stage1. These earlier MTL-tau changes were not associated with
elevations in MTL-A´ but rather with proximal lateral temporal regions (Figure2D).
Conclusions. The timeline to caTAUstrophe differed based on the level of existing MTL-tau, with rapid tau
proliferation at the first signs of A´ when high but delayed tau proliferation until after A´ was widespread when
low. While MTL A´ was detectable after A´ became widespread, it was proximal lateral temporal regions that
predicted the earlier, rapid tau proliferation seen in spreading A´ stage.
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