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Keywords:

  • Amyloid;
  • dementia;
  • fMRI;
  • neuropathology;
  • PET;
  • resting state;
  • tau

Abstract

Asymptomatic Alzheimer disease (ASYMAD) is characterized by normal cognition despite substantial AD pathology. To identify factors contributing to cognitive resilience, we compared early changes in regional cerebral blood flow (rCBF) in individuals subsequently diagnosed as ASYMAD with changes in cognitively impaired (CI) and normal older participants from the Baltimore Longitudinal Study of Aging. Participants underwent annual positron emission tomography (PET) rCBF measurements beginning 10.0 (SD 3.6) years before death and while cognitively intact. Based on clinical and autopsy information, subjects were grouped as cognitively normal (CN = 7), ASYMAD (n= 6), and CI (=6). Autopsy material was analyzed using CERAD and Braak scores and quantitative stereologic measures of tau and amyloid. ASYMAD and CI groups had similar CERAD and Braak scores, similar amounts of β-amyloid and tau in middle frontal (MFG), middle temporal (MTG), and inferior parietal (IP) regions, and more β-amyloid than CN in precuneus, MFG, and IP areas. Voxel-based PET analysis identified similarities and differences in longitudinal rCBF change among groups across a 7.2-year interval. Both ASYMAD and CI groups showed similar longitudinal rCBF declines in precuneus, lingual, and MTG regions relative to CN. The CI also showed greater rCBF decreases in anterior and posterior cingulate, cuneus, and brainstem regions relative to ASYMAD and CN, whereas ASYMAD showed greater relative rCBF increases over time in medial temporal and thalamic regions relative to CI and CN. Our findings provide evidence of early functional alterations that may contribute to cognitive resilience in those who accumulate AD pathology but maintain normal cognition.