Amyloid-β, cortical thickness, and subsequent cognitive decline in cognitively normal oldest-old

Ann Clin Transl Neurol. 2021 Feb;8(2):348-358. doi: 10.1002/acn3.51273. Epub 2021 Jan 9.


Objective: To investigate the relationship between amyloid-β (Aβ) deposition and markers of brain structure on cognitive decline in oldest-old individuals with initial normal cognition.

Methods: We studied cognitive functioning in four domains at baseline and change over time in fifty-seven cognitively intact individuals from the EMIF-AD 90+ study. Predictors were Aβ status determined by [18 F]-flutemetamol PET (normal = Aβ - vs. abnormal = Aβ+), cortical thickness in 34 regions and hippocampal volume. Mediation analyses were performed to test whether effects of Aβ on cognitive decline were mediated by atrophy of specific anatomical brain areas.

Results: Subjects had a mean age of 92.7 ± 2.9 years, of whom 19 (33%) were Aβ+. Compared to Aβ-, Aβ+ individuals showed steeper decline on memory (β ± SE = -0.26 ± 0.09), and processing speed (β ± SE = -0.18 ± 0.08) performance over 1.5 years (P < 0.05). Furthermore, medial and lateral temporal lobe atrophy was associated with steeper decline in memory and language across individuals. Mediation analyses revealed that part of the memory decline observed in Aβ+ individuals was mediated through parahippocampal atrophy.

Interpretation: These results show that Aβ abnormality even in the oldest old with initially normal cognition is not part of normal aging, but is associated with a decline in cognitive functioning. Other pathologies may also contribute to decline in the oldest old as cortical thickness predicted cognitive decline similarly in individuals with and without Aβ pathology.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged, 80 and over
  • Amyloid beta-Peptides / metabolism*
  • Apolipoproteins E / genetics
  • Atrophy / diagnostic imaging
  • Atrophy / pathology
  • Atrophy / physiopathology
  • Brain Cortical Thickness*
  • Cerebral Cortex / diagnostic imaging
  • Cerebral Cortex / pathology*
  • Cerebral Cortex / physiopathology*
  • Cognition*
  • Cognitive Aging*
  • Cognitive Dysfunction / diagnostic imaging
  • Cognitive Dysfunction / pathology*
  • Cognitive Dysfunction / physiopathology*
  • Female
  • Humans
  • Longitudinal Studies
  • Magnetic Resonance Imaging
  • Male
  • Mediation Analysis
  • Neuropsychological Tests
  • Positron-Emission Tomography


  • Amyloid beta-Peptides
  • Apolipoproteins E

Grants and funding

This work was funded by EU/EFPIA Innovative Medicines Initiative Joint Undertaking grant 115372; GE Healthcare grant .