High Soluble Amyloid-β42 Predicts Normal Cognition in Amyloid-Positive Individuals with Alzheimer's Disease-Causing Mutations

J Alzheimers Dis. 2022;90(1):333-348. doi: 10.3233/JAD-220808.


Background: In amyloid-positive individuals at risk for Alzheimer's disease (AD), high soluble 42-amino acid amyloid-β (Aβ42) levels are associated with normal cognition. It is unknown if this relationship applies longitudinally in a genetic cohort.

Objective: To test the hypothesis that high Aβ42 preserves normal cognition in amyloid-positive individuals with Alzheimer's disease (AD)-causing mutations (APP, PSEN1, or PSEN2) to a greater extent than lower levels of brain amyloid, cerebrospinal fluid (CSF) phosphorylated tau (p-tau), or total tau (t-tau).

Methods: Cognitive progression was defined as any increase in Clinical Dementia Rating (CDR = 0, normal cognition; 0.5, very mild dementia; 1, mild dementia) over 3 years. Amyloid-positivity was defined as a standard uptake value ratio (SUVR) ≥1.42 by Pittsburgh compound-B positron emission tomography (PiB-PET). We used modified Poisson regression models to estimate relative risk (RR), adjusted for age at onset, sex, education, APOE4 status, and duration of follow-up. The results were confirmed with multiple sensitivity analyses, including Cox regression.

Results: Of 232 mutation carriers, 108 were PiB-PET-positive at baseline, with 43 (39.8%) meeting criteria for progression after 3.3±2.0 years. Soluble Aβ42 levels were higher among CDR non-progressors than CDR progressors. Higher Aβ42 predicted a lower risk of progression (adjusted RR, 0.36; 95% confidence interval [CI], 0.19-0.67; p = 0.002) better than lower SUVR (RR, 0.81; 95% CI, 0.68-0.96; p = 0.018). CSF Aβ42 levels predicting lower risk of progression increased with higher SUVR levels.

Conclusion: High CSF Aβ42 levels predict normal cognition in amyloid-positive individuals with AD-causing genetic mutations.

Keywords: Alzheimer’s disease; FDG-PET; amyloid-β; atrophy; cognition.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Alzheimer Disease* / cerebrospinal fluid
  • Alzheimer Disease* / diagnostic imaging
  • Alzheimer Disease* / genetics
  • Amyloid beta-Peptides / cerebrospinal fluid
  • Amyloidosis*
  • Biomarkers / cerebrospinal fluid
  • Cognition
  • Cognitive Dysfunction* / cerebrospinal fluid
  • Cognitive Dysfunction* / diagnostic imaging
  • Cognitive Dysfunction* / genetics
  • Dementia* / genetics
  • Humans
  • Mutation / genetics
  • Peptide Fragments / cerebrospinal fluid
  • Positron-Emission Tomography / methods
  • tau Proteins / cerebrospinal fluid


  • tau Proteins
  • Peptide Fragments
  • Biomarkers
  • Amyloid beta-Peptides