High Soluble Amyloid-β ₄₂ Predicts Normal Cognition in Amyloid-Positive Individuals with Alzheimer’s Disease-Causing Mutations

Abstract

Background:

In amyloid-positive individuals at risk for Alzheimer’s disease (AD), high soluble 42-amino acid amyloid-β (Aβ ₄₂) 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 Aβ ₄₂ 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 Aβ ₄₂ levels were higher among CDR non-progressors than CDR progressors. Higher Aβ ₄₂ 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 Aβ ₄₂ levels predicting lower risk of progression increased with higher SUVR levels.

Conclusion:

High CSF Aβ ₄₂ levels predict normal cognition in amyloid-positive individuals with AD-causing genetic mutations.