High Soluble Amyloid-beta(42) Predicts Normal Cognition in Amyloid-Positive Individuals with Alzheimer's Disease-Causing Mutations

Sturchio, Andrea; Dwivedi, Alok K.; Malm, Tarja; Wood, Matthew J. A.; Cilia, Roberto; Sharma, Jennifer S.; Hill, Emily J.; Schneider, Lon S.; Graff-Radford, Neill R.; Mori, Hiroshi; Nuebling, Georg; El Andaloussi, Samir; Svenningsson, Per; Ezzat, Kariem und Espay, Alberto J. (2022): High Soluble Amyloid-beta(42) Predicts Normal Cognition in Amyloid-Positive Individuals with Alzheimer's Disease-Causing Mutations. In: Journal of Alzheimers Disease, Bd. 90, Nr. 1: S. 333-348

Abstract

Background: In amyloid-positive individuals at risk for Alzheimer's disease (AD), high soluble 42-amino acid amyloid-beta (A beta(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 A beta(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 A beta(42) levels were higher among CDR non-progressors than CDR progressors. Higher A beta(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 A beta(42) levels predicting lower risk of progression increased with higher SUVR levels. Conclusion: High CSF A beta(42) levels predict normal cognition in amyloid-positive individuals with AD-causing genetic mutations.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• ISSN: 1387-2877
• Sprache: Englisch