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High Soluble Amyloid-β42 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 (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.

SUBMITTER: Sturchio A 

PROVIDER: S-EPMC9661329 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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

Sturchio Andrea A   Dwivedi Alok K AK   Malm Tarja T   Wood Matthew J A MJA   Cilia Roberto R   Sharma Jennifer S JS   Hill Emily J EJ   Schneider Lon S LS   Graff-Radford Neill R NR   Mori Hiroshi H   Nübling Georg G   El Andaloussi Samir S   Svenningsson Per P   Ezzat Kariem K   Espay Alberto J AJ  

Journal of Alzheimer's disease : JAD 20220101 1


<h4>Background</h4>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.<h4>Objective</h4>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, ce  ...[more]

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