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

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

Andrea Sturchio  1   2 , Alok K Dwivedi  3 , Tarja Malm  4 , Matthew J A Wood  5   6 , Roberto Cilia  7 , Jennifer S Sharma  1 , Emily J Hill  1 , Lon S Schneider  8 , Neill R Graff-Radford  9 , Hiroshi Mori  10 , Georg Nübling  11   12 , Samir El Andaloussi  13 , Per Svenningsson  2 , Kariem Ezzat  13 , Alberto J Espay  1 ; Dominantly Inherited Alzheimer Consortia (DIAN)
Affiliations

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

Andrea Sturchio et al. J Alzheimers Dis. 2022.

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.

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

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Conflict of interest statement

Authors’ disclosures available online (https://www.j-alz.com/manuscript-disclosures/22-0808).

Figures

Fig. 1
Fig. 1
Adjusted prediction of CDR progression with baseline CSF Aβ42, p-tau, t-tau, and amyloid (PiB)-PET SUVR levels. CSF, cerebrospinal fluid; PiB-PET, Pittsburgh compound B positron emission tomography; SUVR, standardized uptake value ratio; CDR, Clinical Dementia Rating; Aβ42, 42-amino acid amyloid-beta peptide; p-tau, phospho-Tau; t-tau, total-Tau; HR, hazard ratio; CI, confidence interval. RR reflects effect size for the association with a one standard deviation higher in CSF Aβ42 levels and lower in SUVR, CSF t-tau and p-tau levels. Analyses were adjusted for age at onset, sex, education, APOE4, and duration of follow up. Overall cohort includes PiB-PET-positive and negative samples.
Fig. 2
Fig. 2
Comparison of CSF Aβ42 levels between non-progressors and progressors. PiB-PET-positive cohort: non-CDR progressors (297.73±13.66) versus CDR progressors (218.73±17.22); overall cohort: non-CDR progressors (380.83±14.5) versus CDR progressors (313.35±26.46). Error bar represents the standard error of mean. CSF, cerebrospinal fluid; PiB-PET, Pittsburgh compound B positron emission tomography; CDR, Clinical Dementia Rating; Aβ42, 42-amino acid amyloid-beta peptide. Overall cohort includes PiB-PET-positive and negative samples.
Fig. 3
Fig. 3
Adjusted probability of CDR progression. A) scatter plot of CSF Aβ42 and PiB-PET SUVR levels; B) contour plot of CSF Aβ42 and PiB-PET SUVR levels. CSF, cerebrospinal fluid; Aβ42, 42-amino acid amyloid-beta peptide; PiB-PET, Pittsburgh compound B positron emission tomography; CDR, Clinical Dementia Rating; p-tau, phospho-Tau; t-tau, total-Tau. All models were adjusted for age at onset, sex, education, APOE4, p-tau, and t-tau levels. Overall cohort includes PiB-PET-positive and negative samples.
See this image and copyright information in PMC

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