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Abstract
Background and Objectives CSF biomarkers β‐amyloid 1-42 (Aβ42), phosphorylated tau 181 (p-tau181), total tau (t-tau), and neurogranin (Ng) can diagnose Alzheimer disease (AD) in life. However, it is unknown whether CSF concentrations, and thus their accuracies, are affected by concomitant pathologies common in AD, such as α-synuclein (αSyn). Our primary goal was to test whether biomarkers in patients with AD are altered by concomitant αSyn. We compared CSF Aβ42, p-tau181, t-tau, and Ng levels across autopsy-confirmed AD and concomitant AD and αSyn (AD + αSyn). Antemortem CSF levels were related to postmortem accumulations of αSyn. Finally, we tested how concommitant AD + αSyn affected the diagnostic accuracy of 2 CSF-based strategies: the amyloid/tau/neurodegeneration (ATN) framework and the t-tau/Aβ42 ratio.
Methods Inclusion criteria were neuropathologic diagnoses of AD, mixed AD + αSyn, and αSyn. A convenience sample of nonimpaired controls was selected with available CSF and a Mini-Mental State Examination (MMSE) ≥ 27. αSyn without AD and controls were included as reference groups. Analyses of covariance (ANCOVAs) tested planned comparisons were CSF Aβ42, p-tau181, t-tau, and Ng differences across AD and AD + αSyn. Linear models tested how biomarkers were altered by αSyn accumulation in AD, accounting for pathologic β-amyloid and tau. Receiver operating characteristic and area under the curve (AUC), including 95% CI, evaluated diagnostic accuracy.
Results Participants were 61 patients with AD, 39 patients with mixed AD + αSyn, 20 patients with αSyn, and 61 controls. AD had similar median age (73 [interquartile range {IQR} = 12] years), MMSE (23 [IQR = 9]), and sex distribution (male = 49%) compared with AD + αSyn age (70 [IQR = 13] years; p = 0.3), MMSE (25 [IQR = 9.5]; p = 0.19), and sex distribution (male = 69%; p = 0.077). ANCOVAs showed that AD + αSyn had lower p-tau181 (F(1,94) = 17, p < 2.6e-16), t-tau (F(1,93) = 11, p = 0.0004), and Ng levels (F(1,50) = 12, p = 0.0004) than AD; there was no difference in Aβ42 (p = 0.44). Models showed increasing αSyn related to lower p-tau181 (β = −0.26, SE = 0.092, p = 0.0065), t-tau (β = −0.19, SE = 0.092, p = 0.041), and Ng levels (β = −0.2, SE = 0.066, p = 0.0046); αSyn was not a significant factor for Aβ42 (p = 1). T-tau/Aβ42 had the highest accuracy when detecting AD, including mixed AD + αSyn cases (AUC = 0.95; CI 0.92–0.98).
Discussion Findings demonstrate that concomitant αSyn pathology in AD is associated with lower CSF p-tau181, t-tau, and Ng levels and can affect diagnostic accuracy in patients with AD.
Glossary
- AD=
- Alzheimer disease;
- ADNC=
- AD neuropathologic change;
- ANCOVAs=
- analyses of covariance;
- ATN=
- amyloid/tau/neurodegeneration;
- AUC=
- area under the curve;
- Aβ42=
- β42amyloid 1-42;
- DLB=
- dementia with Lewy bodies;
- IQR=
- interquartile range;
- LBD=
- Lewy body disease;
- MMSE=
- Mini-Mental State Examination;
- NfL=
- neurofilament light chain;
- Ng=
- neurogranin;
- PD=
- Parkinson disease;
- p-tau181=
- phosphorylated tau;
- ROC=
- receiver operating characteristic;
- SNAP=
- suspected non-AD pathophysiology;
- TDP-43=
- transactive response DNA-binding protein of 43 kDa;
- t-tau=
- total tau;
- αSyn=
- α-synuclein
Footnotes
Go to Neurology.org/N for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.
↵† Author is deceased.
Submitted and externally peer reviewed. The handling editor was Linda Hershey, MD, PhD, FAAN.
Editorial, page 877
- Received February 16, 2022.
- Accepted in final form July 19, 2022.
- © 2022 American Academy of Neurology
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