Cerebrospinal fluid biomarkers distinguish postmortem-confirmed Alzheimer's disease from other dementias and healthy controls in the OPTIMA cohort.
Cerebrospinal fluid (CSF) amyloid-β (Aβ) and tau have been studied as markers of Alzheimer's disease (AD). Combined Aβ42 and t-tau distinguishes AD from healthy controls with a sensitivity and specificity (sens/spec) near 89% across studies. This study examined these markers in the homogeneous OPTIMA cohort, using extensive longitudinal follow up and postmortem evaluation to confirm clinicopathological status. Baseline CSF was analyzed from 227 participants with AD (97% autopsy-confirmed), mild cognitive impairment (MCI; 73% confirmed), other dementia syndrome (ODS; 100% confirmed), and controls (CTL; 27% confirmed, follow up approximately 9-13 years). Biomarker concentrations were analyzed using validated ELISAs. AD patients had lower CSF Aβ42 and higher t-tau, p-tau, t-tau/Aβ42, and t-tau/Aβ40 compared to CTLs, with MCI intermediate. CTL and MCI participants who progressed to AD demonstrated more AD-like profiles. Aβ40, sAβPPα, and sAβPPβ were lower in AD compared to CTL. High-level discriminators of AD from CTL were t-tau/Aβ40 (AUROC 0.986, sens/spec of 92%/94%), p-tau/Aβ42 (AUROC 0.972, sens/spec of 94%/90%), and Aβ42 (AUROC 0.941, sens/spec of 88%). For discriminating AD from ODS, p-tau/Aβ42 demonstrated sens/spec of 88%/100% (95%/86% at the AD versus CTL cutoff) and Aβ42 demonstrated sens/spec of 84%/100% (88%/100% at the AD versus CTL cutoff). In a well-characterized, homogeneous population, a single cutoff for baseline CSF Aβ and tau markers can distinguish AD with a high level of sens/spec compared to other studies. It may be important to characterize sources of demographic and biological variability to support the effective use of CSF diagnostic assays in the broader AD population.
Merck Research Laboratories, Merck & Co., Inc., Whitehouse Station, NJ, USA.
Jeffrey L
JL
Seeburger
Merck Research Laboratories, Merck & Co., Inc., Whitehouse Station, NJ, USA.
Daniel J
DJ
Holder
OPTIMA, University of Oxford, John Radcliffe Hospital, Headington, Oxford, UK Current address: University of Cape Town, Groote Schuur Hospital, Cape Town, ZA.
Marc
M
Combrinck
OPTIMA, University of Oxford, John Radcliffe Hospital, Headington, Oxford, UK.
Catharine
C
Joachim
Merck Research Laboratories, Merck & Co., Inc., Whitehouse Station, NJ, USA.
Omar
O
Laterza
Merck Research Laboratories, Merck & Co., Inc., Whitehouse Station, NJ, USA.
Michael
M
Tanen
Merck Research Laboratories, Merck & Co., Inc., Whitehouse Station, NJ, USA.
Aimee
A
Dallob
Merck Research Laboratories, Merck & Co., Inc., Whitehouse Station, NJ, USA.
Derek
D
Chappell
Merck Research Laboratories, Merck & Co., Inc., Whitehouse Station, NJ, USA.
Karen
K
Snyder
Merck Research Laboratories, Merck & Co., Inc., Whitehouse Station, NJ, USA.
Mary
M
Flynn
Merck Research Laboratories, Merck & Co., Inc., Whitehouse Station, NJ, USA.
Adam
A
Simon
Merck Research Laboratories, Merck & Co., Inc., Whitehouse Station, NJ, USA.
Vijay
V
Modur
Merck Research Laboratories, Merck & Co., Inc., Whitehouse Station, NJ, USA.
William Z
WZ
Potter
OPTIMA, University of Oxford, John Radcliffe Hospital, Headington, Oxford, UK.
Gordon
G
Wilcock
Merck Research Laboratories, Merck & Co., Inc., Whitehouse Station, NJ, USA.
Mary J
MJ
Savage
OPTIMA, University of Oxford, John Radcliffe Hospital, Headington, Oxford, UK OPTIMA, Department of Pharmacology, Mansfield Rd., Oxford, UK.
A David
AD
Smith
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000134:cerebrospinal fluid* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000134:cerebrospinal fluid*; D016564:Amyloid beta-Protein Precursor / Q000134:cerebrospinal fluid*; D015415:Biomarkers / Q000134:cerebrospinal fluid; D060825:Cognitive Dysfunction / Q000134:cerebrospinal fluid*; D003704:Dementia / Q000134:cerebrospinal fluid*; D005500:Follow-Up Studies; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D010446:Peptide Fragments / Q000134:cerebrospinal fluid*; D010766:Phosphorylation; D012680:Sensitivity and Specificity; D016875:tau Proteins / Q000134:cerebrospinal fluid*
C545487:APP protein, human; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D015415:Biomarkers; C054369:MAPT protein, human; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D016875:tau Proteins
Alzheimer's disease; amyloid-β; biomarker; cerebrospinal fluid; frontotemporal dementia; mild cognitive impairment; postmortem examination; tau