Diagnosis-independent Alzheimer disease biomarker signature in cognitively normal elderly people.
OBJECTIVE
To identify biomarker patterns typical for Alzheimer disease (AD) in an independent, unsupervised way, without using information on the clinical diagnosis.


METHODS
Mixture modeling approach.


METHODS
Alzheimer's Disease Neuroimaging Initiative database.


METHODS
Cognitively normal persons, patients with AD, and individuals with mild cognitive impairment.


METHODS
Cerebrospinal fluid-derived beta-amyloid protein 1-42, total tau protein, and phosphorylated tau(181P) protein concentrations were used as biomarkers on a clinically well-characterized data set. The outcome of the qualification analysis was validated on 2 additional data sets, 1 of which was autopsy confirmed.


RESULTS
Using the US Alzheimer's Disease Neuroimaging Initiative data set, a cerebrospinal fluid beta-amyloid protein 1-42/phosphorylated tau(181P) biomarker mixture model identified 1 feature linked to AD, while the other matched the "healthy" status. The AD signature was found in 90%, 72%, and 36% of patients in the AD, mild cognitive impairment, and cognitively normal groups, respectively. The cognitively normal group with the AD signature was enriched in apolipoprotein E epsilon4 allele carriers. Results were validated on 2 other data sets. In 1 study consisting of 68 autopsy-confirmed AD cases, 64 of 68 patients (94% sensitivity) were correctly classified with the AD feature. In another data set with patients (n = 57) with mild cognitive impairment followed up for 5 years, the model showed a sensitivity of 100% in patients progressing to AD.


CONCLUSIONS
The mixture modeling approach, totally independent of clinical AD diagnosis, correctly classified patients with AD. The unexpected presence of the AD signature in more than one-third of cognitively normal subjects suggests that AD pathology is active and detectable earlier than has heretofore been envisioned.
De Meyer
Geert
G
Innogenetics, Industriepark Zwijnaarde 7, Box 4, B-9052 Gent, Belgium.
Shapiro
Fred
F
Vanderstichele
Hugo
H
Vanmechelen
Eugeen
E
Engelborghs
Sebastiaan
S
De Deyn
Peter Paul
PP
Coart
Els
E
Hansson
Oskar
O
Minthon
Lennart
L
Zetterberg
Henrik
H
Blennow
Kaj
K
Shaw
Leslie
L
Trojanowski
John Q
JQ
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000134:cerebrospinal fluid* / Q000175:diagnosis* / Q000235:genetics / Q000503:physiopathology; D016229:Amyloid beta-Peptides / Q000134:cerebrospinal fluid; D053327:Apolipoprotein E4 / Q000235:genetics; D015415:Biomarkers / Q000134:cerebrospinal fluid; D003071:Cognition / Q000502:physiology*; D005260:Female; D005500:Follow-Up Studies; D015577:Geriatric Assessment; D006801:Humans; D008297:Male; D010446:Peptide Fragments / Q000134:cerebrospinal fluid; D012372:ROC Curve; D015203:Reproducibility of Results; D016875:tau Proteins / Q000134:cerebrospinal fluid
D016229:Amyloid beta-Peptides; D053327:Apolipoprotein E4; D015415:Biomarkers; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D016875:tau Proteins