The Latent Dementia Phenotype δ is Associated with Cerebrospinal Fluid Biomarkers of Alzheimer's Disease and Predicts Conversion to Dementia in Subjects with Mild Cognitive Impairment.
BACKGROUND
The recently proposed latent variable δ is a new tool for dementia case finding. It is built in a structural equation modeling framework of cognitive and functional data and constitutes a novel endophenotype for Alzheimer's disease (AD) research and clinical trials.


OBJECTIVE
To investigate the association of δ with AD biomarkers and to compare the prediction of δ with established scales for conversion to dementia in patients with mild cognitive impairment (MCI).


METHODS
Using data from a multicenter memory clinic study, we examined the external associations of the latent variable δ and compared δ with well-established cognitive and functional scales and cognitive-functional composite scores. For that purpose, logistic regressions with cerebrospinal fluid (CSF) biomarkers and conversion to dementia as dependent variables were performed with the investigated scores. The models were tested for significant differences.


RESULTS
In patients with MCI, δ based on a broad range of cognitive scales (including the ADAS-cog, the MMSE, and the CERAD neuropsychological battery) predicted an abnormal CSF Aβ42/tau ratio indicative of AD (n = 340, AUC = 0.78, p <  0.001), and predicted incident dementia within 1-3 years of follow-up (n = 525, AUC = 0.84, p <  0.001). These associations were generally stronger than for any other scale or cognitive-functional composite examined. Homologs of δ based on reduced test batteries yielded somewhat lower effects.


CONCLUSIONS
These findings support the interpretation of δ as a construct capturing the disease-related "essence" of cognitive and functional impairments in patients with MCI and dementia, and suggest that δ might become an analytical tool for dementia research.
Department of Psychiatry, University of Bonn, Germany.|German Center for Neurodegenerative Diseases, Bonn, Germany.
Alexander
A
Koppara
Department of Psychiatry, University of Bonn, Germany.|German Center for Neurodegenerative Diseases, Bonn, Germany.
Steffen
S
Wolfsgruber
Department of Psychiatry, University of Bonn, Germany.|German Center for Neurodegenerative Diseases, Bonn, Germany.
Luca
L
Kleineidam
Center for Geriatric Medicine, Ortenau Klinikum, Offenburg-Gengenbach, Germany.
Klaus
K
Schmidtke
Department of Gerontopsychiatry, Central Institute of Mental Health, Mannheim, Germany.
Lutz
L
Frölich
Department of Psychiatry, Technical University of Munich, Germany.
Alexander
A
Kurz
Department of Neurology, University of Aachen, Germany.
Stefanie
S
Schulz
Department of Neurology, Université Pierre et Marie Curie (Sorbonne), and AXA Research Fund & UPMC Chair, Paris, France.
Harald
H
Hampel
Department of Psychiatry, Charité Berlin, Campus Benjamin Franklin, Berlin, Germany.
Isabella
I
Heuser
Department of Psychiatry, Charité Berlin, Campus Benjamin Franklin, Berlin, Germany.
Oliver
O
Peters
Department of Psychiatry, Charité Berlin, Campus Benjamin Franklin, Berlin, Germany.
Friedel M
FM
Reischies
Department of Psychiatry, University of Hamburg, Germany.
Holger
H
Jahn
Department of Psychiatry, University of Düsseldorf, Germany.
Christian
C
Luckhaus
Center for Psychiatry, Clinic for Geronto- and Neuropsychiatry Emmendingen and Dep. of Psychiatry, University of Freiburg, Germany.
Michael
M
Hüll
Department of Psychiatry, University of Leipzig, Germany.
Hermann-Josef
HJ
Gertz
Section for Geriatric Psychiatry/Institute of Gerontology, University of Heidelberg, Germany.
Johannes
J
Schröder
Institute of General Medicine University of Frankfurt, Frankfurt am Main, Germany.
Johannes
J
Pantel
Department of Medical Informatics, University of Göttingen, Germany.
Otto
O
Rienhoff
Department of Psychiatry and Psychotherapy, University of Göttingen, Germany.
Eckart
E
Rüther
Ichan School of Medicine at Mt. Sinai, New York, USA.
Fritz
F
Henn
Department of Psychiatry and Psychotherapy, University of Göttingen, Germany.
Jens
J
Wiltfang
Department of Psychiatry, University of Bonn, Germany.|German Center for Neurodegenerative Diseases, Bonn, Germany.
Wolfgang
W
Maier
Department of Psychiatry, University of Bonn, Germany.|German Center for Neurodegenerative Diseases, Bonn, Germany.|Department of Psychiatry, Medical Faculty University of Cologne, Germany.
Frank
F
Jessen
Department of Psychiatry, Friedrich-Alexander-University Erlangen, Germany.
Johannes
J
Kornhuber
Department of Psychiatry, University of Bonn, Germany.|German Center for Neurodegenerative Diseases, Bonn, Germany.
Michael
M
Wagner
D000203:Activities of Daily Living; D000368:Aged; D000544:Alzheimer Disease / Q000134:cerebrospinal fluid* / Q000523:psychology*; D016229:Amyloid beta-Peptides / Q000134:cerebrospinal fluid; D015415:Biomarkers / Q000134:cerebrospinal fluid*; D060825:Cognitive Dysfunction / Q000134:cerebrospinal fluid* / Q000523:psychology*; D003704:Dementia / Q000134:cerebrospinal fluid / Q000175:diagnosis*; D018450:Disease Progression; D005260:Female; D006801:Humans; D016015:Logistic Models; D008137:Longitudinal Studies; D008297:Male; D008609:Mental Status Schedule; D008875:Middle Aged; D009483:Neuropsychological Tests; D010446:Peptide Fragments / Q000134:cerebrospinal fluid; D010641:Phenotype; D011237:Predictive Value of Tests; D012189:Retrospective Studies; D016875:tau Proteins / Q000134:cerebrospinal fluid
D016229:Amyloid beta-Peptides; D015415:Biomarkers; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D016875:tau Proteins
CSF AD biomarker signature; delta model; incident dementia; mild cognitive impairment