Decreased cerebrospinal fluid Abeta(42) correlates with brain atrophy in cognitively normal elderly.
OBJECTIVE
For therapies for Alzheimer's disease (AD) to have the greatest impact, it will likely be necessary to treat individuals in the "preclinical" (presymptomatic) stage. Fluid and neuroimaging measures are being explored as possible biomarkers of AD pathology that could aid in identifying individuals in this stage to target them for clinical trials and to direct and monitor therapy. The objective of this study was to determine whether cerebrospinal fluid (CSF) biomarkers for AD suggest the presence of brain damage in the preclinical stage of AD.


METHODS
We investigated the relation between structural neuroimaging measures (whole-brain volume) and levels of CSF amyloid-beta (Abeta)(40), Abeta(42), tau, and phosphorylated tau(181) (ptau(181)), and plasma Abeta(40) and Abeta(42) in well-characterized research subjects with very mild and mild dementia of the Alzheimer type (n = 29) and age-matched, cognitively normal control subjects (n = 69).


RESULTS
Levels of CSF tau and ptau(181), but not Abeta(42), correlated inversely with whole-brain volume in very mild and mild dementia of the Alzheimer type, whereas levels of CSF Abeta(42), but not tau or ptau(181), were positively correlated with whole-brain volume in nondemented control subjects.


CONCLUSIONS
Reduction in CSF Abeta(42), likely reflecting Abeta aggregation in the brain, is associated with brain atrophy in the preclinical phase of AD. This suggests that there is toxicity associated with Abeta aggregation before the onset of clinically detectable disease. Increases in CSF tau (and ptau(181)) are later events that correlate with further structural damage and occur with clinical onset and progression.
Fagan
Anne M
AM
Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, USA. fagana@neuro.wustl.edu
Head
Denise
D
Shah
Aarti R
AR
Marcus
Daniel
D
Mintun
Mark
M
Morris
John C
JC
Holtzman
David M
DM
D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000473:pathology / Q000502:physiology / Q000523:psychology; D000544:Alzheimer Disease / Q000134:cerebrospinal fluid / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000134:cerebrospinal fluid*; D000814:Aniline Compounds / Q000378:metabolism; D016009:Chi-Square Distribution; D005260:Female; D015577:Geriatric Assessment; D006801:Humans; D007091:Image Processing, Computer-Assisted / Q000379:methods; D008279:Magnetic Resonance Imaging / Q000379:methods; D008297:Male; D008875:Middle Aged; D009483:Neuropsychological Tests; D010446:Peptide Fragments / Q000134:cerebrospinal fluid*; D020774:Pick Disease of the Brain / Q000134:cerebrospinal fluid* / Q000000981:diagnostic imaging / Q000473:pathology*; D049268:Positron-Emission Tomography / Q000379:methods; D013844:Thiazoles / Q000378:metabolism
C475519:2-(4'-(methylamino)phenyl)-6-hydroxybenzothiazole; D016229:Amyloid beta-Peptides; D000814:Aniline Compounds; D010446:Peptide Fragments; D013844:Thiazoles; C075222:amyloid beta-protein (1-42)