CSF biomarkers predict rate of cognitive decline in Alzheimer disease.
OBJECTIVE
CSF biomarkers amyloid beta 1-42 (Abeta(42)), total tau (tau), and tau phosphorylated at threonine 181 (p-tau-181) are useful diagnostic markers for Alzheimer disease (AD). Less is known about these biomarkers as predictors for further cognitive decline in patients with AD. We hypothesized that high tau, especially in combination with relatively low p-tau-181, is a marker of rapid decline, since it has been associated with fast neuronal degeneration.


METHODS
A total of 151 patients with AD of whom we had baseline CSF were included from our memory clinic. All patients had at least 2 Mini-Mental State Examination (MMSE) scores, obtained no less than 1 year apart. Linear mixed models were used to assess associations between CSF biomarkers and the rate of cognitive decline as measured with the MMSE. CSF biomarkers were used in quintiles, random intercept and random slope with time were assumed, and the analyses were corrected for sex and age.


RESULTS
The patients with AD (45% women, age 66 +/- 9 years, baseline MMSE 22 +/- 4) had a follow-up period of 2.0 (1.0-5.0) years. Linear mixed models revealed no relations between any CSF biomarker and baseline MMSE. However, CSF biomarkers did predict cognitive decline over time. A low p-tau-181/tau ratio was the strongest predictor with a dose-dependent effect (lowest vs highest quintile: 2.9 vs 1.3 MMSE points annual decline, p for trend <0.001). In addition, low Abeta(42), high tau, and high tau/Abeta(42)-ratio were associated with rapid cognitive decline (p < 0.05).


CONCLUSIONS
At the time of diagnosis, a combination of high CSF tau without proportionally elevated p-tau-181 is associated with a faster rate of cognitive decline.
Alzheimer Center and Department of Neurology, VU University Medical Center, Amsterdam, the Netherlands.
M I
MI
Kester
A E
AE
van der Vlies
M A
MA
Blankenstein
Y A L
YA
Pijnenburg
E J
EJ
van Elk
P
P
Scheltens
W M
WM
van der Flier
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000134:cerebrospinal fluid* / Q000175:diagnosis; D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000134:cerebrospinal fluid*; D015415:Biomarkers / Q000134:cerebrospinal fluid; D003072:Cognition Disorders / Q000134:cerebrospinal fluid* / Q000175:diagnosis; D018450:Disease Progression; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D016014:Linear Models; D008297:Male; D008875:Middle Aged; D009483:Neuropsychological Tests; D010446:Peptide Fragments / Q000134:cerebrospinal fluid*; D010766:Phosphorylation; D011379:Prognosis; D012720:Severity of Illness Index; D013997:Time Factors; D016875:tau Proteins / Q000134:cerebrospinal fluid* / Q000235:genetics
D016229:Amyloid beta-Peptides; D015415:Biomarkers; C054369:MAPT protein, human; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D016875:tau Proteins