Biochemical markers in persons with preclinical familial Alzheimer disease.
BACKGROUND
Persons at risk for familial Alzheimer disease (FAD) provide a model in which biomarkers can be studied in presymptomatic disease.


METHODS
Twenty-one subjects at risk for presenilin-1 (n = 17) or amyloid precursor protein (n = 4) mutations underwent evaluation with the Clinical Dementia Rating (CDR) scale. We obtained plasma from all subjects and CSF from 11. Plasma (Abeta(40), Abeta(42), F(2)-isoprostanes) and CSF (F(2)-isoprostanes, t-tau, p-tau(181), Abeta(40), Abeta(42), and Abeta(42)/Abeta(40) ratio) levels were compared between FAD mutation carriers (MCs) and noncarriers (NCs).


RESULTS
Plasma Abeta(42) levels (25.1 pM vs 15.5 pM, p = 0.031) and the ratio of Abeta(42)/Abeta(40) (0.16 vs 0.11, p = 0.045) were higher in presymptomatic MCs. Among MCs, those with CDR scores of 0.5 had lower plasma Abeta(42) levels than those with CDR scores of 0 (14.1 pM vs 25.1, p = 0.02). The ratio of Abeta(42) to Abeta(40) was also reduced in the CSF (0.08 vs 0.15, p = 0.046) of nondemented MCs compared to NCs. Total CSF tau and p-tau(181) levels were elevated in presymptomatic FAD MCs. CSF levels of F(2)-isoprostanes were also elevated in MCs (n = 7, 48.6 pg/mL) compared to NCs (n = 4, 21.6 pg/mL, p = 0.031).


CONCLUSIONS
Our data indicate that Abeta(42) is elevated in plasma in familial Alzheimer disease (FAD) mutation carriers (MCs) and suggests that this level may decrease with disease progression prior to the development of overt dementia. We also demonstrated that the ratio of Abeta(42) to Abeta(40) was reduced in the CSF of nondemented MCs and that elevations of t-tau and p-tau(181) are sensitive indicators of presymptomatic disease. Our finding of elevated F(2)-isoprostane levels in the CSF of preclinical FAD MCs suggests that oxidative stress occurs downstream to mismetabolism of amyloid precursor protein.
UCLA Department of Neurology, Alzheimer Disease Research Center, 10911 Weyburn Ave, Suite 200, Los Angeles, CA 90095-7226, USA. jringman@mednet.ucla.edu
J M
JM
Ringman
S G
SG
Younkin
D
D
Pratico
W
W
Seltzer
G M
GM
Cole
D H
DH
Geschwind
Y
Y
Rodriguez-Agudelo
B
B
Schaffer
J
J
Fein
S
S
Sokolow
E R
ER
Rosario
K H
KH
Gylys
A
A
Varpetian
L D
LD
Medina
J L
JL
Cummings
D000328:Adult; D000544:Alzheimer Disease / Q000097:blood / Q000134:cerebrospinal fluid / Q000175:diagnosis* / Q000235:genetics / Q000517:prevention & control*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D015415:Biomarkers / Q000097:blood / Q000134:cerebrospinal fluid; D005260:Female; D006579:Heterozygote; D006801:Humans; D028421:Isoprostanes / Q000097:blood / Q000134:cerebrospinal fluid; D008297:Male; D009154:Mutation; D009460:Neurologic Examination; D053764:Presenilin-1 / Q000235:genetics; D058255:Protease Nexins; D011956:Receptors, Cell Surface / Q000235:genetics; D012680:Sensitivity and Specificity; D016875:tau Proteins / Q000134:cerebrospinal fluid
C489697:APLP1 protein, human; D016564:Amyloid beta-Protein Precursor; D015415:Biomarkers; D028421:Isoprostanes; C508853:PSEN1 protein, human; D053764:Presenilin-1; D058255:Protease Nexins; D011956:Receptors, Cell Surface; D016875:tau Proteins