BACKGROUND/AIMS: Biological markers of utility in tracking Alzheimer's disease (AD) during the presymptomatic prodromal phase are important for prevention studies. Changes in cerebrospinal fluid (CSF) levels of 42-amino-acid β-amyloid (Aβ(42)), total tau protein (t-tau) and phosphorylated tau at residue 181 (p-tau(181)) during this state are incompletely characterized. METHODS: We measured CSF markers in 13 carriers of familial AD (FAD) mutations that are fully penetrant for causing AD (PSEN1 and APP) and in 5 non-mutation-carrying family members. RESULTS: Even among the entirely presymptomatic mutation carriers (n = 9), Aβ(42) was diminished (388.7 vs. 618.4 pg/ml, p = 0.004), and t-tau (138.5 vs. 50.5 pg/ml, p = 0.002) and p-tau(181) (71.7 vs. 24.6 pg/ml, p = 0.003) were elevated. There was a negative correlation between Aβ(42) levels and age relative to the family-specific age of dementia diagnosis. CONCLUSIONS: Our data are consistent with a decline in CSF Aβ(42) levels occurring at least 20 years prior to clinical dementia in FAD.
BACKGROUND/AIMS: Biological markers of utility in tracking Alzheimer's disease (AD) during the presymptomatic prodromal phase are important for prevention studies. Changes in cerebrospinal fluid (CSF) levels of 42-amino-acid β-amyloid (Aβ(42)), total tau protein (t-tau) and phosphorylated tau at residue 181 (p-tau(181)) during this state are incompletely characterized. METHODS: We measured CSF markers in 13 carriers of familial AD (FAD) mutations that are fully penetrant for causing AD (PSEN1 and APP) and in 5 non-mutation-carrying family members. RESULTS: Even among the entirely presymptomatic mutation carriers (n = 9), Aβ(42) was diminished (388.7 vs. 618.4 pg/ml, p = 0.004), and t-tau (138.5 vs. 50.5 pg/ml, p = 0.002) and p-tau(181) (71.7 vs. 24.6 pg/ml, p = 0.003) were elevated. There was a negative correlation between Aβ(42) levels and age relative to the family-specific age of dementia diagnosis. CONCLUSIONS: Our data are consistent with a decline in CSF Aβ(42) levels occurring at least 20 years prior to clinical dementia in FAD.
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