Cerebrospinal Fluid Biomarkers and Proximity to Diagnosis in Preclinical Familial Alzheimer’s Disease

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 (Aβ₄₂), total tau protein (t-tau) and phosphorylated tau at residue 181 (p-tau₁₈₁) 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), Aβ₄₂ 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-tau₁₈₁ (71.7 vs. 24.6 pg/ml, p = 0.003) were elevated. There was a negative correlation between Aβ₄₂ levels and age relative to the family-specific age of dementia diagnosis. Conclusions: Our data are consistent with a decline in CSF Aβ₄₂ levels occurring at least 20 years prior to clinical dementia in FAD.