Cerebrospinal fluid biomarkers in Alzheimer's disease families with PSEN1 mutations

Background/aims: Familial Alzheimer's disease allows studies in the preclinical phases of the disease. We studied cerebrospinal fluid (CSF) amyloid β1-42 (Aβ1-42), total tau (t-tau) and phospho-tau181 (p-tau) levels in PSEN1 families and correlated the results with the genetic status, age and clinical stage.

Methods: Thirteen subjects from 3 families with 2 PSEN1 mutations (L286P, M139T) were recruited from the genetic counseling program for familial dementia. Eight mutation carriers (MC) and 5 noncarriers (NC) underwent clinical and cognitive evaluations. CSF concentrations were obtained by ELISA methodology.

Results: Symptomatic MC presented reduced CSF Aβ1-42 (mean = 175 pg/ml) and elevated t-tau (mean = 635 pg/ml) compared to controls, but not asymptomatic MC (mean = 684 and 255 pg/ml, respectively) at a median of -12.8 years from the predicted disease onset (adjusted age). Aβ1-42 levels presented an inverse correlation with the adjusted age (r = -1, p < 0. 01) in asymptomatic MC, but not in symptomatic MC or NC. t-tau presented a trend towards a negative correlation with Mini Mental State Examination (MMSE; r = -0.949, p = 0.051) in symptomatic MC but not in asymptomatic MC. In the whole group of MC, t-tau presented a significant positive correlation with Clinical Dementia Rating sum of boxes (r = 0.913, p = 0.002) and a negative correlation with MMSE (r = -0.946, p < 0.001).

Conclusions: CSF Aβ1-42 levels correlate with time to disease onset in asymptomatic MC to reach floor levels when symptoms appear. CSF t-tau levels become elevated in symptomatic MC and correlate with clinical severity. These findings may suggest that the changes in Aβ1-42 precede t-tau elevation in PSEN1 MC.