Cerebrospinal Fluid Biomarkers in Alzheimer’s Disease Families with <i>PSEN1</i> Mutations

Abstract

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.

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

“…Consistent with the findings of Fortea et al [11], these differences persisted when only presymptomatic MCs were analyzed, indicating they occur during the presymptomatic stage. Relating these levels with adjusted age indicates a decline in Aβ 42 occurring between 20 and 10 years prior to the expected age of disease diagnosis.…”

“…We previously showed that a cohort of 7 FAD mutation carriers (5 presymptomatic) who were an average of 11 years younger than the typical age of AD diagnosis in their family had elevated CSF t-tau and p- tau 181 , and decreased CSF Aβ 42 /Aβ 40 ratios compared to non-mutation-carrying family members [10]. Fortea et al [11] found Aβ 42 levels to be diminished prior to elevation in tau levels in presymptomatic FAD mutation carriers. In 1 subject studied prospectively by our group who was 22 years prior to the characteristic age of disease diagnosis in his/her family at the initial lumbar puncture and underwent repeat lumbar puncture 4.5 years later, Aβ 42 levels had diminished and t-tau and p-tau 181 had increased markedly in the interim [12].…”

Cerebrospinal Fluid Biomarkers in Familial Forms of Alzheimer's Disease and Frontotemporal Dementia

“…In both symptomatic and presymptomatic APP , PSEN1 and PSEN2 mutation carriers, the majority of the studies found a decrease in Aβ 42 and an increase in both t-tau and p-tau levels when compared with healthy control individuals, consistent with a typical AD profile [7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26] (table 1). In some cases, 1 or more markers were found to be unchanged compared to controls [27,28,29,30].…”

Identifying Earlier Alzheimer’s Disease: Insights from the Preclinical and Prodromal Phases

“…We initially studied 13 subjects from 3 families with 2 PSEN1 mutations (L286P, M139T) that were recruited from our genetic counseling program for familial dementia [6] . CSF A ␤ 1-42 and t-tau levels were analyzed in both asymptomatic mutation carriers (AMC) and symptomatic mutation carriers (SMC).…”

“…In addition, memory performance presents distinct associations in the AD continuum, being related to A ␤ 1-42 levels in AsymR subjects and to t-tau and p-tau in prodromal AD. Furthermore, an increase in cortical thickness of typical AD areas was observed when The objectives of this review paper are to summarize the results on preclinical and prodromal AD (prodAD) of our group [6][7][8][9][10] presented at the AD/PD 2011 in Barcelona.…”