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

Abstract

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.

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

“…Further, Fagan et al [13] found that VILIP-1, a marker of neuronal injury and cell death, was increased in mutation carriers up to 15 years before the estimated onset of symptoms. These studies and others [10,28] demonstrate that disease pathogenesis in dementia most likely starts many years before the onset of dementia symptoms in individuals with autosomal dominant AD. It is therefore of great importance to discover specific biomarkers which can detect early disease pathogenesis and enable patients to begin medical evaluation and treatment in an attempt at potentially delaying the onset of symptoms.…”

“…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].…”

Brain imaging and fluid biomarker analysis in young adults at genetic risk for autosomal dominant Alzheimer's disease in the presenilin 1 E280A kindred: a case-control study

“…In comparison with the non-carriers, the PSEN1 E280A mutation carriers had significantly higher CSF Aβ 1-42 levels, consistent with Aβ 1-42 overproduction and in contrast to previously published findings in the later preclinical and clinical stages of LOAD 22 and autosomal dominant AD. 23 The groups did not differ significantly in their CSF t-tau or p-tau 181 levels. Mutation carriers had significantly lower CSF t-tau/Aβ 1-42 and p-tau/Aβ1-42 ratios, in contrast to the elevated ratios reported in the clinical and later preclinical stages of LOAD 22 and autosomal dominant AD 23 , and mostly attributable to elevated CSF Aβ1-42 levels.…”

“…23 The groups did not differ significantly in their CSF t-tau or p-tau 181 levels. Mutation carriers had significantly lower CSF t-tau/Aβ 1-42 and p-tau/Aβ1-42 ratios, in contrast to the elevated ratios reported in the clinical and later preclinical stages of LOAD 22 and autosomal dominant AD 23 , and mostly attributable to elevated CSF Aβ1-42 levels.…”

Clinical utility of cerebrospinal fluid biomarkers in the diagnosis of early Alzheimer's disease

“…1). This is supported in some biomarker studies in sporadic AD that showed that lowering of Aβ 42 in CSF is a very early change [49,50], but studies on familial AD suggest that reductions in CSF Aβ 42 and elevations in tau compared with normal occur around 10 to 15 years before the expected onset of symptoms [51,52]. However, studies on large neuropathology case series suggest that tau pathology precedes amyloid plaque pathology [6].…”