Identifying earlier Alzheimer's disease: insights from the preclinical and prodromal phases

Alzheimer's disease (AD) has been traditionally conceptualized as a clinicopathological entity, its definite diagnosis requiring the presence of characteristic pathology together with a dementia clinical picture. The fact that certain AD biomarkers show an acceptable sensitivity and specificity to detect AD pathology has shifted the diagnostic paradigm towards a clinicobiological approach. The objective of this paper is to present recent data that show how cerebrospinal fluid (CSF) biomarkers behave in preclinical AD. These studies have been performed in presymptomatic subjects (PreS) and asymptomatic subjects at risk for the disease (AsymR). In brief, the results show in PreS subjects that CSF biomarkers present a positive correlation with time to disease onset to reach floor levels at symptom onset. In addition, memory performance presents distinct associations in the AD continuum, being related to Aβ(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 mean Aβ(1-42) levels were still within the normal range in PreS subjects, or they presented transitional values in AsymR subjects. Overall, these findings suggest that the preclinical stage is biologically active and that there may be structural changes when amyloid is starting its deposition.