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

Abstract

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.

Cerebrospinal Fluid Levels of Amyloid Beta 1-43 Mirror 1-42 in Relation to Imaging Biomarkers of Alzheimer’s Disease

“…FreeSurfer version, operating system and workstation used in the processing can also impact the cortical thickness measurements ( Gronenschild et al, 2012 ), but were identical for the two cohorts in this study. Some have suggested that there could be a transitional phase in the development of AD with increased thickness of certain cortical areas ( Chételat et al, 2010b ; Fortea et al, 2011 ; Molinuevo et al, 2012 ), but this has mainly been described in pre-clinical stages. Because we suspected a significant scanner effect, the imaging data were analyzed in each cohort separately, with a lower number of subjects in each analysis as a consequence.…”

Antioxidant, Anti-inflammatory and Neuroprotective Profiles of Novel 1,4-Dihydropyridine Derivatives for the Treatment of Alzheimer’s Disease

“…The complex etiology of AD and the mechanistic study of sporadic AD cases have pointed to several pathological pathways involved in the onset of the disease, including mitochondrial failure, oxidative stress (OS), chronic neuroinflammation and proteostasis deregulation. More importantly, these pathological modifications are thought to be initiated almost twenty years earlier than the appearance of the first symptoms [ 4 ].…”

Circulating biomarkers that predict incident dementia

“…Several other, recently identified genetic variants have also been associated with risk of AD, but their additive value to risk prediction over age, sex and APOE genotype is low; this is largely because the effect of each non-APOE gene is small, ranging from a 12 to 30% increase in risk [9,10]. CSF levels of beta-amyloid (Aβ 40 and Aβ 42 isoforms), tau and phospho-tau have been associated with risk of AD, and other CSF molecules may further improve risk stratification [11,12]. Brain amyloid imaging techniques [13] are also promising.…”