Diagnosis and biomarkers of predementia in Alzheimer's disease

Abstract

In view of the growing prevalence of Alzheimer's disease (AD) worldwide, there is an urgent need for the development of better diagnostic tools and more effective therapeutic interventions. At the earliest stages of AD, no significant cognitive or functional impairment is detected by conventional clinical methods. However, new technologies based on structural and functional neuroimaging, and on the biochemical analysis of cerebrospinal fluid (CSF) may reveal correlates of intracerebral pathology in individuals with mild, predementia symptoms. These putative correlates are commonly referred to as AD-related biomarkers. The relevance of the early diagnosis of AD relies on the hypothesis that pharmacological interventions with disease-modifying compounds are likely to produce clinically relevant benefits if started early enough in the continuum towards dementia. Here we review the clinical characteristics of the prodromal and transitional states from normal cognitive ageing to dementia in AD. We further address recent developments in biomarker research to support the early diagnosis and prediction of dementia, and point out the challenges and perspectives for the translation of research data into clinical practice.

Figure 1

Hypothetical model of the pathological processes in Alzheimer's disease (AD), focusing on the amyloid β peptide (Aβ) cascade. (Other relevant mechanisms have been omitted or presented in a secondary perspective for didactic purposes.) Dotted arrows indicate possible or secondary mechanisms affecting core pathological processes within the amyloid cascade. Background shades of gray separated by dotted lines are a schematic representation to integrate the progression of pathological events along with the development of the cognitive syndrome of AD (these thresholds are arbitrary and not experimentally validated, and represent the authors' point of view of the disease process). Three clinical phases of the disease are defined: presymptomatic (or preclinical) AD may last for several years or decades until the overproduction and accumulation of Aβ in the brain reaches a critical level that triggers the amyloid cascade; in the predementia phase, compatible with the definition of mild cognitive impairment secondary to AD, early stage pathology is present in varying degrees, from mild neuronal dystrophy to early stage Braak pathology, according to individual resilience and brain reserve. Finally, in the clinically defined dementia phase, there is a progressive accumulation of the classical pathological hallmarks of AD (that is, neuritic plaques and neurofibrillary tangles), bearing relationship with the progression of cognitive deficits and the magnitude of functional impairment. APP = amyloid precursor protein; PS1/2 = presenilin 1/2; TAU = microtubule-associated protein Tau.

Figure 2

Relationship between the progression of cognitive and functional symptoms and the neuropathological events in the transition from asymptomatic Alzheimer's disease (AD) to mild cognitive impairment due to AD and clinically manifest dementia of the AD type.

Figure 3

Hypothetical outcomes according to distinct mild cognitive impairment (MCI) subtypes [14,23].