Preclinical Alzheimer disease: identification of cases at risk among cognitively intact older individuals

Maciej J Lazarczyk, Patrick R Hof, Constantin Bouras, Panteleimon Giannakopoulos, Maciej J Lazarczyk, Patrick R Hof, Constantin Bouras, Panteleimon Giannakopoulos

Abstract

Since the first description of the case of Auguste Deter, presented in Tübingen in 1906 by Alois Alzheimer, there has been an exponential increase in our knowledge of the neuropathological, cellular, and molecular foundation of Alzheimer's disease (AD). The concept of AD pathogenesis has evolved from a static, binary view discriminating cognitive normality from dementia, towards a dynamic view that considers AD pathology as a long-lasting morbid process that takes place progressively over years, or even decades, before the first symptoms become apparent, and thus operating in a continuum between the two aforementioned extreme states. Several biomarkers have been proposed to predict AD-related cognitive decline, initially in cases with mild cognitive impairment, and more recently in cognitively intact individuals. These early markers define at-risk individuals thought to be in the preclinical phase of AD. However, the clinical relevance of this preclinical phase remains controversial. The fate of such individuals, who are cognitively intact, but positive for some early AD biomarkers, is currently uncertain at best. In this report, we advocate the point of view that although most of these preclinical cases will evolve to clinically overt AD, some appear to have efficient compensatory mechanisms and virtually never develop dementia. We critically review the currently available early AD markers, discuss their clinical relevance, and propose a novel classification of preclinical AD, designating these non-progressing cases as 'stable asymptomatic cerebral amyloidosis'.

Figures

Figure 1
Figure 1
Possible trajectories of the conversion process from cognitively normal to Alzheimer's disase (AD)-type dementia. (A) Three different possible trajectories of the conversion to dementia in a group of cognitively normal (CN) individuals (100% of non-demented subjects at t0), at risk of AD. In the first trajectory (red line), the group comprises at baseline (t0) CN individuals at different stages of preclinical AD, with roughly the same number of subjects at each stage. The total conversion time (the time between appearance of an early AD marker and dementia onset) is constant and is the same for all subjects (t), and the number of converters in a given period is constant. In the second scenario (green line), the group comprises peole with preclinical AD, with a Gaussian distribution of the individuals at different stages of advancement (most individuals being at the intermediate stage). The total conversion time is constant and the same for all the individuals (t). Most of the group converts to dementia at around t1/2. Finally, the black line shows the group comprising CN at preclinical AD, with the constant conversion rate (proportion of the individuals that develop dementia in a given time period). Most individuals convert to dementia early, and the mean time of conversion is higher than the respective median. (B) Preclinical AD individuals with a passive compensatory mechanism that delays conversion for a given time (Δt), until the mechanism is exhausted. Subsequently, all patients convert to dementia, following one of the trajectories presented on the panel A. (C) Preclinical AD individuals with an active compensatory mechanism that prevents, in a certain proportion of cases (p), conversion to dementia, whichever trajectory the conversion process follows.
Figure 2
Figure 2
Hypothetical model of preclinical Alzheimer's disease (AD). According to the proposed model, the group currently defined as 'preclinical AD' is heterogeneous and comprises two subpopulations. Firstly, there is the group of individuals at different stages of preclinical AD defined by the biomarkers indicated in the lower panel of the figure. All of these individuals will progress to dementia, and we call this phase 'presymptomatic AD'. The second group comprises individuals who are positive for amyloid markers and neuronal injury markers, and fall into one of the stages of preclinical AD, based on the current classification. However, this population has efficient active compensatory mechanisms, and remains resistant to dementia (stable asymptomatic cerebral amyloidosis).

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Source: PubMed

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