Cognitive reserve and lifestyle: moving towards preclinical Alzheimer's disease

Abstract

The large majority of neuroimaging studies in Alzheimer's disease (AD) patients have supported the idea that lifestyle factors may protect against the clinical manifestations of AD rather than influence AD neuropathological processes (the cognitive reserve hypothesis). This evidence argues in favor of the hypothesis that lifestyle factors act as moderators between AD pathology and cognition, i.e., through indirect compensatory mechanisms. In this review, we identify emerging evidence in cognitively normal older adults that relate lifestyle factors to established AD neuroimaging biomarkers. While some of these investigations are in agreement with the compensatory view of cognitive reserve, other studies have revealed new clues on the neural mechanisms underlying beneficial effects of lifestyle factors on the brain. Specifically, they provide novel evidence suggesting direct effects of lifestyle factors on AD neuropathological processes. We propose a tentative theoretical model where lifestyle factors may act via direct neuroprotective and/or indirect compensatory mechanisms. Importantly, we suggest that neuroprotective mechanisms may have a major role during early stages and compensatory mechanisms in later stages of the disease. In the absence of an effective treatment for AD and considering the potential of lifestyle factors in AD prevention, understanding the neural mechanisms underlying lifestyle effects on the brain seems crucial. We hope to provide an integrative view that may help to better understand the complex effects of lifestyle factors on AD neuropathological processes, starting from the preclinical stage.

Keywords: Alzheimer’s disease; amyloid; brain reserve; cognitive reserve; compensation; neuroimaging; neuroprotection; preclinical Alzheimer’s disease.

Figure 1

Theoretical illustration of how cognitive reserve may mediate the relationships between AD neuropathology and cognitive function (adapted from Stern, 2009).

Figure 2

Illustration of the interactions between Aβ status (positive vs. negative) and cognitive reserve proxies on hippocampal volume reprinted from Arenaza-Urquijo et al. (; with permission from IOS Press). The scatterplot shows an inverse relationships between cognitive reserve markers and AD neuroimaging biomarkers restricted to cognitively normal Aβ positive subjects (in red).

Figure 3

(A) Association between past cognitive activity score and cortical PIB-uptake, reprinted from Landau et al. (; with permission) and interaction between cognitive activity and APOE ε4 on global PIB retention reprinted from Wirth et al. (; with permission). (B) Association between physical activity and PIB mean cortical binding potential reprinted from Liang et al. (; with permission) and interaction between physical activity and APOE ε4 on mean cortical binding potential, reprinted from Head et al. (; with permission).

Figure 4

Theoretical illustrations of the potential effects of lifestyle factors. (A) Lifestyle factors may act as moderators between brain pathology and cognition, as posited by the cognitive reserve model. (B) Lifestyle factors may have a direct (neuroprotective) effect on AD neuropathology, as shown by more recent neuroimaging studies. (C) Lifestyle factors may act through both neuroprotective and compensatory pathways, that may coexist. Lifesytle factors may have a direct effect on AD pathological processes in cognitively normal older adults. However, when the pathology reaches a certain level, lifestyle factors may only moderate the relation between AD pathology and cognition. In other words, neuroprotective processess may have a major role in early stages, and compensatory processess later in the disease progression.