Resistance vs resilience to Alzheimer disease: Clarifying terminology for preclinical studies

Abstract

Preventing or delaying Alzheimer disease (AD) through lifestyle interventions will come from a better understanding of the mechanistic underpinnings of (1) why a significant proportion of elderly remain cognitively normal with AD pathologies (ADP), i.e., amyloid or tau; and (2) why some elderly individuals do not have significant ADP. In the last decades, concepts such as brain reserve, cognitive reserve, and more recently brain maintenance have been proposed along with more general notions such as (neuro)protection and compensation. It is currently unclear how to effectively apply these concepts in the new field of preclinical AD specifically separating the 2 distinct mechanisms of coping with pathology vs avoiding pathology. We propose a simplistic conceptual framework that builds on existing concepts using the nomenclature of resistance in the context of avoiding pathology, i.e., remaining cognitively normal without significant ADP, and resilience in the context of coping with pathology, i.e., remaining cognitively normal despite significant ADP. In the context of preclinical AD studies, we (1) define these concepts and provide recommendations (and common scenarios) for their use; (2) discuss how to employ this terminology in the context of investigating mechanisms and factors; (3) highlight the complementarity and clarity they provide to existing concepts; and (4) discuss different study designs and methodologies. The application of the proposed framework for framing hypotheses, study design, and interpretation of results and mechanisms can provide a consistent framework and nomenclature for researchers to reach consensus on identifying factors that may prevent ADP or delay the onset of cognitive impairment.

Figure. Relation between the concepts of resistance and resilience, brain mechanisms, and contributing factors

Lifestyle factors, vascular risk, sleep, sex, and genetics are contributors to resistance and resilience. Mechanisms specific to resistance include those related to (Aβ) and tau clearance. Common mechanisms comprise initial differences in brain structure (brain reserve) and function (neural reserve–cognitive reserve) and brain maintenance processes, including the preservation of brain structure, glucose metabolism, and functional networks. Specific brain mechanisms of resilience include those that appear as an active response to pathology including neural compensation and compensatory glucose metabolism increases. Light blue indicates the concept, definition, and brain mechanisms associated with resistance to Alzheimer disease (AD). Dark blue indicates the concept, definition, and brain mechanisms associated with resilience to AD. Green indicates factors and mechanisms associated with both concepts. Aβ = β-amyloid.