Cognitive and brain reserve and the diagnosis and treatment of preclinical Alzheimer disease

“Reserve” hypotheses in neurodegenerative disease are theoretical concepts that attempt to explain how some individuals are able to maintain normal cognition despite pathologic disease burden sufficient to cause cognitive decline or overt dementia in others.¹ This idea was born out of the seminal work of Katzman et al.² who described, at postmortem, a subset of older individuals with preserved cognition who harbored substantial levels of neocortical plaques. To explain this disconnect between pathologic burden and clinical state, 2 “reserve” terms have been proposed. Brain reserve refers to intrinsic differences in brain structure or neuronal capacity and is measured by assessment of brain volume and by postmortem assessment of synaptic density and neuronal number or size.^1,3 Cognitive reserve, on the other hand, refers to differences in how individuals utilize adaptive cognitive strategies and engage neural networks to maintain normal cognition in the face of pathologic burden.¹ Cognitive reserve is traditionally measured by surrogate markers, such as overall ability level, and lifestyle factors, such as education, occupation, and cognitive, social, and physical leisure activities.⁴ With the advent of in vivo antemortem biomarkers of Alzheimer disease (AD) that allow us to quantify brain structure, function, and molecular composition, we now know that approximately 30% of elderly individuals with no clinical impairment have evidence for preclinical AD (pAD), indicated by abnormal Aβ levels by imaging or CSF analysis.^1,5 As the field moves toward preclinical diagnosis and eventual treatment of individuals with pAD, it is critical that we understand the mediating factors of the relationships among cognition, function, and pathologic burden.⁶ One potential mediating factor is the influence of cognitive and brain reserve.