Lesions without symptoms: understanding resilience to Alzheimer disease neuropathological changes

Abstract

Since the original description of amyloid-β plaques and tau tangles more than 100 years ago, these lesions have been considered the neuropathological hallmarks of Alzheimer disease (AD). The prevalence of plaques, tangles and dementia increases with age, and the lesions are considered to be causally related to the cognitive symptoms of AD. Current schemes for assessing AD lesion burden examine the distribution, abundance and characteristics of plaques and tangles at post mortem, yielding an estimate of the likelihood of cognitive impairment. Although this approach is highly predictive for most individuals, in some instances, a striking mismatch between lesions and symptoms can be observed. A small subset of individuals harbour a high burden of plaques and tangles at autopsy, which would be expected to have had devastating clinical consequences, but remain at their cognitive baseline, indicating 'resilience'. The study of these brains might provide the key to understanding the 'black box' between the accumulation of plaques and tangles and cognitive impairment, and show the way towards disease-modifying treatments for AD. In this Review, we begin by considering the heterogeneity of clinical manifestations associated with the presence of plaques and tangles, and then focus on insights derived from the rare yet informative individuals who display high amounts of amyloid and tau deposition in their brains (observed directly at autopsy) without manifesting dementia during life. The resilient response of these individuals to the gradual accumulation of plaques and tangles has potential implications for assessing an individual's risk of AD and for the development of interventions aimed at preserving cognition.

Figure 1 |. Putative role of tau and microglia in resilience

a | In individuals with Alzheimer disease (AD), tau, which is largely bound to axonal microtubules in normal conditions, detaches from microtubules, becomes hyperphosphorylated and misfolded, and coalesces into neurofibrillary tangles in the neuronal soma. In individuals with clinically manifest AD, soluble hyperphosphorylated tau species are mis-targeted and preferentially accumulate within the synaptic compartment in parallel with microglial cell activation. Over time, these changes are associated with the most frequently observed tissue injury response in AD brains, that is, neuronal cell death and synaptic loss. b | In the brains of ‘resilient’ individuals, a negligible accumulation of soluble hyperphosphorylated tau in synapses and a suppressed inflammatory brain response have been observed. These features are associated with the preservation of neurons and synapses amid a burden of plaques and tangles equal to that observed in the brains of individuals with clinically manifest AD. This differential tissue response to the progressive accumulation of plaques and tangles in individuals with clinically manifest AD and resilient individuals is likely to contribute to their widely divergent clinical phenotypes.