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  • Review Article
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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.

Key points

  • Plaques of amyloid-β (Aβ) and tangles containing hyperphosphorylated tau accumulate in the brain over time as part of the Alzheimer disease process; as the lesion burden increases, most people become cognitively impaired.

  • A subset of individuals are identified at autopsy as having a lesion burden that would be expected to have caused cognitive impairment during life yet they remain clinically unaffected; this dissociation between lesions and symptoms is termed resilience.

  • Biomarker studies are identifying a similar mismatch between lesions and cognition in some people, although more prospective longitudinal data will need to be collected to determine the clinical trajectory of such individuals.

  • Various mechanisms link the deposition of Aβ and tau to neuronal and synaptic loss, and it remains uncertain which of these is most associated with resilience; however, differences in lesion-associated immune response and properties of soluble tau aggregates are both likely to be contributors.

  • Understanding resilience could provide insights into key mechanisms of brain injury in Alzheimer disease and identify new therapeutic opportunities.

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Fig. 1: Putative role of tau and microglia in resilience.

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The authors contributed equally to all aspects of the Review.

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Correspondence to Teresa Gómez-Isla.

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T.G.-I. has participated as a speaker in an Eli Lilly-sponsored educational symposium and serves as member of an Eli Lilly Data Monitoring Committee (DMC). M.P.F. declares no competing interests.

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Nature Reviews Neurology thanks Timothy Hohman, who co-reviewed with Vaibhav Janve; David Knopman; Prashanthi Vemuri; and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Glossary

C5b-9 membrane attack complex

Terminal components of the complement cascade.

APP transgenic mice

Transgenic mice engineered to over-express disease-associated mutant forms of human amyloid precursor protein and develop elevated levels of amyloid-β in the brain.

Tau-P301S mice

Transgenic mice engineered to over-express disease-associated mutant forms of human tau and develop abnormally phosphorylated tau and tau aggregates.

5xfAD mice

Transgenic mice harbouring mutant forms of human APP, PSEN1 and MAPT.

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Gómez-Isla, T., Frosch, M.P. Lesions without symptoms: understanding resilience to Alzheimer disease neuropathological changes. Nat Rev Neurol 18, 323–332 (2022). https://doi.org/10.1038/s41582-022-00642-9

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