Asymptomatic Alzheimer disease: Defining resilience

Neurology. 2016 Dec 6;87(23):2443-2450. doi: 10.1212/WNL.0000000000003397. Epub 2016 Nov 4.


Objective: To define robust resilience metrics by leveraging CSF biomarkers of Alzheimer disease (AD) pathology within a latent variable framework and to demonstrate the ability of such metrics to predict slower rates of cognitive decline and protection against diagnostic conversion.

Methods: Participants with normal cognition (n = 297) and mild cognitive impairment (n = 432) were drawn from the Alzheimer's Disease Neuroimaging Initiative. Resilience metrics were defined at baseline by examining the residuals when regressing brain aging outcomes (hippocampal volume and cognition) on CSF biomarkers. A positive residual reflected better outcomes than expected for a given level of pathology (high resilience). Residuals were integrated into a latent variable model of resilience and validated by testing their ability to independently predict diagnostic conversion, cognitive decline, and the rate of ventricular dilation.

Results: Latent variables of resilience predicted a decreased risk of conversion (hazard ratio < 0.54, p < 0.0001), slower cognitive decline (β > 0.02, p < 0.001), and slower rates of ventricular dilation (β < -4.7, p < 2 × 10-15). These results were significant even when analyses were restricted to clinically normal individuals. Furthermore, resilience metrics interacted with biomarker status such that biomarker-positive individuals with low resilience showed the greatest risk of subsequent decline.

Conclusions: Robust phenotypes of resilience calculated by leveraging AD biomarkers and baseline brain aging outcomes provide insight into which individuals are at greatest risk of short-term decline. Such comprehensive definitions of resilience are needed to further our understanding of the mechanisms that protect individuals from the clinical manifestation of AD dementia, especially among biomarker-positive individuals.

MeSH terms

  • Aged
  • Alzheimer Disease / cerebrospinal fluid*
  • Alzheimer Disease / diagnostic imaging*
  • Alzheimer Disease / genetics
  • Alzheimer Disease / psychology
  • Apolipoprotein E4 / genetics
  • Biomarkers / cerebrospinal fluid
  • Cognitive Aging / physiology
  • Cognitive Dysfunction / cerebrospinal fluid*
  • Cognitive Dysfunction / diagnostic imaging*
  • Cognitive Dysfunction / genetics
  • Cognitive Dysfunction / psychology
  • Databases, Factual
  • Disease Progression
  • Disease Resistance / genetics
  • Disease Resistance / physiology*
  • Female
  • Hippocampus / diagnostic imaging
  • Humans
  • Least-Squares Analysis
  • Male
  • Memory / physiology
  • Neuroprotection / genetics
  • Neuroprotection / physiology
  • Neuropsychological Tests
  • Organ Size
  • Prognosis


  • Apolipoprotein E4
  • Biomarkers