Asymptomatic Alzheimer disease: Defining resilience.
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.
From the Vanderbilt Memory & Alzheimer's Center (T.J.H., K.A.G., A.L.J.), Vanderbilt University Medical Center, Nashville, TN; Biospective Inc (D.G.M.), Montreal, Quebec, Canada; Department of Neurology (E.C.M.), Massachusetts General Hospital, Harvard Medical School, Boston; and Department of Geriatric and Gerontology (D.J.L.), New Jersey Institute for Successful Aging and Department of Psychology, Rowan University School of Osteopathic Medicine, Stratford. Timothy.J.Hohman@Vanderbilt.edu.
Timothy J
TJ
Hohman
From the Vanderbilt Memory & Alzheimer's Center (T.J.H., K.A.G., A.L.J.), Vanderbilt University Medical Center, Nashville, TN; Biospective Inc (D.G.M.), Montreal, Quebec, Canada; Department of Neurology (E.C.M.), Massachusetts General Hospital, Harvard Medical School, Boston; and Department of Geriatric and Gerontology (D.J.L.), New Jersey Institute for Successful Aging and Department of Psychology, Rowan University School of Osteopathic Medicine, Stratford.
Donald G
DG
McLaren
From the Vanderbilt Memory & Alzheimer's Center (T.J.H., K.A.G., A.L.J.), Vanderbilt University Medical Center, Nashville, TN; Biospective Inc (D.G.M.), Montreal, Quebec, Canada; Department of Neurology (E.C.M.), Massachusetts General Hospital, Harvard Medical School, Boston; and Department of Geriatric and Gerontology (D.J.L.), New Jersey Institute for Successful Aging and Department of Psychology, Rowan University School of Osteopathic Medicine, Stratford.
Elizabeth C
EC
Mormino
From the Vanderbilt Memory & Alzheimer's Center (T.J.H., K.A.G., A.L.J.), Vanderbilt University Medical Center, Nashville, TN; Biospective Inc (D.G.M.), Montreal, Quebec, Canada; Department of Neurology (E.C.M.), Massachusetts General Hospital, Harvard Medical School, Boston; and Department of Geriatric and Gerontology (D.J.L.), New Jersey Institute for Successful Aging and Department of Psychology, Rowan University School of Osteopathic Medicine, Stratford.
Katherine A
KA
Gifford
From the Vanderbilt Memory & Alzheimer's Center (T.J.H., K.A.G., A.L.J.), Vanderbilt University Medical Center, Nashville, TN; Biospective Inc (D.G.M.), Montreal, Quebec, Canada; Department of Neurology (E.C.M.), Massachusetts General Hospital, Harvard Medical School, Boston; and Department of Geriatric and Gerontology (D.J.L.), New Jersey Institute for Successful Aging and Department of Psychology, Rowan University School of Osteopathic Medicine, Stratford.
David J
DJ
Libon
From the Vanderbilt Memory & Alzheimer's Center (T.J.H., K.A.G., A.L.J.), Vanderbilt University Medical Center, Nashville, TN; Biospective Inc (D.G.M.), Montreal, Quebec, Canada; Department of Neurology (E.C.M.), Massachusetts General Hospital, Harvard Medical School, Boston; and Department of Geriatric and Gerontology (D.J.L.), New Jersey Institute for Successful Aging and Department of Psychology, Rowan University School of Osteopathic Medicine, Stratford.
Angela L
AL
Jefferson
D000368:Aged; D000544:Alzheimer Disease / Q000134:cerebrospinal fluid* / Q000000981:diagnostic imaging* / Q000235:genetics / Q000523:psychology; D053327:Apolipoprotein E4 / Q000235:genetics; D015415:Biomarkers / Q000134:cerebrospinal fluid; D000066492:Cognitive Aging / Q000502:physiology; D060825:Cognitive Dysfunction / Q000134:cerebrospinal fluid* / Q000000981:diagnostic imaging* / Q000235:genetics / Q000523:psychology; D016208:Databases, Factual; D018450:Disease Progression; D060467:Disease Resistance / Q000235:genetics / Q000502:physiology*; D005260:Female; D006624:Hippocampus / Q000000981:diagnostic imaging; D006801:Humans; D016018:Least-Squares Analysis; D008297:Male; D008568:Memory / Q000502:physiology; D000066829:Neuroprotection / Q000235:genetics / Q000502:physiology; D009483:Neuropsychological Tests; D009929:Organ Size; D011379:Prognosis
D053327:Apolipoprotein E4; D015415:Biomarkers