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Abstract
Objective: Since Alzheimer disease (AD) neuropathology is thought to develop years before dementia, it may be possible to detect subtle AD-related atrophy in preclinical AD. Here we hypothesized that the “disease signature” of AD-related cortical thinning, previously identified in patients with mild AD dementia, would be useful as a biomarker to detect anatomic abnormalities consistent with AD in cognitively normal (CN) adults who develop AD dementia after longitudinal follow-up.
Methods: We studied 2 independent samples of adults who were CN when scanned. In sample 1, 8 individuals developing AD dementia (CN-AD converters) after an average of 11.1 years were compared to 25 individuals who remained CN (CN-stable). In sample 2, 7 CN-AD converters (average follow-up 7.1 years) were compared to 25 CN-stable individuals.
Results: AD-signature cortical thinning in CN-AD converters in both samples was remarkably similar, about 0.2 mm (p < 0.05). Despite this small absolute difference, Cohen d effect sizes for these differences were very large (>1). Of the 11 CN individuals with baseline low AD-signature thickness (≥1 SD below cohort mean), 55% developed AD dementia over nearly the next decade, while none of the 9 high AD-signature thickness individuals (≥1 SD above mean) developed dementia. This marker predicted time to diagnosis of dementia (hazard ratio = 3.4, p < 0.0005); 1 SD of thinning increased dementia risk by 3.4.
Conclusions: By focusing on cortical regions known to be affected in AD dementia, subtle but reliable atrophy is identifiable in asymptomatic individuals nearly a decade before dementia, making this measure a potentially important imaging biomarker of early neurodegeneration.
Footnotes
Study funding: Supported by the NIH (NIA R01-AG29411, R21-AG29840, P50-AG005134, P01-AG09466, P01-AG14449, P30-AG10161, R01-AG17917, and R01-AG10688, and NCRR P41-RR14075 and U24-RR021382), the Alzheimer's Association, the Mental Illness and Neuroscience Discovery (MIND) Institute, and the Illinois Department of Public Health.
Supplemental data at www.neurology.org
-
- AD=
- Alzheimer disease;
- CI=
- confidence interval;
- CN=
- cognitively normal;
- HR=
- hazard ratio;
- MCI=
- mild cognitive impairment;
- MGH=
- Massachusetts General Hospital;
- MMSE=
- Mini-Mental State Examination;
- MTL=
- medial temporal lobe;
- ROI=
- region of interest
- Received November 16, 2010.
- Accepted January 11, 2011.
- Copyright © 2011 by AAN Enterprises, Inc.
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