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Original Investigation
June 13, 2017

Association Between Elevated Brain Amyloid and Subsequent Cognitive Decline Among Cognitively Normal Persons

Author Affiliations
  • 1Alzheimer's Therapeutic Research Institute, Department of Neurology, University of Southern California, San Diego
  • 2Center for Alzheimer Research and Treatment, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts
  • 3Department of Neurology, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts
  • 4Massachusetts General Hospital, Boston
  • 5Department of Neurology, Mayo Clinic, Rochester, Minnesota
  • 6Center for Imaging of Neurodegenerative Diseases, University of California-San Francisco
  • 7San Francisco VA Medical Center, San Francisco, California
JAMA. 2017;317(22):2305-2316. doi:10.1001/jama.2017.6669
Key Points

Question  Is there an association between elevated brain amyloid and cognitive changes among cognitively normal individuals?

Findings  In this prospective cohort study of 445 cognitively normal individuals, baseline elevated brain amyloid was significantly associated with worse cognitive measures after a median of 3.1 years (eg, 1.59 points worse on the Preclinical Alzheimer Cognitive Composite and 0.56 points worse on the Mini-Mental State Examination after 4 years).

Meaning  Elevated baseline brain amyloid was associated with higher likelihood of cognitive decline among cognitively normal individuals, although further research is needed to assess the clinical importance of these differences and longer-term associations.

Abstract

Importance  Among cognitively normal individuals, elevated brain amyloid (defined by cerebrospinal fluid assays or positron emission tomography regional summaries) can be related to risk for later Alzheimer-related cognitive decline.

Objective  To characterize and quantify the risk for Alzheimer-related cognitive decline among cognitively normal individuals with elevated brain amyloid.

Design, Setting, and Participants  Exploratory analyses were conducted with longitudinal cognitive and biomarker data from 445 cognitively normal individuals in the United States and Canada. Participants were observed from August 23, 2005, to June 7, 2016, for a median of 3.1 years (interquartile range, 2.0-4.2 years; maximum follow-up, 10.3 years) as part of the Alzheimer’s Disease Neuroimaging Initiative (ADNI).

Exposures  Individuals were classified at baseline as having normal (n = 243) or elevated (n = 202) brain amyloid using positron emission tomography amyloid imaging or a cerebrospinal fluid assay of amyloid β.

Main Outcomes and Measures  Outcomes included scores on the Preclinical Alzheimer Cognitive Composite (PACC; a sum of 4 baseline standardized z scores, which decreases with worse performance), Mini-Mental State Examination (MMSE; 0 [worst] to 30 [best] points), Clinical Dementia Rating Sum of Boxes (CDR–Sum of Boxes; 0 [best] to 18 [worst] points), and Logical Memory Delayed Recall (0 [worst] to 25 [best] story units).

Results  Among the 445 participants (243 with normal amyloid, 202 with elevated amyloid), mean (SD) age was 74.0 (5.9) years, mean education was 16.4 (2.7) years, and 52% were women. The mean score for PACC at baseline was 0.00 (2.60); for MMSE, 29.0 (1.2); for CDR–Sum of Boxes, 0.04 (0.14); and for Logical Memory Delayed Recall, 13.1 (3.3). Compared with the group with normal amyloid, those with elevated amyloid had worse mean scores at 4 years on the PACC (mean difference, 1.51 points [95% CI, 0.94-2.10]; P < .001), MMSE (mean difference, 0.56 points [95% CI, 0.32-0.80]; P < .001), and CDR–Sum of Boxes (mean difference, 0.23 points [95% CI, 0.08-0.38]; P = .002). For Logical Memory Delayed Recall, between-group score was not statistically significant at 4 years (mean difference, 0.73 story units [95% CI, −0.02 to 1.48]; P = .056).

Conclusions and Relevance  Exploratory analyses of a cognitively normal cohort followed up for a median of 3.1 years suggest that elevation in baseline brain amyloid level, compared with normal brain amyloid level, was associated with higher likelihood of cognitive decline, although the findings are of uncertain clinical significance. Further research is needed to assess the clinical importance of these differences and measure longer-term associations.

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