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

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.

Figure 1. Mean Cognitive Profiles

Linearmixed-effectsmodelswerecontrolledforageandotherbaselinecovariatesand are conditional on covariates as follows: mean age (74 years), mean education (16.4 years), men, and APOEε4=0.5 (range, 0–1 APOEε4 alleles) (Supplement). Likelihood ratio tests comparing models (elevated amyloid group vs normal) were used for χ² statistics and P values. Shaded regions indicate 95% CIs. Dot sizes are proportional to the number of observations. Continuous time models include a quadratic term. ^aSelected covariates were sex, ventricular volume, family history, and education (sum of 4 baseline standardized Z scores that decrease with worse performance). ^bSelected covariates were sex and education (score range, 0 [worst] to 30 [best]). ^cNo additional covariates were selected (score range, 0 [best] to 18 [worst]). ^dSelected covariates were APOEε4, sex, ventricular volume, and education (score range, 0 [worst] to 25 [best] story units).

Figure 2. Progression Event Rates

See Figure 1 for explanation of statistical components. ^aSelected covariates were education, Preclinical Alzheimer Cognitive Composite (PACC), and ventricular volume. Model includes a quadratic effect. ^bSelected covariates were PACC and ventricular volume. ^cThe selected covariate was PACC. ^dThe selected covariate was education.

Figure 3. Mean Profiles of Markers of Amyloid (Cerebrospinal Fluid Aβ and Florbetapir PET) and Glucose Metabolism (FDG-PET)

Profiles are from linear mixed-effects models controlling for age and other baseline covariates selected by Akaike Information Criterion. Profiles are conditional on covariates as follows: mean age (74 years) and ventricular volume (2.2% ICV), men, APOEε4=0.5 (APOEε4=0 indicates 0 alleles; APOEε4=1 indicates ≥1 allele). Shaded regions indicate 95% CIs. Dot sizes are proportional to the number of observations. Abbreviations: FDG, fluorodeoxyglucose; PET, positron emission tomography. ^aSelected covariates were APOEε4 and ventricular volume. ^bSelected covariates were APOEε4 and sex, and this model did not include longitudinal Pittsburgh Compound B observations. ^cSelected covariates were APOEε4 and sex.

Figure 4. Mean Profiles of Neurodegeneration Markers

Profiles are from linear mixed-effects models controlling for age and other baseline covariates selected by Akaike Information Criterion. P values are from likelihood ratio tests comparing models (elevated amyloid group vs normal). Shaded regions indicate 95% CIs. Dot sizes are proportional to the number of observations. ^aSelected covariates were APOEε4 and ventricular volume. ^bSelected covariates were APOEε4, education, and ventricular volume. ^cSelected covariates were APOEε4, sex, and education. ^dSelected covariates were sex and education.