Association of Longitudinal Cognitive Decline With Amyloid Burden in Middle-aged and Older Adults

Abstract

IMPORTANCE Presently, the clinical standard for reporting the results of an amyloid positron emission tomography scan is to assign a dichotomous rating of positive or negative for the presence of amyloid. In a 4-year longitudinal study, we investigated whether using a continuous measure of the magnitude of baseline amyloid burden would provide valuable information about the rate of future cognitive decline over the subsequent 4 years compared with a dichotomous measure in middle-aged and older adults.OBJECTIVE To examine whether a continuous, dose-response relationship between amyloid burden and cognitive decline was present among middle-aged and older adults. DESIGN, SETTING, AND PARTICIPANTSThis cohort study included 174 participants from the Dallas Lifespan Brain Study who were 40 to 89 years old at the beginning of the study, were cognitively normal at baseline (a Mini-Mental State Examination score of 26 or higher) with no history of neurological or psychiatric disorders, and had completed amyloid imaging ([ 18 F]-florbetapir) at baseline and cognitive assessments at baseline and a 4-year follow-up. Continuous amyloid burden was measured as the mean cortical standardized uptake value ratio (SUVR) at baseline. MAIN OUTCOMES AND MEASURESLinear mixed models assessed the effect of increasing baseline amyloid over time (SUVR × time interaction) on episodic memory, reasoning, processing speed, vocabulary, and Mini-Mental State Examination performance. Age, sex, education, apolipoprotein ε4, and the random effect of intercepts were included as covariates. RESULTSThe mean (SD) age for all participants (n = 174) was 66.44 (11.74) years, and 65 participants (37%) were men. The primary analyses yielded significant SUVR × time interactions in episodic memory, processing speed, vocabulary, and Mini-Mental State Examination performance, but not in reasoning performance. Higher baseline SUVR projected greater cognitive decline over 4 years. When controlling for variance related to a dichotomized positive/negative classification, most effects on cognition remained. Dichotomized amyloid status alone yielded fewer significant effects of amyloid on cognitive decline than continuous SUVR. Among amyloid-positive participants, increasing baseline SUVR predicted an increasing decline in episodic memory, but other effects on cognition were more limited. Finally, higher baseline amyloid burden among middle-aged adults was related to changes in vocabulary, with the effect driven by 3 apolipoprotein ε4 homozygotes.CONCLUSIONS AND RELEVANCE These results suggest that the magnitude of amyloid burden at baseline is associated with the rate of cognitive decline over 4 years and potentially provides important information about the rate of future cognitive decline that is not available from a dichotomous positive/negative categorization.

Simultaneously evaluating the effect of baseline levels and longitudinal changes in disease biomarkers on cognition in dominantly inherited Alzheimer's disease

“…Consistent with previous reports [4–6], we found that higher cerebral amyloid deposition at baseline predicted longitudinal cognitive decline; however, the individual rate of change in amyloid did not. Xiong et al.…”

“…Future research should also directly analyze a sporadic AD cohort and include subgroup analyses for age and ethnic groups to evaluate whether or not our findings replicate. Second, our cognitive composite score is composed of tests that are different from those used in previous studies [4–9]; therefore, caution is needed to interpret the discrepancies in various findings, which may be due to the relative sensitivity of various cognitive tests. Third, there are challenges to interpret the findings when using z‐scores—primarily, the loss of meaningfulness of the raw score and its standard deviation, magnifying small changes, not reflecting the reality of memory declines [36].…”

The impact of amyloid‐beta and tau on prospective cognitive decline in older individuals

“…8,9,12 Thus, we may be underpowered to detect change with the smaller sample size with both Aβ and tau imaging using this EF composite. 8,9,12 Thus, we may be underpowered to detect change with the smaller sample size with both Aβ and tau imaging using this EF composite.…”

Predicting sporadic Alzheimer's disease progression via inherited Alzheimer's disease‐informed machine‐learning

“…Biomarker‐based point prediction of cognitive decline is, thus, a challenge to sufficiently power clinical trials via risk enrichment and to identify subjects at imminent risk of cognitive deterioration. Previous studies have shown that higher amyloid‐PET, 11,12 MRI‐assessed hippocampal atrophy, 13 FDG‐PET hypometabolism, 12 and tau levels 14,15 are associated with faster cognitive decline. Because biomarker combinations can enhance the accuracy for predicting clinical progression, 16 a critical yet unresolved question is how to merge multimodal and increasingly complex (eg, voxel‐wise PET and MRI) data to maximize the prediction accuracy while keeping the number of assessments and costs low.…”