Regional amyloid accumulation and cognitive decline in initially amyloid-negative adults

Abstract

Objective: To assess whether global or regional changes in amyloid burden over 4 years predict early declines in episodic memory in initially amyloid-negative adults.

Methods: One hundred twenty-six initially amyloid-negative, cognitively normal participants (age 30-89 years) were included from the Dallas Lifespan Brain Study who completed florbetapir PET and a cognitive battery at baseline and 4-year follow-up. Standardized uptake value ratio (SUVR) change was computed across 8 bilateral regions of interest. Using general linear models, we examined the relationship between change in global and regional SUVR and change in episodic memory, controlling for baseline SUVR, baseline memory, age, sex, education, and APOE status.

Results: In initially amyloid-negative adults, we detected a regionally specific relationship between declining episodic memory and increasing amyloid accumulation across multiple posterior cortical regions. In addition, these amyloid-related changes in memory persisted when we focused on middle-aged adults only and after controlling for atrophy in global cortical, hippocampal, and Alzheimer disease signature cortical volume.

Conclusion: Our results indicate that assessing regional changes in amyloid, particularly in posterior cortical regions, can aid in the early detection of subclinical amyloid-related decline in episodic memory as early as middle age. Future research incorporating tau and other markers of neurodegeneration is needed to clarify the sequence of events that lead to this early, subclinical memory decline.

Figure 1. Individual trajectories of SUVR change across ROIs

Lines represent each individual’s raw change in standardized uptake value ratio (SUVR) for (A) global SUVR and (B–I) each of the 8 regions of interest (ROIs), color-coded by the magnitude of change. Large increases are shown in warmer (red) colors; no change is shown in yellow; and decreases are shown in cooler (green) colors. The dashed line on each figure represents the positivity threshold, set at an SUVR of 0.76 based on global SUVR. ACC = anterior cingulate cortex; LPFC = lateral prefrontal cortex; OFC = orbitofrontal cortex; PCC = posterior cingulate cortex.

Figure 2. Increasing regional amyloid accumulation in posterior cortical ROIs predicts declining episodic memory over 4 years

The correlations between standardized uptake value ratio (SUVR) change in each of the 3 posterior cortical regions of interest (ROI) (posterior cingulate [PCC], precuneus, lateral parietal cortices) and change in episodic memory are shown (A.a–A.c) for all initially amyloid-negative adults 30 to 89 years of age and (B.a–B.c) within the middle-aged subsample 30 to 59 years of age. Episodic memory change is measured as a residual after controlling for baseline memory and SUVR, as well as age, sex, and APOE. APOE status is coded by shape for descriptive purposes, with ε4 carriers as triangles and noncarriers as circles.

Figure 3. Minimal association between increasing amyloid accumulation and structural atrophy

(A.a–A.c) In initially amyloid-negative adults 30 to 89 years of age, increasing global standardized uptake value ratio (SUVR) change is marginally related to (A.a) declining hippocampal volume and (A.b) global cortical volume but not (A.c) Alzheimer disease (AD) signature volume. (B.a–B.c) In the middle-aged subsample 30 to 59 years of age, increasing global SUVR was significantly related to (B.a) declining hippocampal volume but not (B.b) global cortical volume or (B.c) AD signature volume. Structural data are standardized residuals after controlling for baseline SUVR and the baseline measure of neurodegeneration, as well as age, sex, and APOE. APOE status is coded by shape for descriptive purposes, with ε4 carriers as triangles and noncarriers as circles.