Memory decline accompanies subthreshold amyloid accumulation

Abstract

Objective: Extensive cortical β-amyloid (Aβ positivity) has been linked to cognitive decline, but the clinical significance of elevations in Aβ within the negative range is unknown.

Methods: We examined amyloid and cognitive trajectories (memory, executive function) in 142 cognitively normal older individuals enrolled in the Alzheimer's Disease Neuroimaging Initiative who were Aβ-negative at baseline and who had at least 2 [¹⁸F]-florbetapir PET scans over 3.9 ± 1.4 years. We determined whether Aβ accumulation was associated with longitudinal changes in memory or executive function.

Results: Among baseline-negative individuals, florbetapir slope (mean annual increase 0.002 ± 0.008 standardized uptake value ratio units/y) was not related to age, sex, education, APOE4 status, baseline memory or executive function, temporoparietal glucose metabolism, baseline hippocampal volume, or hippocampal volume change; but it was related to higher baseline cortical florbetapir, indicating that Aβ accumulation was ongoing at baseline in those who accumulated during the study. Over the course of follow-up, 13 individuals converted to florbetapir+ and 14 nearly nonoverlapping individuals converted to mild cognitive impairment or Alzheimer disease. Amyloid accumulation among baseline-negative individuals was associated with poorer longitudinal memory performance (p = 0.019), but it was not associated with changes in executive function. Reducing the sample to individuals with at least 3 timepoints to estimate the florbetapir slope strengthened the relationship further between florbetapir accumulation and memory decline (p = 0.007).

Conclusions: Memory decline accompanies Aβ accumulation in otherwise healthy, Aβ-negative older adults. Amyloid increases within the negative range may represent the earliest detectable indication of pathology with domain-specific cognitive consequences.

Figure 1. Florbetapir change in cognitively normal individuals

(A) Longitudinal florbetapir trajectories for baseline-negative or baseline-positive cognitively normal individuals who had florbetapir scans at approximately 2-year time intervals. For visual clarity, only individuals with >2 florbetapir scans (65% of normal controls) are shown. Note the y-axis between the upper and lower panels. The dotted line indicates the baseline composite reference threshold of 0.79, which is approximately equivalent to a whole-cerebellum-based threshold of 1.11 (see Methods). (B) Mean and SD of annual florbetapir standardized uptakevalueratio (SUVR) slopes are shown for baseline florbetapir-negative (nonaccumulators, n = 66; accumulators, n = 94) and florbetapir-positive individuals (nonaccumulators, n = 4 [not shown]; accumulators, n = 49).

Figure 2. Conversions to mild cognitive impairment (MCI), Alzheimer disease (AD), or florbetapir-positive status

Of 142 cognitively normal individuals who were florbetapir-negative at baseline and followed for 3.9 ± 1.4 years, 116 (about 82%) remained florbetapir-negative and normal. Thirteen converted to florbetapir+ and 14 converted to a non-normal diagnosis (MCI or AD). Only 1 individual who converted to florbetapir+ was also part of the group that converted to MCI.

Figure 3. Florbetapir accumulation is associated with decline in memory but not executive function

Among baseline-negative cognitively normal individuals (n = 142), florbetapir slope was associated with decline on memory composite scores (A) (p = 0.019; table 2) but not on executive function composite scores (B). Scatterplots and dotted best-fit regression lines represent an approximation of the effects of interest from the linear mixed effects model results shown in table 2. Markers represent the diagnosis and florbetapir status at the end of the follow-up period (figure 2). Aβ = β-amyloid; AD = Alzheimer disease; MCI = mild cognitive impairment.