Subthreshold Amyloid Predicts Tau Deposition in Aging

Abstract

Current approaches to the early detection of Alzheimer's disease (AD) rely upon classifying individuals as "positive" or "negative" for biomarkers related to the core pathology of β-amyloid (Aβ). However, the accumulation of Aβ begins slowly, years before biomarkers become abnormal. We used longitudinal [¹¹C] Pittsburgh Compound B PET scanning and neuropsychological assessment to investigate the earliest changes in AD pathology and how it affects memory in cognitively normal older humans (N = 71; mean age 75 years; 35% male). We used [¹⁸F] AV-1451 PET scanning at the end of the observation period to measure subsequent tau deposition in a subset of our sample (N = 37). We found evidence for an inverted-U relationship between baseline Aβ levels and Aβ slope in asymptomatic older adults, suggesting a slowing of Aβ accumulation even in cognitively normal adults. In participants who were nominally amyloid negative, both the rate of amyloid accumulation and the baseline levels of Aβ predicted early tau deposition in cortical Braak regions associated with AD. Amyloid measures were only sensitive to memory decline as baseline levels of Aβ increased, suggesting that pathological accumulation occurs before impacting memory. These findings support the necessity of early intervention with amyloid-lowering therapies even in those who are amyloid negative.SIGNIFICANCE STATEMENT The progressive nature of Alzheimer's disease (AD) necessitates the earliest possible detection of pathological or cognitive change if disease progression is to be slowed. We examined cognitively normal older adults in whom AD pathology is starting to develop, with the goal of early detection of AD pathology or cognitive changes. We found amyloid measures to be sensitive early on in predicting subsequent early tau deposition. Further, it appears that rates of amyloid accumulation already begin to slow in preclinical AD, suggesting that it is a relatively late stage of AD progression. Thus, it is crucial to examine older adults early, before amyloid levels have saturated, to intervene to slow disease progression.

Keywords: PET; aging; amyloid; memory; preclinical; tau.

Figure 1.

Relative frequency (%) of participant's baseline PIB DVR. We predefined the number of clusters to two to determine a sensitive cutoff value between low and high baseline PIB levels, which was determined based on the point where the two clusters met but did not overlap. K-means clustering analyses yielded one cluster centered at the 1.54 baseline PIB DVR (N = 10), including participants with a >1.30 PIB DVR and another cluster centered at the 1.03 baseline PIB DVR (N = 61), including participants with a <1.30 PIB DVR. The 1.30 threshold was based on this approach; the threshold for PIB positivity was 1.07, as previously reported.

Figure 2.

Quadratic relationship between baseline PIB level and PIB slope. Participants had two (black), three (green), or four (pink) PIB PET scans. We performed linear and quadratic correlations to determine the best fit of the data.

Figure 3.

Relationship between PIB measures and AV-1451 uptake in Braak stages I–II, III–IV, and V–VI ROIs in PIB⁻ individuals. Participants (N = 27) were identified as PIB⁻ (blue) and PIB⁺ converters (purple) based on a standard threshold of 1.07 PIB DVR. A, Correlation between baseline PIB DVR and AV-1451 uptake in Braak stages I–II in PIB⁻ participants. B, Correlation between PIB DVR slope and AV-1451 uptake in Braak stages I–II in PIB⁻ participants. C, Correlation between baseline PIB DVR and AV-1451 uptake in Braak stages III–IV in PIB⁻ participants. D, Correlation between PIB DVR slope and AV-1451 uptake in Braak stages III–IV in PIB⁻ participants. E, Correlation between baseline PIB DVR and AV-1451 uptake in Braak stages V–VI in PIB⁻ participants. F, Correlation between PIB DVR slope and AV-1451 uptake in Braak stages V–VI in PIB⁻ participants.

Figure 4.

AV-1451 uptake in Braak stages I–II, III–IV, and V–VI regions. Participants were identified as PIB⁻ (blue), PIB⁺ converters (purple), and PIB⁺ based on a standard threshold of 1.07 PIB DVR. Dotted lines in each panel indicate the threshold for classification as meeting that Braak stage. A, AV-1451 SUVR uptake in Braak stages I–II regions, with most participants being classified as stages I–II (Braak stage I/II mean SUVR, >1.129). B, AV-1451 SUVR uptake in Braak stages III–IV regions, with five participants being classified as stages III–IV (Braak stage III/IV mean SUVR, >1.304). C, AV-1451 SUVR uptake in Braak stages V–VI regions, with no participants being classified as stage V–VI (Braak stage V/VI mean SUVR, >1.873).

Figure 5.

Relationship between PIB measures and change in episodic memory performance over time. Participants were identified as PIB⁻ (<1.07 PIB DVR at all time points; N = 38; blue), individuals who converted to PIB⁺ (PIB⁺ converter; N = 13; purple), and those who remained PIB⁺ (at all time points; N = 20; red). A, Correlation between baseline PIB DVR and ΔEpisodic Memory Composite in PIB⁻ participants (N = 51). B, Correlation between PIB DVR slope and ΔEpisodic Memory Composite in PIB⁻ participants. C, Correlation between baseline PIB DVR and ΔEpisodic Memory Composite in PIB participants with a <1.30 baseline value (N = 61). D, Correlation between PIB DVR slope and ΔEpisodic Memory Composite in PIB participants with a <1.30 baseline value. E, Correlation between baseline PIB DVR and ΔEpisodic Memory Composite in all participants (N = 71). F, Correlation between PIB DVR slope and ΔEpisodic Memory Composite in all participants.