Longitudinal assessment of Aβ and cognition in aging and Alzheimer disease

Abstract

Objective: Assess Aβ deposition longitudinally and explore its relationship with cognition and disease progression.

Methods: Clinical follow-up was obtained 20 ± 3 months after [¹¹C]Pittsburgh compound B (PiB)-positron emission tomography in 206 subjects: 35 with dementia of the Alzheimer type (DAT), 65 with mild cognitive impairment (MCI), and 106 age-matched healthy controls (HCs). A second PiB scan was obtained at follow-up in 185 subjects and a third scan after 3 years in 57.

Results: At baseline, 97% of DAT, 69% of MCI, and 31% of HC subjects showed high PiB retention. At 20-month follow-up, small but significant increases in PiB standardized uptake value ratios were observed in the DAT and MCI groups, and in HCs with high PiB retention at baseline (5.7%, 2.1%, and 1.5%, respectively). Increases were associated with the number of apolipoprotein E ε4 alleles. There was a weak correlation between PiB increases and decline in cognition when all groups were combined. Progression to DAT occurred in 67% of MCI with high PiB versus 5% of those with low PiB, but 20% of the low PiB MCI subjects progressed to other dementias. Of the high PiB HCs, 16% developed MCI or DAT by 20 months and 25% by 3 years. One low PiB HC developed MCI.

Interpretation: Aβ deposition increases slowly from cognitive normality to moderate severity DAT. Extensive Aβ deposition precedes cognitive impairment, and is associated with ApoE genotype and a higher risk of cognitive decline in HCs and progression from MCI to DAT over 1 to 2 years. However, cognitive decline is only weakly related to change in Aβ burden, suggesting that downstream factors have a more direct effect on symptom progression.

FIGURE 1

Relationships between neocortical [¹¹C]Pittsburgh compound B (PiB) standardized uptake value ratio (SUVR) and age. Open and filled circles indicate participants with low and high PiB SUVRs, respectively. There was a significant correlation between neocortical PiB SUVR and age in the healthy control (HC) and mild cognitive impairment (MCI) groups, but not in the dementia of the Alzheimer type (DAT) group. n.s. = not significant.

FIGURE 2

Scatterplots showing individual baseline and follow-up neocortical standardized uptake value ratio (SUVR) values in the healthy control (HC), mild cognitive impairment (MCI), and dementia of the Alzheimer type (DAT) groups. Red full circles in the HC and MCI groups indicate subjects who were reclassified as probable DAT at follow-up. Purple full circles in the HC group indicate subjects who were reclassified as MCI at follow-up. Green, brown, and black full circles in the MCI group indicate subjects who were reclassified at follow-up as probable dementia with Lewy bodies, vascular dementia, or frontotemporal dementia, respectively. Dotted line indicates the SUVR threshold of 1.5 established to separate low [¹¹C]Pittsburgh compound B (PiB) from high PiB participants.

FIGURE 3

Box and whiskers plots showing the relation between the number of apolipoprotein E (ApoE) ε4 alleles and change in neocortical [¹¹C]Pittsburgh compound B (PiB) standardized uptake value ratio (SUVR) at 20-month follow-up. ApoE ε4 heterozygotes (HTZ) and homozygotes (HMZ) had a significant gene dose-dependant increase in neocortical PiB SUVR at follow-up when compared to noncarriers in the mild cognitive impairment group, but not in health controls and dementia of the Alzheimer type. †p < 0.05.