Cortical Amyloid Burden Differences Across Empirically-Derived Mild Cognitive Impairment Subtypes and Interaction with APOE ɛ4 Genotype

Abstract

We examined cortical amyloid-β (Aβ) levels and interactions with apolipoprotein (APOE) ɛ4 genotype status across empirically-derived mild cognitive impairment (MCI) subgroups and cognitively normal older adults. Participants were 583 ADNI participants (444 MCI, 139 normal controls [NC]) with baseline florbetapir positron emission tomography (PET) amyloid imaging and neuropsychological testing. Of those with ADNI-defined MCI, a previous cluster analysis [1] classified 51% (n = 227) of the current sample as amnestic MCI, 8% (n = 37) as dysexecutive/mixed MCI, and 41% (n = 180) as cluster-derived normal (cognitively normal). Results demonstrated that the dysexecutive/mixed and amnestic MCI groups showed significantly greater levels of amyloid relative to the cluster-derived normal and NC groups who did not differ from each other. Additionally, 78% of the dysexecutive/mixed, 63% of the amnestic MCI, 42% of the cluster-derived normal, and 34% of the NC group exceeded the amyloid positivity threshold. Finally, a group by APOE genotype interaction demonstrated that APOE ɛ4 carriers within the amnestic MCI, cluster-derived normal, and NC groups showed significantly greater amyloid accumulation compared to non-carriers of their respective group. Such an interaction was not revealed within the dysexecutive/mixed MCI group which was characterized by both greater cognitive impairment and amyloid accumulation compared to the other participant groups. Our results from the ADNI cohort show considerable heterogeneity in Aβ across all groups studied, even within a group of robust NC participants. Findings suggest that conventional criteria for MCI may be susceptible to false positive diagnostic errors, and that onset of Aβ accumulation may occur earlier in APOE ɛ4 carriers compared to non-carriers.

Keywords: APOE; Amyloid; PET; apolipoprotein E; biomarkers; florbetapir; mild cognitive impairment; neuroimaging; neuropsychology; positron emission tomography.

Fig. 1

Mean z-scores for the three MCI subgroups on neuropsychological measures included in the cluster analysis of conventional Petersen/Winblad ADNI criteria. Error bars denote standard error of the mean.

Fig. 2

Distribution of amyloid positivity for the three MCI subgroups and normal controls based on the recommended threshold for cross-sectional florbetapir analyses of 1.11 using the whole cerebellum as the reference region.

Fig. 3

Distribution of mean cortical amyloid standard uptake value ratios (SUVRs) for the three MCI subgroups and normal controls.

Fig. 4

Mean cortical and regional florbetapir standard uptake value ratios (SUVRs) for MCI and cognitively normal groups. Error bars denote standard error of the mean. Symbols denote significant (p < 0.008) pairwise comparisons: Amnestic MCI versus Cluster Derived Normal; ^{^}Amnestic MCI versus Normal Controls; ^ϕDysexecutive/Mixed MCI versus Cluster Derived Normal;^*Dysexecutive/Mixed MCI versus Normal Controls; ^#Amnestic MCI versus Dysexecutive/Mixed MCI; No significant Cluster Derived Normal versus Normal Controls findings were observed. All models were adjusted for age and APOE genotype (ε4 carrier versus noncarrier).

Fig. 5

Interaction of cognitive status (Amnestic MCI, Dysexecutive/Mixed MCI, Cluster-Derived Normal, Normal Control) and APOE genotype (ε4 carrier versus noncarrier) on regional florbetapir standard uptake value ratios (SUVRs). Error bars denote standard error of the mean. * p < 0.008