Cortical Amyloid Burden Differences Across Empirically-Derived Mild Cognitive Impairment Subtypes and Interaction
Katherine J Bangen1,2, Alexandra L Clark1,3, Madeline Werhane3
1Veterans Affairs San Diego Healthcare System, San Diego, CA, USA.
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.
Insights
Mild cognitive impairment (MCI) subgroups show varied amyloid-beta (Aβ) levels. APOE ɛ4 carriers accumulate Aβ earlier, highlighting diagnostic heterogeneity and potential for earlier intervention in Alzheimer's disease research.
Area of Science:
- Neuroscience
- Alzheimer's Disease Research
- Biomarkers
Background:
- Cortical amyloid-beta (Aβ) accumulation is a hallmark of Alzheimer's disease (AD).
- Mild cognitive impairment (MCI) represents a transitional stage with heterogeneous presentations.
- The role of apolipoprotein E (APOE) ɛ4 genotype in Aβ deposition across MCI subtypes is not fully elucidated.
Purpose of the Study:
- To investigate cortical Aβ levels and their interaction with APOE ɛ4 genotype across distinct MCI subgroups and cognitively normal (NC) older adults.
- To assess Aβ deposition heterogeneity within empirically-derived MCI classifications.
- To explore potential diagnostic implications of Aβ accumulation patterns.
Main Methods:
- Analysis of 583 participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort, including 444 MCI and 139 NC individuals.
- Baseline florbetapir positron emission tomography (PET) for amyloid imaging and comprehensive neuropsychological testing.
- Classification of MCI into amnestic MCI, dysexecutive/mixed MCI, and cluster-derived normal groups based on prior cluster analysis.
Main Results:
- Dysexecutive/mixed and amnestic MCI groups exhibited significantly higher cortical Aβ levels than cluster-derived normal and NC groups.
- Amyloid positivity thresholds were exceeded by a substantial proportion of MCI subgroups (78% dysexecutive/mixed, 63% amnestic MCI).
- APOE ɛ4 carriers showed increased Aβ accumulation in amnestic MCI, cluster-derived normal, and NC groups, but not in the dysexecutive/mixed MCI group.
Conclusions:
- Significant heterogeneity in Aβ deposition exists across all studied groups, including cognitively normal individuals.
- Conventional MCI diagnostic criteria may lead to false positive errors due to underlying Aβ variability.
- Earlier onset of Aβ accumulation in APOE ɛ4 carriers suggests potential for earlier detection and intervention strategies in AD.
