Graduation Year

2023

Document Type

Dissertation

Degree

Ph.D.

Degree Name

Doctor of Philosophy (Ph.D.)

Degree Granting Department

School of Aging Studies

Major Professor

Ross Andel, Ph.D.

Co-Major Professor

Brent J. Small, Ph.D.

Committee Member

Victor A. Molinari, Ph.D.

Committee Member

Jason L. Salemi, Ph.D., M.P.H.

Committee Member

Jakub Hort, M.D., Ph.D.

Keywords

Alzheimer’s disease, cognitive reserve, latent profile analysis, magnetic resonance imaging, resistance and resilience framework, survival analysis

Abstract

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that has extensive biological heterogeneity. It is not clear the extent to which this heterogeneity may be detected in participants without dementia, how it relates to incident AD dementia, and whether contextual factors may change how neuropathology relates to incident AD dementia. Therefore, this dissertation was completed using data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI; n = 1,703) and the Czech Brain Aging Study (CBAS; n = 385) to address the following aims: to assess biological heterogeneity in participants without dementia, to relate this heterogeneity to incident AD dementia, and to determine whether contextual factors modify the association between neuropathology profiles and incident AD dementia.

First, we identified latent subgroups of neuropathology analyzed using latent profile analysis and measured via structural magnetic resonance imaging and described differences between profiles in sociodemographic characteristics, cognition, and contextual factors. Four profiles emerged in ADNI, and two profiles emerged in CBAS with significant differences in nearly all volumetric regions. Differences emerged in magnitude rather than pattern of atrophy. Participants belonging to profiles with less severe atrophy were younger, more likely to have normal objective cognition, and less likely to progress to AD dementia compared to participants belonging to profiles with more severe atrophy.

Next, we related the neuropathology profiles and contextual factors to incident AD dementia and assessed whether contextual factors modified the association between neuropathology profiles and incident AD dementia using survival analysis. Participants belonging to profiles with greater atrophy had a higher risk of incident AD dementia compared to participants belonging to profiles with less severe atrophy, contextual factors were related to a reduced risk of incident AD dementia, and contextual factors modified the association between neuropathology profiles and incident AD dementia on the multiplicative (CBAS) and additive (ADNI and CBAS) scales.

Contrary to past work, we identified biological heterogeneity based on magnitude instead of the distribution of atrophy in different brain regions. Evidence for resilience, or an attenuating effect of contextual factors on the atrophy-incident AD dementia relationship, was found on the multiplicative (CBAS) and additive (ADNI and CBAS) scales. Results suggest that although more severe atrophy relates to incident AD dementia risk, contextual factors can reduce this association. Future research should aim to uncover the mechanisms underlying the moderating role of contextual factors on the atrophy-incident AD dementia association.

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