Author ORCID Identifier

https://orcid.org/0000-0001-5371-6908

Year of Publication

2021

Degree Name

Doctor of Philosophy (PhD)

Document Type

Doctoral Dissertation

College

Public Health

Department/School/Program

Epidemiology and Biostatistics

First Advisor

Dr. Erin L. Abner

Abstract

Most age-related neurodegenerative disorders are associated with the aggregation of misfolded and aberrant proteins. Alzheimer’s disease (AD) is one of the most common neurodegenerative disorders and is highly prevalent in older adults. Neuropathologically, AD is characterized by the accumulation of amyloid-β (Aβ) plaques and neurofibrillary tangles (NFTs). Other misfolded proteins, including α-synuclein and transactive response DNA-binding protein 43 (TDP-43), are also commonly observed in aged brains. Aberrant α-synuclein has been associated with Parkinson's disease, Dementia with Lewy bodies, and multiple system atrophy, whereas TDP-43 has been associated with multiple neurological diseases, the most common of which was designated as limbic-predominant, age-related TDP-43 encephalopathy (LATE). Each neurodegenerative disorder exhibits aggregation of specific proteins, but very commonly there is an aggregation of multiple proteinopathies.

The three studies in this dissertation are focused on the co-existence of multiple proteinopathies. The primary data were drawn from the University of Kentucky Alzheimer’s Disease research center (UK- ADRC), and additionally, for the second study, we used data drawn from the National Alzheimer’s Coordinating Center (NACC). While in the third study, the participants from UK-ADRC were linked to the Kentucky Cancer Registry to obtain data regarding their history of cancer, along with additional details such as cancer site, stage, and treatment received.

In the first study, “Prevalence and Clinical Phenotype of Quadruple Misfolded Proteins in Older Adults,” using brain autopsy data from 375 older adults, quadruple misfolded proteins (tau, amyloid-β, α-synuclein, and transactive response DNA-binding protein 43) were commonly detected. Mild cognitive impairment transitioned to dementia most rapidly for those with all four proteinopathies, which were present in 19% of individuals with dementia. Overall, 12% of cases had QMP, while 38% had three proteinopathies. Dementia frequency was highest among those with QMP (89%), and participants with QMP had the lowest final mean MMSE (Mean=13.4, SD=9.8). Adjusting for age and sex, ≥1 apolipoprotein ε4 (APOE ε4) allele was associated with higher odds of QMP (OR=2.55; 95% CI, 1.16, 5.62, P= 0.02). The QMP group had both the lowest probability of having normal MMSE, even 12 years before death and the highest probability of having severe impairment on the MMSE. In the second study, “Four common late-life cognitive trajectories patterns associate with replicable underlying neuropathologies,” using group-based multi-trajectory models we found evidence that there are distinct, common trajectories that define the end of life cognition. The four distinct subgroups were determined by the shape of the trajectories using scores from the Mini-Mental State Examination, Logical Memory, and Animal Naming tests obtained in the last ten years of life; trajectories were labeled as No decline, Mild decline, Moderate decline, and Accelerated decline. The Accelerated and the Moderate decline groups were associated with lower age at death, lower educational attainment, higher Braak NFT stage, and more frequent hippocampal sclerosis and TDP-43 proteinopathy. Further, we validated the models using the NACC data. In the third study, “Cancer history associates with a lower burden of dementia and Alzheimer’s-type neuropathology in autopsied research volunteers.” History of cancer was reported in 190 (24.2%) participants. The prevalence of ≥1 APOE ε4 allele was lower among the participants with cancer history compared to cancer-free participants (32.6% vs 42.0%). Participants with cancer history had significantly lower odds of MCI/dementia at the last UK-ADRC visit (OR = 0.45; 95% CI, 0.31, 0.64; P < 0.0001), and had a reduced burden of AD neuropathological changes in the brain. Additionally, the change in cognitive test scores from baseline to the last available assessment showed relatively less decline in the participants with a cancer history. The examination of AD-associated genes showed that history of cancer was inversely associated with ≥1 APOE ε4 allele and higher odds of T allele of SNP rs11136000 located in the CLU gene on chromosome 8.

Digital Object Identifier (DOI)

https://doi.org/10.13023/etd.2021.055

Funding Information

This study was funded by the National Institute of Aging grant Nos: P30 AG028383 and R01 AG038651 from 2019-2021.

Available for download on Saturday, April 30, 2022

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