Alzheimer's disease impacts many older adults within the United States and African Americans are at a higher risk for developing Alzheimer's disease. Most of their care is provided by their adult daughters, who are often tasked with managing multiple care responsibilities within their families. Prior research has examined one aspect of the caregiving experience for African American caregivers but not how their intersecting identities impact their experiences. As such, this study served to contextualize and highlight the nuances of their caregiving experiences. Using Intersectionality Theory as a guiding theoretical framework, this qualitative study explored how African American adult daughter caregivers navigated their family relationships while caring for a parent with Alzheimer's disease. Semi-structured interviews were conducted with twenty-six African American adult daughters caring for a parent with Alzheimer's disease. Findings revealed that 1) families came together by collaborating on decisions, connecting as a family and speaking regularly, and directly assisting and helping the caregiver, 2) family ideology about African American women and care influenced what the family expected of caregivers and what caregivers expected of themselves, and 3) caregivers are under compounding amounts of stress related to general caregiving strain, time, and racism/discrimination. These findings provide a more contextualized and holistic depiction of African American caregivers and their families. Future research and practical implications are discussed. / Doctor of Philosophy / There are high rates of Alzheimer's disease among older adults within the United States and African Americans are more likely to develop Alzheimer's disease. Alzheimer's disease impacts the individual, their main caregivers, and their families. Adult daughters provide most of the care to individuals with Alzheimer's disease while also having other responsibilities within their families. The goal of this study was to get a better understanding of changes in caregivers' family relationships as they care for their parents with Alzheimer's disease. I interviewed 26 African American adult daughter caregivers. The caregivers shared important information about changes in their family relationships and explained how they had been impacted by caregiving. Findings revealed that African American families came together to support the caregiver, families have unspoken rules about how care should be provided, and caregivers experience high amounts of stress because of caregiving. The results can help clinicians, medical professionals, and policymakers be better able to support African American families of individuals with Alzheimer's disease. Future research studies and best practices for clinicians are discussed.

Layer II neurons of the entorhinal cortex (ECII) are selectively vulnerable to Alzheimer’s disease (AD). Investigations into the molecular mechanisms of this ECII vulnerability provide unique opportunities to better understanding the pathology of AD. Preliminary data has suggested teneurin-3 (Tenm3) to have a role in this vulnerability due to its ECII enrichment, genetic variants associated with AD, and altered electrophysiology in Tenm3-knockout (KO) mice. In this study, the impacts of Tenm3- KO in mice were further explored. Electron tomography and immunofluorescent confocal microscopy were utilized to compare wild-type (WT) and KO mice’s perforant pathway synaptic densities and structures. A slight trend was found for increased synaptic density in Tenm3-KO mice. The structural changes in Tenm3-KO mice were more pronounced and encompassed alterations to active zones, bouton volumes, and synaptic vesicle pools. Overall, this work suggests Tenm3’s involvement in structural remodeling of both axonal boutons and dendritic spines thus providing a hypothesis for its role in ECII’s selective vulnerability to AD.

Caspases are cysteine proteases best known for their controlling roles in apoptosis and inflammation. Caspase-6 has recently been shown to play a key role in the cleavage of neurodegenerative substrates that causes Huntington and Alzheimer's Disease, heightening interest in caspase-6 and making it a drug target. All thirteen human caspases have related specificities for binding and cleaving substrate, so achieving caspase-specific regulation at the active site has been extremely challenging if not impossible. We have determined the structures of four unliganded forms of caspase-6, which attain a novel helical structure not observed in any other caspases. In this conformation, rotation of the 90's helix results in formation of a cavity that can function as an allosteric site, locking caspase-6 into an inactive conformation. We are using this cavity to look for chemical ligands that target this cavity and maintain caspase-6 in the inactive, helical conformation. We found that known allosteric inhibitors of caspase-3 and -7 also inhibit caspase-6 through a cavity at the dimer interface. We have determined new structures of a phosphomimetic state and a zinc-bound conformation of caspase-6, which show the molecular details of two additional allosteric sites. The phosphomimetic form of caspase-6 inactivates caspase-6 by disrupting formation of the substrate binding-groove by steric clash of the phosphorylated residue with P201 in the L2' loop. Another allosteric site was found on the "back" of caspase-6 that coordinates a zinc molecule that leads to inactivation. In total we have uncovered four independent allosteric sites in caspase-6, structurally characterized inhibition from these sites and demonstrated that each of these sites might be targeted for caspase-6 specific inhibition by synthetic or natural-product ligands.

Alzheimer's disease (AD), marked by a serious and progressive decline in cognitive abilities, is a severely debilitating disease that is becoming an increasing concern with our aging population. Defects in neurogenesis have been shown to exist in AD and aggravate the neuropathology and cognitive deficits associated with the disease. In this study, I aimed to characterize the cellular and molecular defects of neurogenesis in the triple transgenic mouse model of AD (3xTG). To do so, I first performed a detailed immunohistochemistry characterization using neurogenic markers that were quantified and analyzed in the hippocampus of control and 3xTG mice. This analysis not only revealed an overall decrease in the pool of neural stem and progenitor cells (NSPCs) in 3xTG brains, but also defects in proliferation, differentiation and a loss within the neuroblast, immature neuron and mature neuron populations. Subsequent immunohistochemistry analysis of two molecular targets, Hopx and LPAR1, involved in NSC maintenance and proliferation respectively, revealed their dysregulation in 3xTG brains, providing some indication of molecular defects underlying this loss. The neurosphere assay was next employed to assess cell-autonomous defects and fewer neurospheres were formed from cultured 3xTG NSPCs, suggesting a defect in NSPC pool expansion that is intrinsic to 3xTG NSPC function. Molecular characterization of these cultured NSPCs via qPCR revealed the upregulation of mitochondrial and fatty acid oxidation genes in 3xTG NSPCs, suggesting not only a dysregulation of metabolic functions, but also an acclimation to oxidative stress conditions. Interestingly, 3xTG NSPCs formed larger and more neurospheres when grown in galactose medium - which is used to simulate oxidative stress - relative to the control, confirming an adaptative response to oxidative stress conditions. Further characterization of these cellular defects and underlying molecular mechanisms can reveal novel therapeutic strategies for AD.

Neurotrophins, such as nerve growth factor (NGF) and brain derived neurotrophic factor (BDNF), are key factors in neuronal survival and function. In Alzheimer's disease (AD), there is a change in the normal level of these neurotrophins and their precursors (proNGF and proBDNF). The mechanism/s underlying changes in the levels of these neurotrophins in AD is not fully understood. According to the amyloid cascade hypothesis, amyloid-β is the original insult in AD and tau pathology is a downstream event. Amyloid-β interferes with axonal transport and reduces BDNF levels. However, it is not clear if amyloid-β affects neurotrophin levels directly or through tau hyperphosphorylation. If tau is responsible for changes in the level of neurotrophins in AD, we expect to observe the same alteration in neurotrophin levels in other diseases with tau dysfunction such as tauopathies. We tested the levels of BDNF mRNA and proNGF protein in subjects with tauopathies. We observed significant decrease in BDNF mRNA levels in subjects with Corticobasal degeneration. Our result suggests that BDNF may be down-regulated by tau hyperphosphorylation. Moreover, we showed that there was a significant increase in the level of proNGF in Pick's disease (PiD). Interestingly, AD and PiD share common tau modifications. Our result demonstrates a role for tau dysfunction in changes in the level of proNGF. Therefore, study of the levels of NGF and BDNF in non-AD tauopathies has shed light on the mechanisms underlying neurotrophin dysregulation in AD. How do increased levels of proNGF impact the brain in AD or PiD? Is neuronal degeneration in AD or PiD due to the lack of neurotrophic support of proNGF or do increased levels of apoptotic proNGF cause neurodegeneration? Lee et al. (2001b) and Fahnestock et al. (2004a) produced two different cleavage-resistant proNGFs with opposite activities (apoptotic versus neurotrophic). Structural and procedural differences between the two cleavage resistant proNGFs and different bioassays can cause opposite activities. We showed that proNGF from Lee's lab was neurotrophic when it was expressed in the expression system used by Fahnestock et al. or when it was purified. ProNGF expressed in a different expression system was also neurotrophic. ProNGF was neurotrophic in all bioassays except the serum withdrawal assay. We conclude that proNGF is normally neurotrophic but may be apoptotic when cell survival is already compromised. We propose that in AD, cells undergo degeneration due to the lack of neurotrophic support of proNGF (impaired transport). Moreover, TrkA is downregulated in AD which compromises cell survival and may lead to apoptosis induced by increased levels of proNGF. / Thesis / Doctor of Philosophy (PhD)

Alzheimer's Disease (AD) is a neurodegenerative disorder affecting over 35 million people. Early diagnosis and intervention are crucial for improving outcomes. Digital Cognitive Biomarkers (DCBs) offer a promising approach for early detection and disease management, quantifying cognitive processes of encoding and retrieval through a hierarchical Bayesian cognitive processing model using wordlist memory tests. We hypothesize that DCBs will correlate with classic AD cerebrospinal fluid (CSF) biomarkers (Aβ42, T-tau, p-tau) in patients with varying cognitive decline levels compared to healthy elderly controls. Using Alzheimer's Disease Neuroimaging Initiative (ADNI) data and paired Pearson correlation coefficient analysis, our results support the hypothesis, indicating that DCBs correlate with CSF biomarkers and demonstrating their potential as a noninvasive diagnostic tool for AD. Furthermore, DCBs exhibited improved diagnostic accuracy compared to classic AD CSF biomarkers, as indicated by the area under the Receiver Operating Characteristic curve analysis. DCBs hold promise for monitoring disease progression, response to therapeutics, and identifying patients at earlier disease stages. Future research should validate these findings in diverse populations and conduct longitudinal studies to assess DCBs' potential in tracking disease progression and treatment response. Integrating DCBs with other diagnostic approaches, such as neuroimaging, could enhance overall AD diagnosis accuracy and provide a comprehensive understanding of an individual's cognitive health. In conclusion, DCBs may offer a valuable, noninvasive tool for early diagnosis and management of Alzheimer's Disease, supporting the initial hypothesis.

Alzheimer’s Disease (AD) is a chronic neurodegenerative disease commonly characterized by the aggregation and deposition of insoluble amyloid beta plaques throughout the brain, and by an associated neuroinflammatory response to these plaques involving astrocytes and microglia. Choline is an essential nutrient with diverse functional roles that has emerged as a promising candidate for the treatment of AD. Localized plaque regions in the polymorphic layer in the medial dentate gyrus of the hippocampus and in the cortex were examined in 9-month-old APP-NL-G-F knock-in AD model mice to determine the effects of perinatal choline supplementation on astrocytosis and gliosis associated with amyloid beta. The size of ionized calcium-binding adaptor molecule 1 (Iba1)-positive cells and clusters were larger in control diet APPNL-G-F mice, although the number and total area covered by Iba1+ cells/clusters were decreased compared to those of control diet C57BL6/J mice. In comparison, choline supplementation significantly reduced the size of Iba1+ cells/clusters in APPNL-G-F mice. These results suggest that perinatal choline supplementation ameliorates neuroinflammatory processes associated with amyloid plaques in these 9-month-old APPNL-G-F mice, and that dietary supplementation of choline might serve as an effective treatment for AD. / 2026-02-14T00:00:00Z

Mounting evidence has pointed to associations between Alzheimer's disease (AD) and dysbiotic microbiota in the oral cavity and GI tract. However, no studies have compared the role of specific oral and GI-tract pathogens in the development of AD or the roles inflammation severity and sex may play. We compared the effect of chronic exposure to two doses of lipopolysaccharides (LPS) from a periodontal pathogen, Porphyromonas gingivalis, and a GI-tract pathogen, Escherichia coli, on neuroinflammation, cognition, and AD-like pathology. P. gingivalis-LPS, E. coli-LPS, or endotoxin-free PBS was continuously subcutaneously administered to adult male and female C57BL/6 mice for 28 days via osmotic pumps at 250 µg/kg/day (low-dose) or 500 µg/kg/day (high-dose). After 21 days, spatial learning and reference memory were assessed using the Morris Water Maze (MWM) and Y-Maze. After 28 days of LPS treatment, levels of proinflammatory cytokines, TNF-α and IL-β, in serum and brain tissue were measured by ELISA. Markers of AD pathology and inflammation were detected in situ using immunohistochemistry (IHC) in paraffin-embedded brain sections. Western blot (WB) analysis was used to compare the expression of Toll-Like Receptors (TLR) 2 and 4 in brain, bone, liver, and kidney tissues. Sustained exposure to high-dose, but not low-dose, P. gingivalis-LPS or E. coli-LPS significantly impaired cognition in male mice only. P. gingivalis-LPS triggered worse cognitive impairment and neuroinflammation, whereas E. coli-LPS caused more pronounced serum inflammation. IHC analysis revealed that P. gingivalis-LPS-treated male mice had increased amyloid precursor protein and hyperphosphorylated tau protein in both the hippocampus and neocortex, while E. coli-LPS treatment had a less prominent effect. P. gingivalis-LPS also induced a greater degree of astrogliosis. The mechanisms underlying these observations may be related to differential TLR2 and TLR4 expression, as WB analysis showed TLR2 was predominantly expressed in the brain while TLR4 was constitutively expressed in both the brain and peripheral tissues. Overall, P. gingivalis-LPS treatment triggered more prominent neuroinflammation, cognitive impairment, and AD-like pathological brain changes than E. coli-LPS treatment. Moreover, these phenotypes were dose-dependent and sex-dependent. In conclusion, chronic periodontitis may be a significant risk factor for AD, and this relationship warrants further investigation.

As the world is quickly aging, the prevalence of Alzheimer’s Disease (AD) and other dementias is also rapidly growing. AD is a neurodegenerative disease that gradually destroys one’s ability to learn, reason, and carry out daily activities. Memory impairment is the most prominent cognitive symptom of AD and can influence individuals' ability to live independently from the early stages of the disease. Compounding this, despite many promising advances made in the pharmacological treatment of AD, there is yet no treatment that can halt the disease. Non-pharmacological interventions are powerful solutions to help manage cognitive and functional symptoms of AD. However, there are still many challenges to the development of effective strategies. Firstly, little is known about the influence of distinct types of memory symptoms, such as false memories, on the daily life function of AD patients. Secondly, easy-to-use in-vivo biomarkers to detect AD and map disease progression patterns are still lacking making it challenging to implement strategies early on and target the stage of disease and pattern of cognitive impairment. In this dissertation, I will explore current advances made in AD research and outline some of the work done on the influence of false memories on the daily life of patients with AD. I will also investigate the use of Event-Related Potentials (ERPs) to help the diagnosis and characterization of AD. I will examine the feasibility and effectiveness of two behavioral interventions to sustain memory and cognition in AD patients: remote social interactions and a digital home-based cognitive training program. The results of this dissertation will shed light on how behavioral interventions can help sustain daily life function in AD patients, and they will bring forth novel research approaches that can be used to maximize the effectiveness of behavioral strategies. / 2026-02-20T00:00:00Z

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