Indiana University-Purdue University Indianapolis (IUPUI) / Neuroimaging biomarkers play a crucial role in our understanding of Alzheimer’s disease. Beyond providing a fast and accurate in vivo picture of the neuronal structure and biochemistry, these biomarkers make up a research framework, defined in a 2018 as the A(amyloid)/T(tau)/N(neurodegeneration) framework after three of the hallmarks of Alzheimer’s disease. I first used imaging measures of amyloid, tau and neurodegeneration to study clinically diagnosed Alzheimer’s disease. After dividing subjects into early (onset younger than 65) and late-onset (onset of 65 and older) amyloid-positive (AD) and amyloid-negative (nonAD) groups, I saw radically differing topographical distribution of tau and neurodegeneration. AD subjects with an early disease onset had a much more severe amyloid, tau and neurodegeneration than lateonset AD. In the nonAD group, neurodegeneration was found only in early-onset FDG PET data and in a nonAlzheimer’s-like MRI and FDG pattern for late-onset. The late-onset nonAD resembled that of limbic-predominant age-related TDP-43 encephalopathy. I next utilized an imaging genetics approach to associate genome-wide significant Alzheimer’s risk variants to structural (MRI), metabolic (FDG PET) and tau (tau PET) imaging biomarkers. Linear regression was used to select variants for each of the models and included a pooled sample, cognitively normal, mild cognitive impairment and dementia groups in order to fully capture the cognitive spectrum from normal cognition to the most severely impaired. Model selected variants were replicated using voxelwise regression in an exploratory analysis of spatial associations for each modality. For each imaging type, I replicated some associations to the biomarkers previously seen, as well as identified several novel associations. Several variants identified with crucial Alzheimer’s biomarkers may be potential future targets for drug interventions.

Recent epidemiological data have shown that metabolic disease is known to increase the propensity for developing cognitive decline and dementia, particularly Alzheimer’s disease (AD). While this interaction is not completely understood, clinical studies suggest that both hyper- and hypoinsulinemia are associated with an increased risk for developing AD. Indeed, insulin signaling is altered in post-mortem brain tissue from AD patients and insulin and treatments known to enhance insulin signaling, can improve cognitive function. Furthermore, clinical evidence has shown that AD patients and mouse models of AD often display alterations in peripheral metabolism. Since insulin is primarily derived from the periphery it is likely that peripheral alterations can lead to alterations in central nervous system (CNS) insulin signaling and that these changes contribute to cognitive decline. Recent results from our laboratory have shown that in both the APP/PS1 and 3xTg-AD mouse models of AD, peripheral metabolic alterations exist at an early age. Specifically, 3xTg-AD mice demonstrate impaired glucose tolerance at 1 month of age associated with a decrease in insulin and insulin secretion in response to a glucose challenge. This led to the hypothesis that insulin signaling in the CNS would be decreased as a result of decreased peripheral insulin and insulin transport into the CNS. Indeed, insulin signaling through the PI3K/AKT signaling pathway, but not the MAPK/ERK pathway, was decreased in the hippocampus of old, but not young, 3xTg-AD mice. PI3K/AKT signaling can affect several downstream molecules including glycogen synthase kinase 3 (GSK3), glucose transporters (GLUTs), and ATP dependent potassium (KATP) channels. We first examined GSK3 and pTau and found that both GSK3β and pTau were increased in aged 3xTg-AD mice. Next we looked at the translocation of GLUT3 and GLUT4 since both are found in the hippocampus and have recently been shown to be insulin sensitive. Our results showed that GLUT3 translocation, but not GLUT4, was decreased in the hippocampus of aged 3xTg-AD mice. Finally, since KATP channels are found in intracellular organelles as well as in the plasma membrane we examined crude plasma membrane and total fractions of KATP channel subunits Kir6.1 and Kir6.2 and found that the plasma membrane fraction of Kir6.2 was significantly increased. To assess how these changes corresponded with the time course of pathology and cognitive deficits we additionally looked at these changes in 6-8 month and 14-16 month animals. Interestingly, though peripheral insulin was decreased early on, changes in CNS PI3K/AKT insulin signaling did not occur until 18-20 months of age. Changes in GSK3β (but not pTau) and GLUT3 were consistent with this time point suggesting that they were potentially due to the decrease in PI3K/AKT signaling. Since these changes were not consistent with a decrease in peripheral insulin levels it suggests that another factor must be at play. One such factor is inflammation. The AD brain is characterized by inflammation and inflammatory compounds are known to block insulin signaling. KATP channels are not only insulin sensitive but have been shown to play a role in cognition, AD and epilepsy. Thus, to follow up the studies on KATP channels we used immunohistochemistry (IHC), to examine regional and cell specific changes. To our surprise we found that Kir6.2, a subunit typically found primarily in neurons, was present in reactive astrocytes. This finding was further examined in human AD tissue and a similar change was seen. Astrocytes become reactive during damage or under inflammatory conditions, such as AD, diabetes, traumatic brain injury (TBI), epilepsy and in normal aging. When they become reactive both gene expression and functions can change. Since reactive astrocytes and inflammation are a common finding among many neuropathological changes we looked at another neuropathological condition with several similarities to AD, epilepsy. These studies revealed that epileptic mice displayed a similar change in Kir6.2 in reactive astrocytes. Since both conditions are characterized by inflammation we next hypothesized that chronic peripheral inflammation induced by LPS would be enough to drive this change. These studies revealed that while 1 day of LPS treatment was not enough to induce a change in astrogliosis and Kir6.2 expression, three days caused a significant increase in Kir6.2 in reactive astrocytes. This suggests that an increase in Kir6.2 in reactive astrocytes could contribute to the difference in function in these cells and subsequently contribute to altered function in neuropathological disease. Taken together, these studies demonstrate an intricate balance between metabolism and inflammation in the CNS and further suggest that metabolic alterations could be a common link in neuropathological diseases that share similar phenotypic changes, as occurs in AD and epilepsy (i.e. cognitive decline, enhanced seizure susceptibility). Developing a better understanding of metabolism, inflammation, and cortical function/dysfunction could potentially lead to the identification of better treatment options for several neuropathological conditions including AD.

Indiana University-Purdue University Indianapolis (IUPUI) / Background: Alzheimer’s disease (AD) is the third leading cause of death for the older demographic in the United States, just after heart disease and cancer. However, unlike heart disease and cancer, the death rates for AD are increasing. Despite extensive research, the cause or origin of AD remains unclear and there is no existing cure. However, with the improvement of single-cell RNA-sequencing (scRNA-seq) technologies and drug repurposing tools, we can further our knowledge of AD and its pathogenesis. Method: Our primary aim was to identify repurposable drug and compound candidates for AD treatment and identify significant cell types and signaling pathways using two scRNA-seq datasets from cortex samples of AD patients and controls. To achieve this aim, we generated differential gene expression profiles, calculated log fold-changes, and estimated standard errors to make pairwise comparisons between the diseased and healthy samples. We used the 21,304 drugs/compounds with response gene expression profiles in 98 cell lines from the LINCS L1000 project to detect consistent differentially expressed genes (DEGs), that were either i) up-regulated in cells of diseased samples and down-regulated in cells with treatment, or ii) down-regulated in cells from diseased samples but up-regulated in cells with treatment. To evaluate these identified drugs, we compared the p-value, false discovery rate (FDR) and A Single-cell Guided Pipeline to Aid Repurposing of Drugs (ASGARD) drug score for each cell type. We further annotated and assessed doublet cell types within the Grubman et al. dataset using cell type proportions. Result: The analysis provided several potential therapeutic treatments for AD and its target genes and pathways as well as important cell type interactions. Notably, we identified an interaction between endothelial cells and microglia, and further identified drug candidates to target this interaction. Conclusion: We identified repurposable drugs/compounds candidates in each dataset which were also identified in literature. We further identified doublet cell type interactions of interest and drugs that target this interaction.

A total of 61 human brain specimens were analyzed with both ELISA and Western Blot using the ALZ50 monoclonal antibody. The brain specimens included: Alzheimer's Disease (AD, n=31), AD/Down's (n=2), Normal (n=14), Parkinson's Disease (n=7), Huntington's chorea (n=2), Wernicke-Korsakov's Encephalopathy (n=3), and Motor Neuron Disease (n=2). The non-AD cases (n=28) had no detectable A68 by ELISA, and showed no A68 bands by Western blot. The AD cases (n=33), all were positive for A68 by the ELISA, but only 31 of 33 had visible A68 band by Western blot. Additionally, a method for solubilization of A68 is reported.

Alzheimer's disease is a complex neurodegenerative disease whose basic etiology and genetic structure remains elusive, despite decades of intensive investigation. To date, the significant genetic markers identified have no obvious functional effects, and are unlikely to play a role in Alzheimer's disease etiology, themselves. These markers are likely linked to other genetic variations, rare or common. Regardless of what causal mutations are found, research has demonstrated that no single gene determines Alzheimer's disease development and progression. It is clear that Alzheimer's disease development and progression are based on a set of interactions between genes and environmental variables. This dissertation focuses on gene-gene interactions (epistasis) and their effects on Alzheimer's disease case-control status. We genotyped the top Alzheimer's disease genetic markers as found on AlzGene.org (accessed 2014), and tested for interactions that were associated with Alzheimer's disease case- control status. We identified two potential gene-gene interactions between rs11136000 (CLU) and rs670139 (MS4A4E) (synergy factor = 3.81; p = 0.016), and rs3865444 (CD33) and rs670139 (MS4A4E) (synergy factor = 5.31; p = 0.003). Based on one data set alone, however, it is difficult to know whether the interactions are real. We replicated the CLU-MS4A4E interaction in an independent data set from the Alzheimer's Disease Genetics Consortium (synergy factor = 2.37, p = 0.007) using a meta-analysis. We also identified potential dosage (synergy factor = 2.98, p = 0.05) and APOE ε4 effects (synergy factor = 4.75, p = 0.005) in Cache County that did not replicate independently. The APOE ε4 effect is an association with Alzheimer's disease case-control status in APOE ε4 negative individuals. There is minor evidence both the dosage (synergy factor = 1.73, p = 0.02) and APOE ε4 (synergy factor = 2.08, p = 0.004) effects are real, however, because they replicate when including the Cache County data in the meta-analysis. These results demonstrate the importance of understanding the role of epistasis in Alzheimer's disease. During this research, we also developed a novel tool known as the Variant Tool Chest. The Variant Tool Chest has played an integral part in this research and other projects, and was developed to fill numerous gaps in next-generation sequence data analysis. Critical features include advanced, genotype-aware set operations on single- or multi-sample variant call format (VCF) files. These features are critical for genetics studies using next-generation sequencing data, and were used to perform important analyses in the third study of this dissertation.By understanding the role of epistasis in Alzheimer's disease, researchers will begin to untangle the complex nature of Alzheimer's disease etiology. With this information, therapies and diagnostics will be possible, alleviating millions of patients, their families and caregivers of the painful experience Alzheimer's disease inflicts upon them.

Microglia, the resident immune cells of the brain, play a critical role in brain homeostasis and neurological disease progression. In neurodegenerative diseases, microglia acquire a neurodegenerative phenotype (MGnD), the function of which is poorly understood. MicroRNA-155 (miR-155), a multifunctional microRNA enriched in cells of the immune system, and Apolipoprotein E (APOE), a lipoprotein which is significantly associated with Alzheimer’s disease (AD) risk, critically regulate MGnD. However, the role of these molecules in AD pathogenesis remains unclear. Here, we report that microglial deletion of miR-155 induces an early MGnD response activation state via interferon-ɣ (IFNɣ) signaling in mice. This phenotypic transition increases plaque-associated Apoe, enhances amyloid plaque compaction, reduces neuritic dystrophy and attenuates plaque-associated synaptic degradation, resulting in improved cognition. These findings provide a novel mechanism detailing the phenotypic switch from homeostatic microglia to MGnD, and highlight the beneficial role of IFNɣ responsive MGnD in restricting neurodegenerative pathology and preserving cognitive function in a mouse model of AD. In addition, we demonstrate that Apoe deficient microglia induce an MGnD signature comparable to controls, but enhance MGnD physiological phenotypes including enhanced cognitive behavioral performance and reduced plaque associated neuritic dystrophy. Furthermore, we highlight a potential mechanism by which Apolipoprotein C-1 may attenuate synaptic ß-amyloid accumulation in a mouse model of AD. These findings may serve as the basis novel immunomodulatory therapies targeting microglial miR-155 and APOE to treat AD.

Thesis (M.A.)--Boston University / PLEASE NOTE: Boston University Libraries did not receive an Authorization To Manage form for this thesis or dissertation. It is therefore not openly accessible, though it may be available by request. If you are the author or principal advisor of this work and would like to request open access for it, please contact us at open-help@bu.edu. Thank you. / Increasing evidence indicates that the sooner treatment begins for patients with Alzheimer's Disease (AD), the better the chance of delaying progression of the disease. As a result, studies have begun focusing on risk factors for AD with the goal of identifying individuals with AD at the earliest possible stage. Such studies have found that individuals with Mild Cognitive Impairment (MCI) are at increased risk for AD and other forms of dementia. This study examines the potential mediating effect of a set of prospective risk factors, smoking and ApolipoproteinE (ApoE) genotype, on the incidence of MCI and AD. Although results of this study provide some preliminary evidence of an interaction, the study models presented here fail to reach significance. Additional studies are needed to confirm the hypothesis of an ApoE mediated relationship of smoking on MCI and AD. / 2031-01-01

Background: Alzheimer’s disease is the most common form of dementia. The disease includes, amongother things, memory difficulties and impaired orientation. In the later phases of the disease the relative becomes increasingly dependent on others for help. Relatives have an important role in care by helping the relative to manage everyday tasks. Caring for a relative includes many challenges, where nurses have an important supporting role. Aim: The aim of this study was to shed light on relatives' experiences of caring for a loved one with Alzheimer's disease. Method: Qualitative literature review with thematic analysis method. Results: Two themes: To experience a new life situation and To manage a new life situation. Four subthemes: To experience role changes, To feel fear for the future, To find strategies to handle everyday life and Lack of information, knowledge and support. Conclusion: Relatives experienced their new role as overwhelming. Lack of knowledge and support complicates the care of a loved one. Research highlights the importance of focusing on the needs of the relatives and family focused care in health care. More research is needed on relatives' experiences of family-focused nursing in health care.

Alzheimer’s disease is a neurodegenerative disorder characterized by symptoms such as memory loss and behavioral change, and it is the sixth leading cause of death in the U.S. This literature-based thesis aims to detail the history of the disease as well as pertinent information, such as basic brain histology, disease pathogenesis, and genetic profiles of victims. The paper will then discuss the available treatment options, from their annual costs and mechanisms of action to an evaluation of their cost-effectiveness. The information in this paper was collected through an online investigation of sources including research studies and medical journals. The treatments discussed in this thesis consist of six drugs: aducanumab, donepezil, rivastigmine, galantamine, memantine, and memantine-donepezil combination. Aducanumab is the only disease-modifying drug to receive FDA approval, but its efficacy is marred in controversy and it lacks cost-effectiveness. The remaining five drugs all have similar cost-effective values, but generic donepezil is an outlier with significantly better results. This paper’s findings indicate that generic donepezil is the most optimal treatment, but that further research should be conducted on aducanumab. Research also suggests that public health advocates must be vigorous in their attempts to make these drugs more affordable to the general population.

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