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Indiana University-Purdue University Indianapolis (IUPUI) / Alzheimer’s Disease (AD) is one of the most common forms of dementia and is known to have a strong genetic component, but known genetic loci do not fully account for the observed genetic heritability of late onset AD. This genetic complexity is further complicated by disease heterogeneity, with non-uniform presentation and progression of AD neuropathology. Endophenotypes lie upstream of observed AD clinical outcomes and downstream of genetic contributors, allowing for a biological understanding of genetic effects. Understanding the genetic architecture of AD endophenotypes can aid in breaking down AD genetic complexity and heterogeneity. In this study we utilized a variety of models to evaluate the genetic contributors to pathological change and heterogeneity in the top markers of AD pathology: amyloid, tau, neurodegeneration, and cerebrovascular (A/T/N/V framework). Additional composite quantitative measures of cognitive performance were used to relate to downstream AD presentation. These biomarkers allow the investigation of genetic effects contributing to the disease over the stages of disease progression from amyloid deposition to neurofibrillary tangle formation, disruption of metabolism, brain atrophy, and finally to clinical outcomes. First, we performed genome-wide association studies (GWAS) for AD endophenotypes at baseline using a cross-sectional regression model. This method identified sixteen novel or replicated loci, with six (SRSF10, MAPT, XKR3, KIAA1671, ZNF826P, and LOC100507506) associated across multiple A/T/N biomarkers. Cross-sectional data was further utilized to identify three genetic loci (BACH2, EP300, PACRG-AS1) that showed disease stage specific interaction effects. We built upon those results by performing a longitudinal association analysis with linear-mixed effects modeling. Gene enrichment analysis of these results identified 19 significant genetic regions associated with linear longitudinal change in AD endophenotypes. To further break down longitudinal heterogeneity, a latent class mixed model approach was utilized to identify subgroups of longitudinal progression within cognitive and MRI measures, with 16 genetic loci associated with membership in different classes. The genetic patterns of these subgroups show biological relevance in AD. The methods and results from this study provide insight into the complex genetic architecture of AD endophenotypes and a foundation to build upon for future studies into AD genetic architecture. / 2022-11-26

Polymorphisms in the gene encoding SORL1, involved in cellular trafficking of APP, have been implicated in late-onset Alzheimer's disease, by a mechanism thought to affect mRNA expression. To search for regulatory polymorphisms, we have measured allele-specific mRNA expression of SORL1 in human autopsy tissues from the prefrontal cortex of 26 Alzheimer's patients, and 51 controls, using two synonymous marker SNPs (rs3824968 in exon 34 (11 heterozygous AD subjects and 16 controls), and rs12364988 in exon 6 (8 heterozygous AD subjects)). Significant allelic expression imbalance (AEI), indicative of the presence of cis-acting regulatory factors, was detected in a single control subject, while allelic ratios were near unity for all other subjects. We genotyped 7 SNPs in two haplotype blocks that had previously been implicated in Alzheimer's disease. Since each of these SNPs was heterozygous in several subjects lacking AEI, this study fails to support a regulatory role for SORL1 polymorphisms in mRNA expression.

Alzheimer's disease (AD) is a neurodegenerative disease associated with progressive dementia. This mini-review focuses on how the amyloid precursor protein (APP) plays a central role in AD and Down syndrome as the regulator of the APP-BP1/hUba3 activated neddylation pathway. It is argued that the physiological function of APP is to downregulate the level of β-catenin. However, this APP function is abnormally amplified in patients with familial AD (FAD) mutations in APP and presenilins, resulting in the hyperactivation of neddylation and the decrease of β-catenin below a threshold level. Evidence in the literature is summarized to show that dysfunction of APP in downregulating β-catenin may underlie the mechanism of neuronal death in AD and Down syndrome.

Indiana University-Purdue University Indianapolis (IUPUI) / Alzheimer’s disease (AD) is a devastating neurodegenerative disease that is expected to affect approximately 6.2 million Americans. Despite its high prevalence, the mechanisms underlying AD remain poorly understood. In recent years, increasing reports indicate that exposure to urban air pollution is a risk factor for the development of AD. However, the mechanistic underpinnings of this association are not well studied. Rats exposed to diesel exhaust (DE) showed neuroinflammation and impaired expression of TREM2 and disease-associated microglia (DAM), a cell subtype hypothesized to play beneficial roles during neurodegeneration, markers. Microglia in the cortex of rats exposed to DE, also showed decreased association with the vasculature, providing a novel link between the microglia and the brain vasculature. Examining the functional role of TREM2 during DE exposures, Trem2-/- mice showed an altered pro-inflammatory profile in both the brain and lungs in response to DE particles as well as altered phagocytic oxidase related gene expression. Examining another prominent component of air pollution, ozone (O3), in a mouse model of AD, it was discovered that subchronic O3 exposure exacerbates amyloid pathology through impaired microglial-plaque association in 5xFAD mice. 5xFAD mice exposed to O3 also showed increased expression of pro-inflammatory cytokines, increased markers of dystrophic neurites, and decreased expression of key acetylcholinergic pathway components. Examining the peri-plaque microenvironment, it was discovered that O3 dysregulates key DAM proteins and amyloid processing proteins. In the lung, it was found that O3 exacerbated immune cell infiltration in 5xFAD mice compared to WT controls, suggesting that ongoing amyloid pathology regulates pulmonary immune response to air pollution. To examine how O3-induced pulmonary immune responses may be signaling to the CNS, we examined the serum of 5xFAD mice, where HMGB1, VEGF, and IL-9 were upregulated. Injection of rHMGB1 into mice showed similar gene changes to 5xFAD mice exposed to O3, along with impaired Trem2 expression. Using a peripheral myeloid specific knock-out model of HMGB1, we also show that HMGB1 regulates O3-induced Trem2 expression impairment. Taken together, these data support that air pollution exposure impairs TREM2, DAM cells, and the microglial plaque response through a bidirectional lung-brain axis to exacerbate AD-like pathology.

This study utilized life history as a methodological tool to explore the identity formation of Mary, a woman in her eighties who is diagnosed with Alzheimer's disease. The results of this study showed that Mary's sense of self was greatly influenced by her childhood experiences. Five predominate themes emerged in the interview process: Mary's admiration for her father, her willingness to share wisdom, her career as a beautician, her role as a mother, and her devotion as a wife. The Dynamical Identity Model was constructed to help further illustrate Mary's identity development and the model served as a basis to describe possible outcomes in Mary's life, as a woman diagnosed with Alzheimer's disease. Her story reveals that Mary has a wonderful disposition about life and, even though she was diagnosed with this disease, she does not perceive the disease as threatening. / Master of Science