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Longer life expectancies, due to advanced medical care, social, and environmental conditions, helped increase the number and percentage of Americans aging to ≥85. The number of individuals with Alzheimer’s disease (AD) age 65 or older is projected to be 7.1 and 13.8 million by 2025 and 2050, respectively. The total annual health care expense for AD patients is estimated to increase from $290 billion in 2019 to more than $1.1 trillion in 2050 (Association, 2019). Conclusively, AD is expected to become a more common cause of death and a major public health predicament due to aging of the baby boom generation in the United States. Extracellular Aβ plaque deposition resulting from successive proteolytic cleavage of amyloid precursor protein (APP), intracellular neurofibrillary tangles, and neuroinflammation are pathophysiologic features of AD correlating with cognitive decline, language impairment, memory loss, and ultimately, death. Due to the behavioral manifestation and the neurodegenerative hallmarks, AD is typically considered a brain specific disease. However, peripheral inflammatory changes such as increased serum levels of TNF-α, worsen cognitive decline in AD patients. This suggests that systemic inflammatory changes may cross-talk to the brain to influence disease. In support of this idea, long-term use of non-steroidal anti-inflammatory drugs (NSAID) decreases the risk of AD. Interestingly, colitis and colitis-associated colorectal cancer (CAC), which are characterized by accelerated levels of proinflammatory cytokines, induce anxiety, depression and cognitive/memory dysfunction in preclinical and clinical studies. Taken together, these studies suggest that peripheral immune changes influence AD progression in the brain. This dissertation consists of three related but separate studies aimed at understanding the impact of peripheral manipulations on brain pathology using AD mouse models. In our first study, we asked whether the liver-derived hormone, insulin like growth factor-1 (IGF-1), has effects in the brain to potentiate or attenuate disease using the AβPP/PS1 mutant mouse model of AD. To test this idea, we used a brain penetrant IGF-1R inhibitor. The second study shifts to focus on peripheral inflammatory manipulations to examine possible influences on disease. This study utilized a common colitis-like model of oral dextran sulfate sodium (DSS) to quantify brain and intestinal changes in the AppNL-G-F mutant knock-in mouse model of AD. The third study employed a more extensive intestinal inflammatory paradigm of colorectal tumorigenesis to also compare brain and intestinal changes using the AppNL-G-F mice. In the first study, the brain penetrant IGF-1R inhibitor (PPP, 1mg/kg/day) attenuated insoluble Aβ1-40/42 and pro-inflammatory cytokine levels (eotaxin, TNF-α, IL-1α, and IL-1β) in the temporal cortices of AβPP/PS1 mice. Additionally, an attenuation in microgliosis and protein p-tyrosine levels was observed due to drug treatment. Our data suggests IGF-1R signaling is associated with disease progression in this mouse model. More importantly, modulation of the brain IGF-1R signaling pathway was sufficient to attenuate aspects of disease phenotype. This suggested that small molecule therapy targeting liver-derived IGF-1 effects in the brain may be a viable intervention approach. In the second study, chronic intestinal inflammation, induced by dissolving 2% dextran sulfate sodium (DSS) in the drinking water, resulted in bloody diarrhea, disrupted colonic epithelium, and weight loss in wild type and AppNL-G-F male mice, changes similar to human inflammatory bowel disease (IBD). The inflammation correlated with increased levels of brain insoluble Aβ1-40/42 and decreased microglial CD68 immunoreactivity in DSS treated compared to vehicle treated AppNL-G-F mice. These data demonstrated that intestinal dysfunction is capable of altering plaque deposition and immune cell behavior in the brain. This study increased our understanding of the impact of peripheral inflammation on Aβ deposition and neuroinflammation in AD via an IBD-like model system. In the third study, azoxymethane (AOM)/DSS administration produced genotype and sex dependent colitis-associated colorectal cancer (CAC) symptomatic parameters in spleens and colons of wild type, App-/-, and AppNL-G-F mice. As expected, AOM/DSS treatment exacerbated Aβ plaque load in male AppNL-G-F mice. Interestingly, AOM/DSS treated male AppNL-G-F mice also demonstrated worsened intestinal inflammation and increased colonic tumorigenesis compared to wild types. However, AppNL-G-F female mice were protected against intestinal inflammation and tumorigenesis as well as any exacerbation of brain Aβ plaque load. These data demonstrated that the AD-associated autosomal dominant mutations of APP introduced into the AppNL-G-F mouse line provide protection against intestinal disease as well as brain exacerbation in a sex-selective fashion. Collectively, studies in this dissertation demonstrate that peripheral stimuli, whether hormonal or inflammatory, appear capable of altering disease phenotype in two commonly used mouse models of AD. In addition, there may be sex-selectivity of this peripheral to brain communication during disease. One conclusion from this work is that manipulations of peripheral events may be sufficient to alleviate brain changes in AD. This suggests the exciting possibility that therapeutic interventions need not penetrate into the brain to offer benefit.