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Nusaira Shahab. Thesis. ApoE4 − A genetic risk factor for Alzheimer’s Disease and its association with hypertension3.62 MB
Embargoed Access, Embargo ends: 06/29/2028
Dissertation
ApoE4 − a genetic risk factor for Alzheimer’s disease and its association with hypertension
University of Iowa
Doctor of Philosophy (PhD), University of Iowa
Spring 2026
DOI: 10.25820/etd.008452
Abstract
Alzheimer’s disease (AD) is the most common cause of dementia in older adults and represents a rapidly escalating global health challenge. AD is characterized by the presence of amyloid-β (Aβ) plaques and neurofibrillary tangles (NFT) composed of hyperphosphorylated tau (pTau). Among the genetic determinants, the ε4 allele (ApoE4) of the apolipoprotein E gene (APOE) is the most prevalent risk factor for AD with earlier onset, faster progression, and a more severe pathology compared with the neutral ε3 allele (ApoE3). Despite extensive advances in elucidating the molecular underpinnings of AD, existing therapeutic interventions largely provide symptomatic relief, without halting or reversing neurodegeneration. Consequently, growing emphasis is now directed on identifying and managing modifiable risk factors in individuals predisposed to AD. Hypertension is highly prevalent in the aging population and is also a common comorbid condition noticed among individuals with cognitive impairment and dementia. Epidemiological studies indicate a strong association between midlife or early late-life hypertension with an increased risk of dementia. Prior study from our lab have observed a marked increase in systolic blood pressure (SBP) with age in female ApoE4 mice. Furthermore, older ApoE4 female mice showed spatial learning and memory impairment in the Barnes maze test. Guided by this framework, our central hypothesis is hypertension exacerbates cognitive decline in the ApoE4 mice.
To test this hypothesis, my lab generated transgenic mouse models carrying APPsw, PS1dE9 and tauP301S transgenes combined with either human APOE ε3 (3XE3) or human APOE ε4 (3XE4) knockin genes. We used two mediators of hypertension: angiotensin II (AngII), the excitatory effector of the renin angiotensin system (RAS) that binds to AT1R to cause hypertension, and polychlorinated biphenyl 153 (PCB153), an environmental toxicant associated with hypertension.
Under Aim 1, we studied the contributions of AngII on SBP, autonomic tone, cognition, and AD–related pathology in saline, AngII (1000 ng/kg/min via osmotic minipump), and AngII + losartan treated (0.1 mg/mL in drinking water) 3XE3 and 3XE4 mice. AngII elevated SBP in both male and female 3XE4 mice, and selectively in female 3XE3 mice. This increase in SBP was accompanied by loss of body weight, increased locomotor activity in female mice, reduced vagal tone in the 3XE4 males, and enhanced sympathetic tone in the 3XE4 female mice. AngII did not disrupt diurnal SBP, heart rate, or locomotor activity rhythms in the 3XE3 and 3XE4 mice. AngII increased cortical Aβ₁–₄₂ in 3XE3 and 3XE4 female mice, and cortical pTau in 3XE3 female mice. AngII exacerbated depressive-like behaviors in the 3XE4 females and memory deficits in the 3XE4 males. Together, these findings demonstrate that AngII-mediated hypertension evokes cognitive decline predominantly in the male 3XE4 mice.
Under Aim 2, we examined the impact of chronic PCB153 exposure (50 mg/kg/day delivered in peanut butter) on SBP and cognitive outcomes in 3XE3 and 3XE4 mice. PCB153 is one of the most abundant polychlorinated biphenyl congeners detected in human serum that has been epidemiologically associated with hypertension. PCB153 increased SBP in the 3XE3 mice and caused increased anxiety in both 3XE3 and 3XE4 mice. Depression-like behavior worsened with PCB153 exposure in the 3XE4 mice. Furthermore, PCB153 exposed 3XE4 mice exhibit marked impairment in recognition memory. GC-MS/MS confirmed abundant accumulation of PCB153 and its hydroxylated metabolites in the serum, liver, brain, heart, and kidneys of the exposed mice. Therefore, we conclude that environmental stressor PCB153, likely contributes to hypertension, depression, anxiety and cognitive decline in the AD mice. In summary, the findings from this thesis supports the importance of addressing modifiable risk factors in the pathogenesis of AD in individuals carrying the APOE ε4 allele.
Details
- Title: Subtitle
- ApoE4 − a genetic risk factor for Alzheimer’s disease and its association with hypertension
- Creators
- Nusaira Beenta Shahab
- Contributors
- Rasna Sabharwal (Advisor)Hans-Joachim Lehmler (Committee Member)Mark Chapleau (Committee Member)Daniel Tranel (Committee Member)Frank M. Faraci (Committee Member)
- Resource Type
- Dissertation
- Degree Awarded
- Doctor of Philosophy (PhD), University of Iowa
- Degree in
- Human Toxicology
- Date degree season
- Spring 2026
- DOI
- 10.25820/etd.008452
- Publisher
- University of Iowa
- Number of pages
- xvi, 132 pages
- Copyright
- Copyright 2026 Nusaira Beenta Shahab
- Language
- English
- Date submitted
- 04/20/2026
- Description illustrations
- Illustrations, graphs, charts, tables
- Description bibliographic
- Includes bibliographical references (pages 110-132).
- Public Abstract (ETD)
Alzheimer’s disease (AD) is the leading cause of memory loss in older adults, caused by the death of brain cells. It affects million individuals worldwide and is an increasing global health concern. Genetics play a major role in AD risk, with the ApoE4 gene increasing the likelihood of developing the disease. Because there is currently no cure for AD, identifying preventable risk factors, is important in attenuating the risk for AD among individuals carrying the AD risk gene, ApoE4.
High blood pressure (BP) is commonly seen in middle and older-aged adults, and has been associated with memory decline and increased risk of developing AD. However, the role of high BP on memory in the ApoE4 is not fully understood. To explore this, we used a genetically modified mouse model that develops AD. BP was increased in two ways: administering angiotensin II and PCB153. We found that Angiotensin II caused high BP and memory decline while PCB153 caused anxiety and depression-like behavior, and memory impairments in the ApoE4 mice. Therefore, maintaining normal BP may help preserve memory in individuals with the ApoE4 gene.
- Academic Unit
- Interdisciplinary Graduate Program in Human Toxicology
- Record Identifier
- 9985176872302771
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