Hormone Biomarkers for Alzheimer’s Disease: Corticosterone vs. Cortisol

Alzheimer’s disease (AD), characterized by the build-up of abnormal beta-amyloid (Aβ) plaques and tau proteins,¹ is the most prevalent form of dementia. An estimated 6.5 million Americans aged 65 and older are living with Alzheimer’s dementia, a figure which is projected to soar to around 14 million by 2060.² Current treatments only offer temporary symptomatic relief, highlighting the importance of AD research.

It is widely recognized that AD begins to damage the brain years before symptoms appear.³ As such, there is growing interest in the early detection of AD using biomarkers. Among potential biomarkers, hormonal imbalances have gained attention due to their involvement in various neurodegenerative processes. For example, the loss of estrogen in the aging brain of men and women may play a key role in the cognitive decline associated with AD.⁴ In this context, we present a compelling use case for identifying hormone biomarkers of AD progression in animal models.

Using Causaly, over 1000 biomarkers of AD progression have been identified. Two biomarkers with the most evidence were APP (amyloid-β peptides) and MAPT (microtubule-associated protein tau), both of which are involved in formation of plaques in AD (Figure 1). These biomarkers have been extensively studied in the literature, and are considered the hallmarks of AD.

Animal models are invaluable in preclinical research, offering key insights into disease due to their similarities in genetics, physiology and anatomy to humans.⁵ Such models are important in understanding the potential utility of biomarkers in a controlled experimental setting. According to Causaly, approximately 400 biomarkers of AD progression have been studied in animal models. By narrowing down the focus to hormone biomarkers, we discovered evidence for corticosterone as a potential disease progression biomarker.

Corticosterone, synthesized and released by the adrenal glands’ cortex, is a steroid hormone that also plays a crucial role in the brain. High levels of corticosterone can lead to increased accumulation of Aβ plaques and tau tangles in mouse models.⁶ A study from 2020 assessing corticosterone levels in 3xTg-AD mice (a widely used animal model in AD research) reported consistent heightened stress-induced corticosterone levels and Aβ pathology in female 3xTg-AD mice.⁷ These findings provide insights into the relationship between corticosterone and AD, however, further research is needed to establish whether this hormone can predict AD progression.

Rodent corticosterone is akin to human cortisol, a primary adrenal steroid associated with cognitive impairment and AD pathology. Chronic stress and elevated cortisol levels could contribute to neurodegeneration and AD symptom exacerbation. By observing its effects in mice with AD-like pathology, researchers can explore the causal relationship between stress hormones and AD-related changes, providing valuable insights into the role of cortisol in patients with AD.

The identification of hormone biomarkers, such as corticosterone in AD progression, may provide insights into underlying mechanisms of AD pathology. Translating these findings to human research, where cortisol serves as the equivalent hormone, may enhance our understanding of the impact of chronic stress and cortisol dysregulation on neurodegeneration and cognitive decline in AD patients. However, further research is needed to understand the clinical implications.