A new peer-reviewed paper by neuroscientist Dale E. Bredesen proposes a framework that could offer a different perspective on how Alzheimer's disease and other neurodegenerative disorders develop.

Published recently in the Journal of Advanced Therapeutic Science, the paper introduces the Pr2 (prion-priion) theory, which proposes that neurodegeneration may occur when vulnerable neural networks are unable to meet their biological demands in the face of persistent stress.

Rather than identifying amyloid, tau and other pathological features as the primary drivers of Alzheimer's disease, the theory suggests that these proteins may initially form part of an ancient protective response to biological threats. These threats could include chronic infections, toxins, inflammation, metabolic dysfunction and vascular stress.

According to the proposed model, prolonged exposure to such stressors may cause protective mechanisms to become persistent, contributing to chronic inflammation and progressive loss of neural function.

The Pr2 theory also attempts to address a longstanding question in Alzheimer's research: why some individuals can have significant levels of amyloid accumulation in the brain while maintaining normal cognitive function.

Under the proposed framework, amyloid and related proteins may initially have protective, anti-infective or signalling roles. However, when the underlying biological threats persist, the same responses could become associated with inflammation and neurodegeneration.

The theory therefore shifts the focus from pathology alone to the biological conditions that may trigger and sustain the pathological response.

The paper proposes that different neurodegenerative disorders may arise from vulnerabilities affecting distinct neural networks.

For Alzheimer's disease, these vulnerabilities may involve networks responsible for neuroplasticity and cognitive function. The paper identifies a range of factors that could potentially contribute to neurological stress, including metabolic dysfunction, sleep apnoea, chronic infection, air pollution, inflammation and inadequate energetic support.

Similar network-specific vulnerabilities are proposed for other neurodegenerative conditions, including Parkinson's disease and Amyotrophic Lateral Sclerosis (ALS).

This framework could support a more personalised approach to neurodegenerative disease, in which clinicians identify and address the combination of biological factors contributing to an individual's cognitive decline rather than focusing exclusively on a single pathological target.

According to the paper, early clinical translation of the proposed approach has generated encouraging observations, including findings from two proof-of-concept studies and reports of sustained cognitive improvement in some patients.

However, the authors emphasise the need for additional research and clinical testing to establish whether these findings can be consistently replicated and to determine the broader clinical relevance of the framework.

The Pr2 theory ultimately poses a different question for Alzheimer's research: rather than focusing solely on removing pathological proteins, researchers could investigate what caused the brain to enter a protective response in the first place and whether restoring healthier biological conditions can support normal neural function.

Dale Bredesen is a neurologist and neuroscientist whose research has focused on the mechanisms underlying Alzheimer's disease and cognitive decline. His work has explored precision-medicine approaches that seek to identify and address multiple potential contributors to neurodegenerative disease.

Bredesen has held academic positions at institutions including the University of California, San Francisco (UCSF) and the University of California, Los Angeles (UCLA), and served as founding president and CEO of the Buck Institute for Research on Aging.

The newly published Pr2 theory adds to ongoing efforts to understand Alzheimer's disease as a complex disorder involving multiple biological pathways, while highlighting the need for further independent research and clinical evidence to determine the potential of network- and precision-based approaches.