Therapeutic considerations for APOE and TOMM40 in Alzheimers disease: A tribute to Allen Roses MD

ABSTRACT

Introduction: Four years ago this Autumn, pioneering neurologist Prof. Allen. D. Roses passed away. Hence, we have taken time to reflect on his work and legacy in Alzheimer’s disease (AD) research. Prof. Roses rejected the widely accepted amyloid hypothesis, which identifies amyloid beta (Aβ) protein accumulation within the brain as the cause of AD. Instead, he proposed that the epsilon type 4 allele of apolipoprotein (APOE- Ɛ4) and translocase of outer mitochondrial membrane 40 homolog (TOMM40) were preeminent factors in the pathogenesis and progression of AD, particularly in late-onset AD (LOAD). This rejection of the amyloid hypothesis has generated new investigations into APOE and TOMM40 as risk factors for AD.

Areas covered: We discuss the contributions of Prof. Roses to AD research, describe how APOE-Ɛ4 and TOMM40 have been posited to trigger neuropathological changes leading to AD, and explore paths to future clinical applications built on the foundations of his research.

Expert opinion: The unconventional methodology of targeting APOE and TOMM40 offers great potential for the development of effective preventive and disease-modifying AD interventions. Future preclinical and clinical investigations will greatly benefit from the groundbreaking scientific discoveries of Prof. Roses.

KEYWORDS:

• Alzheimer’s disease
• amyloid hypothesis
• apoe
• apoe-Ɛ4
• tomm40
• allen Roses
• dementia
• therapeutic target
• apolipoprotein

Article highlights

• Prof. Allen D. Roses challenged the prevalent hypotheses that identified senile plaques (caused by the accumulation of amyloid beta protein 42 [Aß42]) as the primary cause of Alzheimer’s disease (AD).

• When compared with carriers of APOE-Ɛ2 or APOE-Ɛ3, carriers of the APOE-Ɛ4 allele face a significantly higher risk for developing late-onset AD (LOAD). This provides compelling evidence for more extensive investigations into the role of genetic background in AD pathology.

• The contribution of APOE and TOMM40 to the physiological changes that lead to AD continues to be an area of scrutiny.

• Clinical applications of the findings of Prof Roses include several clinical trials such as the GENERATIONS and TOMORROW studies.

This box summarizes key points contained in the article.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose

Additional information

Funding

The authors are supported by NIH COBRE 5P20GM109025, NIH P20 AG068054, NIH R01AG059008, and the Keep Memory Alive Foundation.