Less than 5% of Alzheimer's disease (AD) is early-onset. Early-onset AD patients experience the AD "memory issue" symptoms in their 40s or 50s. The early-onset AD cases are usually linked to genetic mutation(s) in amyloid and its metabolism genes.
This led to a widely accepted notion that accumulation of amyloid-beta in the brain is a critical triggering event for AD development.
In fact, amyloid-beta regulation is a central theme for scientists studying AD and its drug development. For example, APOE subtype, a known genetic predisposition and a risk factor for late-onset AD, is suspected to be involved in amyloid-beta cleanup.
Speaking of late-onset AD, over 95% of AD is late-onset. Late-onset AD patients see the "memory issue" and other symptoms over age 65.
For late-onset AD, however, amyloid-beta still starts accumulating in the brain in middle age, 10-15 years before clinical (visible) symptoms appear. The silently accumulating amyloid-beta is triggering cascades of events leading to eventual brain destruction by AD.
Unlike early-onset AD patients, many late-onset AD patients do not carry mutations in early-onset genes, leaving a question that how/why amyloid-beta protein starts accumulating in the brain in middle age.
In this review article, we attempted to explain the mechanism of amyloid-beta accumulation in middle age. We named the mechanism as the "Amyloid-beta accumulation cycle".
[link to the article]
https://onlinelibrary.wiley.com/doi/abs/10.1111/acel.13109
[graphic abstract caption] ""Amyloid‐beta accumulation cycle”. Amyloid‐beta accumulation occurs in early latent phase of Alzheimer's disease, triggering its pathology development, yet the mechanism has been elusive. This integrated hypothesis explains that amyloid‐beta accumulation occurs as a vicious cycle and offers insights on how the cycle may be interfered by cell cycle‐ or mitosis‐targeting drugs."
The "Amyloid-beta accumulation cycle" is not what we just came up from thin air. It is an integrated hypothesis synthesized from many previous studies.
We have a mouse model that accumulated amyloid-beta in the brain, which do not normally occur. Studying the mouse led us to this "Amyloid-beta accumulation cycle" concept. We are working on a research manuscript showing our data that support this concept.
After all, theories and hypotheses are powerless in biology. Only theories and hypotheses that are supported by data and experimental results matter. As a research scientist, I have seen many beautiful and convincing hypotheses dead. Idea is cheap. Correct idea is priceless.
We are hoping that this mechanistic explanation leads to prevention or therapy for late-onset AD, for which there is no cure.
We mainly work at a preclinical level for translational studies. In drug development process, theoretical and preclinical works are indispensable for clinical translation.
Unlike 19th century or earlier half of 20th century, clinicians/doctors cannot just test drugs on patients. Convincing theoretical background/compelling rationale, positive/promising data from multiple preclinical studies, funding, institutional support/approval and patients' consent, all are needed.
The "Amyloid-beta accumulation cycle" concept dictates possible solutions for amyloid-beta accumulation. I am hoping that this theoretical background/rationale is going to help clinicians to apply or repurpose drugs to AD, and get results.
