Science: How does amyloid-beta start accumulating in the brain in middle age?

Alzheimer's disease (AD) is a neurodegenerative disease. Brains of AD patients show characteristic pathologies of amyloid-beta plaques and neurofibrillary tangles. Amyloid-beta is neurotoxic small protein with glue-like character. Basically, a toxic waste.

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.

Science: How long does it take to publish a review article?

We got a review manuscript accepted for publication in a well-respected journal. Today I got proofreading for the manuscript and working on it.


Following is the timeline.

Conceptualization of the manuscript and research: June 2019

Writing the first version: June-July 2019

Edit: Early Aug 2019

First submission: Aug 9, 2019

  (Editors decided not to reject it outright, and sent it to expert reviewers. Usual turnaround time for review is 2-3 weeks.)

First decision/response: Oct 8, 2019 (major revision)

  (Revising the manuscript, responding to comments. Needed additional research.)

Second submission: Nov 11, 2019

  (Editors sent it to expert reviewers, requesting their opinions on the revised manuscript.)

Second decision/response: Dec 9, 2019 (Minor revision)

  (Re-revising the manuscript, responding to comments. Additional research. Seeking editorial aid for fixing grammatical errors.)

Third submission: Dec 16, 2019

Third decision/response: Dec 25, 2019 (Accepted for publication)

"Dear Dr. Yamada:

I am very pleased to inform you that following review your manuscript has now been accepted for publication in (the journal). If the editors or reviewers of your paper had additional comments, they have been included at the foot of this letter.

...Thank you for your fine contribution. On behalf of the Editors of (the journal), we look forward to your continued contributions to the Journal.

Sincerely, (signed) Co-Editor in Chief, (the journal)"

  (Then the manuscript was sent to production department)


Proofread request: Jan 14, 2020   (Today!)

  (They usually give us 24(-48) hours to complete proofreading and respond to queries)



I usually do proofreading in 12-24 hours and send it back. So I did.

After sending it back, I got following response:


"Thanks for your email.

Please note that [we] will be closed on 15th Jan 2020 on account of Pongal, a local harvest festival.

We will resume business on 16th Jan 2020, as usual.


Best regards

Author Corrections Team "

The journal's managing editor is in London, UK. Editors-in-chief are in USA and in Germany. Editorial board members are from worldwide, although USA and European countries take the majority.

Now I know that the journal's production department is located in South India (likely, Hyderabad). 

This is how globalization works.

Either way, I am very happy about the manuscript and the concept. 

Yet, we keep on moving. Since this new year I have been working on rewriting an original research manuscript, hoping to sending it out soon.

Like driving, we watch where we are going.

Book: "World fastest Stretching for your personal best flexibility ever" by Takumi Murayama

Japanese Amazon can ship books and many non-food items to the US. When I find something interesting, I order from them.

While searching some books on the subjects of stretching, dance training, figure skating, systema (a Russian martial art), physical conditioning and chiropractics for my leisurely "focused interest" reading, I found this book.

This book, "World fastest Stretching for your personal best flexibility ever", is said to be a Japanese bestselling book with over 100,000 copies sold in 2019. It is for someone who wants to increase flexibility, obviously.

Your flexibility directly affects how you move. It is beneficial to maintain good flexibility. In social settings, stiff dancers just don't look or feel right.

Overly flexible condition (like you see in contortionists) can increase risk of injuries. But for great majority of people, such condition does not apply.


I do stretching in the morning every day. It helps me to figure out my condition for the day. Yet, my "personal best" has stayed about the same for a long time. I picked up this book so that the book might help me get out of the plateau.


A novelty they purport is that they incorporate latest findings from brain science and muscle sheath release technique in the book.

Even so, the book is not too technical nor complicated in the message. That should be a reason that it sold well.

In short, their method comes down to;

(i)   Do active warm-up (like rotating joints, shake, etc. Increase blood flow and warm up the body).

(ii)  Use PNF stretch (proprioceptive neuromuscular facilitation). Know and be conscious about muscles you are stretching and their antagonizing muscles. For two seconds you activate the target muscle(s), then relax it for two seconds, so that you get deeper stretch on the target muscle(s). Repeat 3 times.

(iii) Stimulate and "release" muscle sheath. This helps to correct tense muscles and physical alignments overall, resulting in better moving joints and wider range of motion. Use of props like massage roller, foam roller, rubber band and tennis ball helps.

(iv)  Work on each and all parts of the body (or select part(s) of your interest). They categorized the body parts to twelve; neck, shoulder, arm, back, flank, chest, thigh front, thigh back, thigh outside, thigh inside, calf, and shin, foot and toe.


I tried it a few times during winter break. After the first trial, it did work and I saw increases in  flexibility, although neck stretching left some sore muscles and headache.

I'd include this method once a week (let's say Saturday) and see how it goes. 


Not sure if I seriously try Biellmann myself, though.