Below is Prof. Rappoport’s brief explanation of his research methodology.

After my initial research into how the brain works I compiled a list of major brain disorders and diseases based on textbooks. To analyze each condition, I first reviewed all relevant literature
and identified what is truly known—facts backed by hundreds of studies over decades from multiple research groups.

With this foundation, I formulated an initial hypothesis about the core cause of each disorder. In most cases, this was straightforward. For example, anorexia nervosa involves patients refusing
to eat despite needing food. A logical biological explanation is the activation of
appetite-suppressing receptors like 5-HT2c (SER2c) and CRH2. This approach frames anorexia as a biological phenomenon rather than a psychological one. CRH2’s interaction with gut
serotonin also explains nausea and purging behaviors.

The next step was gathering supporting evidence, which was not difficult given the vast amount of existing research. In 98% of cases, it took anywhere from one minute to an hour to find
substantial supporting data.

This contrasts with conventional research, where scientists design new experiments to test hypotheses. My approach was different: I worked only with validated data, continuously refining
my ideas based on established facts. I would develop a hypothesis, search Google Scholar, and find studies conducted years ago that supported it. In total, I reviewed hundreds of thousands of papers, reading approximately 45,000 in depth.Rather than treating disorders as isolated problems, I structured my findings as an interconnected theory—like a forest rather than separate trees.

Another advantage of this approach is to avoid the sociological bias often present in current research. I completely ignored forums of publication and author identity, focusing on the scientific results themselves. 

During this process, I often found that certain molecules were mistakenly considered the cause
of a disease. The prevailing logic was: “This molecule accumulates, so it must cause the disorder.” Examples include amyloid beta in Alzheimer’s, alpha-synuclein in Parkinson’s, and
TDP-43 in ALS. This reasoning is flawed because accumulation occurs when the brain recruits these molecules to address an issue. Blaming them is like blaming firefighters for a fire.

To refine my understanding, I had to determine each molecule’s physiological role. Knowing its function in a healthy brain allowed me to hypothesize what goes wrong in disease. For example,
I developed a theory that amyloid beta stabilizes synapses after the first 15 minutes of short-term memory. This function is essential; without it, short-term memory would not persist
and would not be converted to long-term memory. Since amyloid beta relies on cholesterol to perform this role, Alzheimer’s may stem from a deficiency of plasma membrane cholesterol
rather than direct amyloid beta accumulation. This aligns with the increased Alzheimer’s risk
associated with the ApoE4 allele, reinforcing an existing body of evidence.