The sheer complexity of the human brain is daunting. A healthy adult brain includes approximately 100 billion nerve cells called neurons. Neurons are connected through minute gaps called synapses across which impulses pass through neurotransmitters that link more than a 100 trillion points in the central nervous system.

A biochemical process called methylation controls the behavior of the central nervous system. More than three billion times a second, methylation cycles throughout our neurons. In less than a blink of an eye, methylation influences myriad critical functions including DNA gene expression, thinking, behavior, neurotransmitter production and metabolism, and manufacturing energy. Without methylation, we would die.

Over millions of years, some genes in human beings have mutated, resulting in the dysregulation of the central nervous system. When the central nervous system goes awry, brain disorders may develop. Let’s look at a few common brain disorders and methylation gene variants, or single nucleotide polymorphisms (SNPs), associated with them.

ALZHEIMER’S DISEASE

The numbers of Alzheimer’s disease patients are growing at an alarming rate. Nearly 50 million people worldwide have developed Alzheimer’s, according to Alzheimer’s Disease International. Moreover, incidences of the deadly disease are expected to increase significantly over the next few decades.

About 5.7 million Americans are living with Alzheimer’s today, according to the Alzheimer’s Association. Furthermore, between the years 2000 and 2015, deaths from Alzheimer’s increased a whopping 123 percent!  By the year 2050, the number of Americans suffering from Alzheimer’s is projected to triple.

The medical community’s views about why the prevalence of Alzheimer’s is rising at a staggering rate remain varied. Many believe genetics and environmental stress, or epigenetics, may serve as risk factors. (Discussed later in this post.)

First, let’s understand what happens to the brain after Alzheimer’s strikes it.

The Brain on Alzheimer’s

The adverse effects of Alzheimer’s disease on the brain are obvious to medical personnel interpreting the images. First, the brain of an Alzheimer’s patient is smaller than one of a healthy adult. Second, the decreased brain size is a result of brain tissue containing beta protein fragments, called plaques, that collect between nerve cells in the brain. Third, dead or dying neurons, called tangles, are visibly present in the brain of an Alzheimer’s patient.

Signals traveling through the brain’s extensive neural network form the basis of memories, thoughts, and feelings. When plaques and tangles develop in the brain, signaling essential to cognitive function becomes disrupted. Consequently, brain cells are destroyed, resulting in progressive cognitive issues including memory loss, poor decision-making and behavioral problems.

APOE4: A Major Risk Factor for Alzheimer’s

A variant of the gene called apolipoprotein E, ApoE4 (rs7412), has emerged as a major risk factor for Alzheimer’s disease as well as other neurodegenerative disorders. Therefore, persons with ApoE4 may be predisposed to developing Alzheimer’s if environmental stress (epigenetics) expresses, or turns on, this particular gene variant. When neurons are stressed or damaged, they produce neurotoxic fragments that escape their usual processing pathway, causing mitochondrial dysfunction and accumulation of tangles.

DEPRESSION

Over 350 million people globally suffer from depression.  An estimated 17.3 million Americans have experienced at least one major depressive disorder.

A major depressive disorder, as described in the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5), is defined as “a period of at least two weeks when a person experienced a depressed mood or loss of interest or pleasure in daily activities.” Depressive symptoms include problems with sleep, eating, energy, concentration or self-worth, and in some cases result in suicide.

Despite depression being identified for centuries, few truly understand this condition. Furthermore, many people unknowingly suffer from depression and do not seek treatment.

The medical community acknowledges that depression can be inherited. In fact, a number of depression-related SNPs have been identified. Let’s look at three common methylation SNPs that are associated with depressive disorders.

MTHFR C677T

One of two primary methylation SNPs associated with depression is MTHFR C677T (rs1801133), found in approximately 40 percent of the population. The MTHFR, or methylenetetrahydrofolate reductase, genes act as the gateways to methylation. If the MTHFR C677T gene variant is turned on by stress or other epigenetics, homocysteine may be elevated, and folate and other B vitamins may be decreased. An expressed MTHFR C677T gene variant may lead to health issues including dysregulation of neurotransmitters, leading to depression.

MTHFR A1298C

The other main methylation SNP connected to depression is MTHFR A1298C (rs1801131). Approximately 20 percent of the population has this less-common MTHFR A1298C SNP. Similar to the MTHFR C677T gene variant, a turned-on MTHFR A1298C gene mutation may decrease the production of neurotransmitters, including serotonin, dopamine, and norepinephrine.

MAO-A R297R

Another common methylation gene variant directly related to depression is called MAO-A R297R (rs6323), found in at least one-third of the population. The MAO-A, or monoamine oxidase A, gene is commonly referred to as the “warrior” gene, owing to its association with aggression in some people. Furthermore, the MAO-A R297R variant may decrease the metabolism of neurotransmitters, resulting in their dysregulation.

It is important to note that there are many other methylation gene variants that may adversely affect the brain’s neurotransmitters, leading to depression. Many of these SNPs and associate research are discussed in the easy-to-read book entitled Silent Inheritance.

PARKINSON’S DISEASE

About ten million persons globally are living with Parkinson’s disease. Nearly one million Americans suffer from Parkinson’s. Men are one and one-half times more likely than women to develop Parkinson’s.

Parkinson’s disease was first described about 200 years ago. Yet treating Parkinson’s patients continue to pose a challenge for the medical community. No two individuals with Parkinson’s appear to experience the same precise symptoms, rate of progression, age of onset, or treatment response. However, genetics plays a role in understanding these differences. Let’s look at a few methylation gene mutations associated with Parkinson’s disease.

LRRK2

Discovered in 2002 by Japanese researchers, the mutation of gene LRRK2 is found in up to two percent of all Parkinson’s patients. Specific ethnic groups including Ashkenazi Jews, North African Arab Berber, and Basque have a higher prevalence (approximately thirty percent) of Parkinson’s than the general population.

The medical community has identified at least twenty Parkinson’s-associated mutations that may occur in the LRRK2 gene. For example, a more common gene mutation of LRRK2 is called G2019S.

In addition, researchers at the Thomas Jefferson University examined the LRRK2 gene mutation and found that Parkinson’s may not start in the brain. The science suggests that that the LRRK2 gene variant may alter how immune cells react to general infections. In turn, the reaction triggers the inflammatory response in the brain.  This research was published in the 2018 issue of the journal Brain. 

SNCA

Identified in 1997 as the first Parkinson’s gene, the SNCA gene produces a protein called alpha-synuclein, found primarily at the tips of neurons. Genetic modifications to the SNCA gene may result in the manufacture of excess alpha-synuclein. The protein accumulates abnormally in the brains of people with Parkinson’s.  Furthermore, the buildup of alpha-synuclein in clumps is toxic. These clumps are found in all persons with Parkinson’s.

GBA

Researchers have identified a number of mutations to the GBA (glucosidase beta acid) gene associated with an increased link to Parkinson’s disease. About five to ten percent of Parkinson’s patients carry a GBA mutation. Scientists have identified more than 380 mutations of the GBA gene, and only a small number of these gene variants have been associated with an increased risk for Parkinson’s.

For example, the GBA1 gene makes a protein that is responsible for the cells’ garbage disposal system. Ultimately, variants in GBA1 are connected to the buildup of alpha-synuclein clumps, a tell-tale indicator of Parkinson’s disease.

REDUCING THE RISK OF GENETIC BRAIN DISORDERS

Discovery of genes and their variants associated with the brain disorders discussed in this piece have aided researchers in the pharmaceutical community in finding effective treatments. While pharmaceutical research has been somewhat successful in treating depression, solutions for Alzheimer’s and Parkinson’s diseases are in their infancy.

Meanwhile, you may be asking, “What can I do to decrease the risk of turning on inherited, brain-disorder gene variants?” As mentioned earlier in this post, environmental factors, called epigenetics, control whether gene variants are expressed or turned on. Think: the air we breathe, the chemicals in indoor materials, the consumption of food and beverages, the application of beauty products, and the intake of medications. It is challenging to avoid these epigenetic factors. Moreover, emotional stress in life itself can affect the status of your gene variants. The bottom-line answer to the question posed at the beginning of this paragraph is to maintain a healthy lifestyle including taking folate, vitamin B6, and vitamin B12.

Editor’s Note: Susan Rex Ryan is the author of the book entitled Silent Inheritance that discusses genetic depression. She also wrote the awarding-winning vitamin D book Defend Your Life as well as its updated 2019 version entitled, Defend Your Life II.

© Copyright 2019. Smilin Sue Publishing, LLC. All rights reserved. Special permission is granted to Curtis Leda (USA) to post this article on his website and Facebook support groups.