Restoring Cognitive Reserve

Building Brain Function Back Up   

There are several known risk factors for the development of Alzheimer’s disease.  Some are non-modifiable such as genetic predispositions and others are modifiable highly related to lifestyle and behavior.

·         Genetics

·         Diet

·         Insulin levels

·         Cognitive reserve

·         Diabetes

·         Omega-3 fatty acid intake

·         B vitamin/methylation factor intake

·         Exercise levels

·         Sleep quality

·         Inflammation

One of the important identified risk factors that is modifiable is cognitive reserve.  In essence, cognitive reserve is the “savings account” of brain resources that have been built up to ensure the brain will still be highly functional with advancing age.   Cognitive reserve is developed by the accumulative effects of “brain exercise” that occurs during early and mid-adult life.  Comparing subjects with the highest levels of cognitive reserve to those with low levels has found that higher levels may reduce the risk of any type of dementia by about 45%.  It also means that having lower levels of cognitive reserve significantly increases the risk of cognitive decline.

It is a natural part of aging for the brain to lose neurons (brain cells) and their connections to other cells that create functions such as memory.  This is analogous to gradually losing muscle mass with advancing age.  As with muscle mass, the higher  the development of brain mass/reserves going into older ages, the less affected brain function will be with the normal age related decline. 

Factors that help cognitive reserves include higher educational attainment, higher occupational attainment and enjoyable and engaging leisure activities.  They literally create brain hypertrophy such as weight lifting does in skeletal muscle or weight bearing exercise does for bone.  What we have to work with after 5-6 decades literally is dependent on what we have built up and then work to maintain.

It is important to appreciate that lower cognitive reserves are like lower amounts of muscle mass.  Generally, someone with either lower muscle mass or lower cognitive reserves can function relatively normal on a day to day basis.  However, as muscle mass is normally lost with age, starting with lower reserves increases the risk of related diseases such as joint degeneration.

The ideal situation with cognitive reserves is to develop and maintain high levels throughout adult life.  However, many persons will find that they are developing some state of cognitive impairment and will be faced with the more challenging task of building cognitive function back up to a fully functional state later in life.  Fortunately, tools have evolved to make this possible.

There are different levels of brain training that can be used for this purpose.  The most sophisticated is neurofeedback, or EEG guided brain training.  The first part of this process is testing with a QEEG brainmap.  This test looks at the brainwave electrical pattern in several different brain areas.  There are multiple changes in brain QEEG brain waves seen in neurodegenerative disease.  The QEEG brainmap becomes the map used to design a training pattern to reactivate and balance brain activity.  This is done with neurofeedback which is brain biofeedback. 

During biofeedback monitoring an activity within the body is done while techniques are used by the individual to learn to improve that body activity.  During neurofeedback EEG monitoring is integrated with stimuli to the brain such as vision and sound such as watching a movie.  If the brain wave pattern is corrected, the person is rewarded with the vision and sound of the movie remaining clear.  If the brain waves wander into the abnormal pattern, the reward is withdrawn stimulating the brain to change and try to restore the reward.

Several studies have examined the ability of neurofeedback to improve cognitive functioning in subjects with cognitive decline. These studies have universally found that neurofeedback significantly improves cognitive function especially with memory function.  In one of the most striking studies 20 subjects, half with Alzheimer’s and half with other forms of dementia were treated with a comprehensive neurofeedback program.  The mean MMSE test score before treatment was 18.8 which is consistent with moderate cognitive decline/Alzheimer’s. 

Follow-up MMSE scores after the series of neurofeedback treatments was 25.2 for the Alzheimer’s group and 23.9 for the other dementia group. 

A secondary problem associated with Alzheimer’s is attention.  This is often impaired and further affects the disease related impairment.  Similarly, favorable changes also occurred in TOVA test scores which measure impairment associated with attention deficit.

The researchers commented on the value of neurofeedback over general forms of brain training.  They found that the pattern of brain wave activation imbalance was unique to each subject and that the neurofeedback training protocol used in each was specific to the imbalance seen in their EEG brainmap.

Cognitive reserves are an important variable in the risk of development of Alzheimer’s and other forms of dementia.  The best time to build-up these protective investments is throughout early and mid-life.  Fortunately for those who have developed the disease and have low cognitive reserves, treatment such as neurofeedback can correct this deficit.

apoE4 and Genetic Mediated Risk of Alzheimer’s

apoE is an apoprotein which means that it is a protein structure that helps to transport fats such as cholesterol.  However, it has several other functions which are important to all tissues including the brain.  One of its jobs is helping to remove a major abnormal protein that is continually being made in the brain called beta amyloid.  Beta amyloid build up in the brain is a primary mechanism involved in Alzheimer’s disease and other forms of dementia.  The excessive build-up of beta amyloid in the brain is a major cause of the degeneration neurons and their connection to other neurons which leads to loss of brain volume and function.  Certain genetic variations in apoE cause it to be heavily impaired in its ability to remove beta amyloid.

apoE is made by a gene located on chromosome 19 and has three different forms: apoE 2, apoE 3, and apoE 4.  The apoE 4 variety greatly increases the risk of developing Alzheimer’s disease. 

As each of us has two copies of the gene, each person may have one of several combinations of the 3 types of apoE.  Having two copies of the same apoE such as apoE3/3 is called homozygous, while having two different copies such as apoE 3/4 is heterozygous.  The functional apoE can be made from either gene so at any time the available apoE can be some good and some bad in someone heterozygous with one higher risk gene and one lower risk gene.  Being homozygous with two lower risk copies lowers the risk more than having only one lower risk copy.  Similarly, risk is greatly increased with two copies of the high risk gene such as apoE 4.

The apoE 2 genotype is the most protective against Alzheimer’s but only 7% of the population is apoE 2/2.  The highest risk group for Alzheimer’s disease is the apoE 4/4 genotype.  This genotype is present in about 15% of the population with another 15-20% having one copy of apoE 4. 

By age 65 approximately 1 in 6 persons will develop the disease with the risk increasing progressively with age.  The apoE 3 geneotype is most common and is used to predict relative risk of the disease.

The risk with apoE 2/2 is reduced 40% compared to apoE 3.  Having one apoE 4 gene increases risk between 2 ½ and 3 ½ times.  The apoE 4/4 genotype increases the risk 15 to 20 times.

Most genetic mediated disease associations are “polygenic” meaning that there are multiple gene abnormalities in addition to apoE which occur in the same person contributing to the overall risk.  This is why some studies looking only at the increased risk associated with apoE4/4 find the risk is increased 10x and others find it is increased by 20x.  These other factors are being discovered and will contribute to the analysis in the progressive future, but the apoE type remains the single greatest genetic risk factor.

A key point to understand in the assessment of real life risk is that the genetic factors do not independently trigger the disease.  The process also involves the presence of environmental stressors which are largely lifestyle related.  Not everyone with the apoE 4 genotype will develop the disease, and a significant number of persons with the lower risk genotypes will still develop it.  The genetic factors appear to make certain persons less tolerant to the different stressors that imbalanced lifestyle generates.  In essence, the higher risk genetic persons require much tighter lifestyle control to minimize the risk.

Lifestyle is completely modifiable and should form the basis of risk modification.  Family history is also an important variable being driven both by genetic and by lifestyle related factors.  It tends to have perhaps more positive predictive value than negative predictive value.  This simply means that if someone’s family history is positive, risk is greatly increased; but if it is negative, they are not necessarily protected.  We have seen progressive increases over the past 50 years in the lifestyle related factors and the diseases they drive such as overweight and diabetes.  The presence of several strong factors in the same person may trigger degenerative brain disease risk in the absence of genetic risk.

One additional important factor in risk evaluation is timing.  The interaction between the lifestyle driven factors such as high inflammatory markers or high insulin levels cause the progressive injury to the brain over several decades.  The onset of symptoms such as memory loss do not occur until significant loss of brain volume has occurred.  The ideal risk reduction program should involve evaluation of genetic and potential triggering lifestyle related factors in mid-life when the cellular level damage is beginning.

Very forward thinking treatment programs such as the Bredesen Protocol  have demonstrated high levels of success in the earlier stages of the process.  The first symptomatic phase is SCI, or subjective cognitive impairment.  In this phase the individual notices some memory deficit, but it is not to the degree that is readily apparent to others.  The next stage is MCI or minor cognitive impairment where the symptoms can now be noticed by others close to the individual, but they do not interfere with normal basic functioning.  Once the diagnosis of early Alzheimer’s is made, the individual has begun to lose some ability to normally function such as working, being able to remember where they are and get where they are going and other similar problems.

The point at which progressive lifestyle management programs become less successful appears to be between mild and moderate Alzheimer’s disease when the impairment has grown enough that evaluation is sought.   Given the rapid increase in the rates of Alzheimer’s disease it is wise to have genetic risk testing early.  If positive genetic risk is combined with a positive family history, extensive testing of lifestyle related risk factors should be undertaken and targeted lifestyle interventions should be implemented.  Genetics are “unfair” as we have no choice in the matter.  Fortunately, lifestyle is the opposite, we all have a choice.