Mild Cognitive Impairment Symposium: Hunting for Genes Behind Neurodegenerative Diseases

Owen A. Ross, Ph.D.

Can genetic tests provide input for a diagnosis of Mild Cognitive Impairment (MCI)?  Dr. Owen Ross, Assistant Professor of Neuroscience at Mayo Clinic College of Medicine in Jacksonville, Florida gave a presentation on this topic at the MCI Symposium.

There’s a lot of interest in genetic testing to determine the risk of common diseases, including Alzheimer’s.  The day before the MCI Symposium started, ABC’s Nightline aired a piece on Alzheimer’s (see Part 1 and Part 2).  [Thanks to my friend Rich Bozanich for sending me a link to this.]  In Part 2 of the video report, Terry Moran, one of the program’s co-hosts, receives the results of his genetic testing.  His results indicate he has a 19% lifetime risk for developing Alzheimer’s.  As the piece ends, he and his wife are making plans for long term care arrangements.   In the same video, an Alzheimer’s advocate whose husband and mother have dementia opens the results of her genetic testing.  Her report says she has a 37% lifetime risk, and she says she will put her life in order.

Based on Dr. Ross’s presentation, making plans based on this kind of genetic testing seems premature.  Researchers are still working to identify genetic variations associated with most neurodegenerative diseases, including Parkinson’s and Alzheimer’s, he said.  Hundreds of genes are being studied in connection with these disorders.  However, as quickly as researchers report a new gene association, other researchers report that their studies do not confirm it. 

There are several reasons the search for these genes is so difficult, according to Dr. Ross.  First, the genes associated with the different neurodegenerative diseases vary widely, and second, even the genes that cause a specific disorder may vary.  For example, the genetic variations causing or contributing to Alzheimer’s in one person might not be the same as those in another person with Alzheimer’s.  Third, the effect of a genetic variation can differ across ethnicities. 

Fourth, it may be that extra copies of a normal gene are enough to increase the risk for or even cause neurodegenerative diseases.    Researchers at the Mayo Clinic and the National Institute on Aging have been following some people with an inherited form of Parkinson’s disease/Dementia with Lewy bodies who have three or even four copies (instead of the usual two) of the normal alpha-synuclein gene.  These extra copies of a normal gene, rather than a genetic variation or mutation of that gene, seem to be enough to cause the disease.  In the families studied, the more extra copies there were, the more severe the disease.

These findings could also apply to sporadic (non-inherited) neurodegenerative diseases, Dr. Ross explained in an email conversation after the Symposium.  It may be that even mild “over-expression” of genes – resulting in extra amounts of the proteins they encode – makes people susceptible to the diseases developed late in life. 

He says the interaction of genes with other factors may also make it hard to predict risk based on a simple genetic test.  “The expression of all genes is complex, with genetic factors and most likely certain environmental agents, affecting gene/protein expression,” says Dr. Ross.  “Age, stress and depression may be factors that alter gene expression, for example.”

What does all this mean about getting genetic tests for Mild Cognitive Impairment?  “At this point, unless you have a strong family history or early-onset age, genetic testing for Alzheimer’s, Parkinson’s or Mild Cognitive Impairment has little relevance,” says Dr. Ross.  [Genetic testing for research purposes would be an exception.]  He notes that even if you were found to have a gene that directly caused a neurodegenerative disease [as with rare early onset, inherited Alzheimer’s], there are currently no treatments for specific genetic forms of disease.

But he’s optimistic that with advances in DNA technology, many more genes associated with neurodegenerative diseases will be found, all with potential to cause or contribute to the different forms of Mild Cognitive Impairment.  “When the time is right, these genetic biomarkers will aid in early diagnosis and help determine the future of individualized therapy for each patient,” he says.

Comments

[Gail Rae Hudson]

I'm pleased that you highlighted, in this article, the growing concern among researchers that genetic research isn't as definitive as we've wanted to think. I, too, recently read an article that talked about the same situation. Genetic research, we're beginning to understand, isn't as simple as, say, a drone being programmed to hit a specified target. We're not even sure, at this point, what constitutes a target.
Good advice, at this point, that it's probably premature to "put one's life in order" when genetic testing, in its current state, reveals a 19% or 37% probability of disease.

[Gerta Farber]

I am an 83 year old woman and a member of a genetic-Alzheimer's family. In
my lifetime I am aware of nine family members who have been victims of AD,
the last four in my generation.

In the 20 years since an autopsy specified my mother's AD, dementia-
research has mostly consisted of the very limited success of pharmaceutical
trials. This tunnel-vision has resulted in my familiy's continuing tragedies.

Currently, researchers are reportedly seeking new ways to identify
pre-symptomatic members of such genetic families. They are searching for
methods to identify those at high-risk, who are not yet experiencing
cognitive impairments, so as to test "preventive" medications or life-styles.

This testing is awaiting procedural determination, but there is no need of
evaluating pre-clinical subjects, when critical diagnostic testing and histories
already exist for those who have been diagnosed, or will be diagnosed, with
dementia!

There could be an unlimited number of study participants; families like mine
that are desperate to find answers. Incredibly, current tests are now
uncovering conditions that may be causing or aggravating cognition, without
the further knowledge of probable linkage to COMMON causes.

True causes and preventives of dementia would undeniably emerge in the
comparative histories of millions of patients. A "National Registry" using
instant computerized technology can provide the imperative missing evidence,
and a vital public-reference for genetic links and statistics.

The factors rightly being researched are "nutritional, pharmaceutical, toxic
and environmental, genetic, social/economic, behavioral, medical (such as
other neurodegenerative diseases and pathologies). The lack of volunteers
that has been noted by the researchers as their greatest obstacle, is easily
overcome if dementia evaluations become comparable statistics.

A diagnostic framework and guiding terminology can be created, to organize
categories, stages, and the ongoing global study of brain disease, but can
the historical impediments of our political and pharmaceutical limitations
finally be overcome?


Gerta Farber
2951 Derby St. #113
Berkeley CA 94705
510 841-2050