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Exploring genetics behind Alzheimer's resiliency
Myriam
Posted: Saturday, May 3, 2014 5:26 PM
Joined: 12/6/2011
Posts: 3326


Autopsies have revealed that some individuals develop the cellular changes indicative of Alzheimer's disease without ever showing clinical symptoms in their lifetime. 

Vanderbilt University Medical Center memory researchers have discovered a potential genetic variant in these asymptomatic individuals that may make brains more resilient against Alzheimer's. 

  

"Most Alzheimer's research is searching for genes that predict the disease, but we're taking a different approach. We're looking for genes that predict who among those with Alzheimer's pathology will actually show clinical symptoms of the disease," said principal investigator Timothy Hohman, Ph.D., a post-doctoral research fellow in the Center for Human Genetics Research and the Vanderbilt Memory and Alzheimer's Center. 

 

The article, "Genetic modification of the relationship between phosphorylated tau and neurodegeneration," was published online recently in the journal Alzheimer's and Dementia. 

 

The researchers used a marker of Alzheimer's disease found in cerebrospinal fluid called phosphorylated tau. In brain cells, tau is a protein that stabilizes the highways of cellular transport in neurons. In Alzheimer's disease tau forms "tangles" that disrupt cellular messages. 

  

Analyzing a sample of 700 subjects from the Alzheimer's Disease Neuroimaging Initiative, Hohman and colleagues looked for genetic variants that modify the relationship between phosphorylated tau and lateral ventricle dilation -- a measure of disease progression visible with magnetic resonance imaging (MRI). One genetic mutation (rs4728029) was found to relate to both ventricle dilation and cognition and is a marker of neuroinflammation. 

  

"This gene marker appears to be related to an inflammatory response in the presence of phosphorylated tau," Hohman said. 

  

"It appears that certain individuals with a genetic predisposition toward a 'bad' neuroinflammatory response have neurodegeneration. But those with a genetic predisposition toward no inflammatory response, or a reduced one, are able to endure the pathology without marked neurodegeneration." 

 

Hohman hopes to expand the study to include a larger sample and investigate gene and protein expression using data from a large autopsy study of Alzheimer's disease. 

  

"The work highlights the possible mechanism behind asymptomatic Alzheimer's disease, and with that mechanism we may be able to approach intervention from a new perspective. Future interventions may be able to activate these innate response systems that protect against developing Alzheimer's symptoms," Hohman said. 

 

Timothy J. Hohman, Mary Ellen I. Koran, Tricia A. Thornton-Wells. Genetic modification of the relationship between phosphorylated tau and neurodegeneration. Alzheimer's & Dementia, 2014; DOI: 10.1016/j.jalz.2013.12.022  

 

  


Mimi S.
Posted: Saturday, May 3, 2014 7:22 PM
Joined: 11/29/2011
Posts: 7029


Myriam,

I’d love to have a discussion about this.

This reminds me of the nun’s study in which some of the nun’s brains showed plaques like those of AD patyients, but the nuns hadf shown o AD signs while living?

This research is trying to get an answer?


Myriam
Posted: Sunday, May 4, 2014 8:19 PM
Joined: 12/6/2011
Posts: 3326


Mimi, below is an abstract from the "Nun Study". It appears that early linguistic ability can determine? AD.  As you know, in my family AD shows up between the ages of late 40's early 50's. My first symptom didn't occur until I was 62. I came to the U.S. as a young girl speaking Spanish. I had to learn English very quickly. It was a traumatic experience for me, but it could be the reason why I am an anomaly in my family. 

 

Here is the abstract: 

 

Abstract: Findings from the Nun Study indicate that low linguistic ability in early life has a strong association with dementia and premature death in late life. In the present study, we investigated the relationship of linguistic ability in early life to the neuropathology of Alzheimer's disease and cerebrovascular disease. The analyses were done on a subset of 74 participants in the Nun Study for whom we had handwritten autobiographies completed some time between the ages of 19 and 37 (mean = 23 years). An average of 62 years after writing the autobiographies, when the participants were 78 to 97 years old, they died and their brains were removed for our neuropathologic studies. Linguistic ability in early life was measured by the idea (proposition) density of the autobiographies, i.e., a standard measure of the content of ideas in text samples. Idea density scores from early life had strong inverse correlations with the severity of Alzheimer's disease pathology in the neocortex: Correlations between idea density scores and neurofibrillary tangle counts were −0.59 for the frontal lobe, −0.48 for the temporal lobe, and −0.49 for the parietal lobe (all p values < 0.0001). Idea density scores were unrelated to the severity of atherosclerosis of the major arteries at the base of the brain and to the presence of lacunar and large brain infarcts. Low linguistic ability in early life may reflect suboptimal neurological and cognitive development, which might increase susceptibility to the development of Alzheimer's disease pathology in late life. 


Lane Simonian
Posted: Sunday, May 4, 2014 10:31 PM
Joined: 12/12/2011
Posts: 4854


I like this quote from the man who ran the nun study:


"Aging is not the cause of the health problems of old age," Snowdon writes. "Disease is the culprit." Through microscopic studies of the brains of those who have died, and through painstaking assessments of genetics, education, lifestyle, diet, personality differences, and even the number of dental fillings a sister has, the Nun Study has offered up important clues to a longer, healthier life.




Lane Simonian
Posted: Monday, May 5, 2014 10:36 AM
Joined: 12/12/2011
Posts: 4854


The presenilin 1 gene mutation causes Alzheimer's disease by cutting off the neuroprotective phosphatidylinositol 3 kinase/Akt pathway.  Could someone with this gene delay the onset of Alzheimer's disease by stimulating this pathway through moderate exercise or perhaps being bilingual?  The following study suggests this. 


 

Together, our data indicate that the neuroprotective role of PS1 

depends on its ability to activate the PI3K/Akt signaling pathway and that PS1 FAD [familial Alzheimer's disease] mutations increase GSK-3 activity and promote neuronal apoptosis by inhibiting the function of PS1 in this pathway. These observations suggest that stimulation of PI3K/Akt signaling may be beneficial to FAD patients. 


 

http://www.jneurosci.org/content/28/2/483.full.pdf 


 

Moreover, the inhibition of the PI3/Akt pathway leads to the production of peroxynitrites and peroxynitrites lead to the inhibition of the PI3/Akt pathway. 


 


 

Peroxynitrite induces inactivation of the Akt pathway. Furthermore, overexpression of constitutively active Akt inhibits both peroxynitrite-induced Bax translocation and cell death. 


 

http://www.nature.com/cdd/journal/v13/n9/full/4401831a.html 


 


 

A Mediterranean diet, a diet from India (high in spices), and certain essential oils via aromatherapy inhibits the formation of peroxynitrites and reverses their damage, thus potentially delaying the onset of Alzheimer's disease both for those with the presenilin gene mutation and those without it. 


Myriam
Posted: Monday, May 5, 2014 2:07 PM
Joined: 12/6/2011
Posts: 3326


Thank you for reminding me of this, Lane.
Lane Simonian
Posted: Monday, May 5, 2014 2:34 PM
Joined: 12/12/2011
Posts: 4854


Very good, Myriam.  I should have added that many of these things that delay the onset of Alzheimer's disease also help treat it.  Maybe there should be studies of people with genetic mutations leading to early onset Alzheimer's disease who developed the disease relatively late in life and for those people with Alzheimer's disease whose cognitive decline was slowed or even stopped and reversed.  It's not a matter of chance.