Study identifies biomarkers that could guide precision medicine therapies for Alzheimer's disease

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Greyhound
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Study identifies biomarkers that could guide precision medicine therapies for Alzheimer's disease

Post by Greyhound »

Well we now have all the information we need?

logo for the University of Arizona Health Sciences April 28, 2022 study identifies biomarkers that could guide precision medicine therapies for Alzheimer's disease novel findings from research at the Center for Innovation in Brain Science indicate the APO
Peer-Reviewed Publication

University of Arizona Health Sciences
TUCSON, Arizona — A University of Arizona Health Sciences study found that a specific genotype of the APOE gene, better known as the Alzheimer’s gene, is able to significantly influence metabolic changes and override sex-specific differences between men and women with Alzheimer’s disease.

The discovery may provide critical insights for personalized medicine related to late-onset Alzheimer’s disease, a complex neurodegenerative disease characterized by multiple progressive stages including cognitive decline.

“One of the most interesting findings of our study is the identification of key drivers of metabolic pathways that discriminate between Alzheimer’s disease and cognitively normal individuals when patient groups were separated by sex and APOE genotype,” said Rui Chang, PhD, a member of the University of Arizona Health Sciences Center for Innovation in Brain Science and lead author of the study. “These patient-specific metabolic targets will shed light on the discovery of precision therapeutics for Alzheimer’s patients, which has not been done in previous studies.”

The paper, “Predictive metabolic networks reveal sex and APOE genotype-specific metabolic signatures and drivers for precision medicine in Alzheimer’s Disease,” was published today in Alzheimer’s and Dementia: The Journal of the Alzheimer’s Association.

The APOE gene is involved in making a protein that helps carry cholesterol and other types of fat in the bloodstream. There are several genotypes, or variations, of APOE based on the specific gene variants an individual inherits. The APOEe4 genotype has been identified as a risk factor for Alzheimer’s disease.

Dr. Chang and the research team integrated a metabolic network model with advanced machine learning approaches to perform a computational analysis on 1,517 serum samples provided by the Alzheimer’s Disease Neuroimaging Initiative.

First, they identified common metabolic signatures of late-onset Alzheimer’s disease. Next, they separated the network into clusters by sex to identify sex-specific metabolic changes and by genotype to identify other metabolic signatures influenced by the APOEe4 genotype.

Finally, they stratified patients by intersection of sex and APOEe4 status together and found that the APOEe4 genotype was able to significantly influence metabolic changes while overriding sex-specific differences in males and females.

Additionally, they identified serum-based metabolic biomarker panels that are predictive of disease state and associated with clinical cognitive function for each of the eight patient subgroups stratified by sex and/or APOEe4 status.

These novel patient-specific metabolic panels identify key metabolic drivers of late-onset Alzheimer’s disease that could be evaluated as therapeutic targets. The findings have the potential to greatly accelerate drug development for Alzheimer’s disease while providing outcome measures for clinical trials.

"Dr. Chang’s research provides an initial but critical step toward the development of personalized and precision medicine for Alzheimer’s disease,” said Roberta Diaz Brinton, PhD, Regents Professor of Pharmacology and director of the Center for Innovation in Brain Science. “This study provides an operational strategy to achieve that goal by integrating clinical cognitive assessments, metabolic profiling and a computational network model to identify targeted therapeutics for patients.”

https://www.eurekalert.org/news-releases/951198
Gail
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Re: Study identifies biomarkers that could guide precision medicine therapies for Alzheimer's disease

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Greyhound,

I could not find the specific biomarkers that this study identified. I pulled up the link and it did not list the biomarkers either.
I wonder if these biomarkers correlate with the biomarkers Bredesen follows?
Thank you for the posting!
BrianR
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Re: Study identifies biomarkers that could guide precision medicine therapies for Alzheimer's disease

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Gail wrote: Fri May 13, 2022 7:43 am Greyhound,

I could not find the specific biomarkers that this study identified. I pulled up the link and it did not list the biomarkers either.
I wonder if these biomarkers correlate with the biomarkers Bredesen follows?
Thank you for the posting!
Gail, I quickly skimmed the paper https://alz-journals.onlinelibrary.wiley.com/doi/full/10.1002/alz.12675 and it appeared that the Results section and the Discussion section referenced various metabolic agents which their model seemed to suggest would be correlated with better AD outcomes.

I would guess that careful reading of those two sections (challenging as that may be), as well as review of their relevant Supplemental MS-WORD tables might give you a list of their interesting biomarkers. I suspect it's much less clear how that list might correspond directly to Dr. Bredesen's recommendations.
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Re: Study identifies biomarkers that could guide precision medicine therapies for Alzheimer's disease

Post by NF52 »

Greyhound wrote:we now have all the information we need?
Gail wrote: Fri May 13, 2022 7:43 am Greyhound,

I could not find the specific biomarkers that this study identified. I pulled up the link and it did not list the biomarkers either.
I wonder if these biomarkers correlate with the biomarkers Bredesen follows?
Thank you for the posting!
BrianR wrote: Fri May 13, 2022 5:02 pm Gail, I quickly skimmed the paper https://alz-journals.onlinelibrary.wiley.com/doi/full/10.1002/alz.12675 and it appeared that the Results section and the Discussion section referenced various metabolic agents which their model seemed to suggest would be correlated with better AD outcomes....
It seems that this is not quite all the information we need, but more of a deep dive into a well-studied cohort (the ADNI study of more than a decade) to find early metabolic changes in markers that may differ by male/females, ApoE4 or not-ApoE4 and diagnosis of normal cognition, MCI or mild Alzheimer's. Not surprisingly, they do find changes in metabolism--and like so many other studies, changes between ApoE 4+ and ApoE4-. But it also seems that the near-term impact of this will be for other studies to retrospectively conduct similar analyses, since they note this was a small group, and while they don't mention it, most of the original ADNI participants were White.
The reduced PC (phosphatidylcholine) levels observed in AD may reflect abnormal membrane functions including synaptic transmission and processing of the amyloid precursor protein contributing to Aβ (amyloid beta) production.31 Furthermore, alterations in PCs may contribute to increased inflammation, one of the underlying mechanisms of LOAD... Overall, our novel findings indicate that APOE ɛ4 genotype drives metabolic signature to a PC-focused profile regardless of the patient sex...the number of subjects in each group was relatively small and studies in larger longitudinal cohorts are warranted to confirm these results.
Based on the biomarker panel of network-derived metabolites and demographic features, we identified... taurine as unique markers for APOE ɛ4+ males; PC aa C34:4 as a specific marker for APOE ɛ4– females; and PC aa C38:0 as a specific marker for APOE ɛ4+ females.
Per Gail's question about biomarkers, this article doesn't mention the role of estrogen and menopause in AD risk, but you might find this interesting, especially since the evidence for hormone replacement therapy (HRT) within 10 years of menopause, but not after age 70, seems to be stronger each year:
Estrogen is a master regulator that functions through a network of estrogen receptors subtypes alpha (ER-α) and beta (ER-β). Estrogen receptor-beta (ER-β) has been shown to regulate a key component of the innate immune response known as the inflammasome, and it also is involved in regulation of neuronal mitochondrial function...ER-β activation in the brain confers ischemic protection, stimulates mitochondrial functions, and inhibits inflammasome activation. ER-β agonists may be safer in that ER-β lacks the ability to stimulate the proliferation of breast or endometrial tissue. The ER-β agonist may be able to act both on the cerebro- and cardiovascular system to reduce the ischemic burden. . The peri-menopause in a woman’s life: a systemic inflammatory phase that enables later neurodegenerative disease
Estrogen is something women can measure and don't have to wait for years more of research--at least if they're within the window of opportunity in mid-life.
4/4 and still an optimist!
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