Alzheimer's Disease Risk Indicated by Novel Genetic Tool

Alzheimer’s Disease Risk Indicated by Novel Genetic Tool

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Highlights
  • Alzheimer's disease (AD) is a progressive neurodegenerative disease and has no cure.
  • Extensive research is going on in the field of AD.
  • New genetic marker predicts lifetime risk of developing AD including age of onset.
  • This data could be important in estimating outcome of the disease and useful for teams conducting clinical trials.
A novel genetic score called the polygenic hazard score (PHS) helps to determine one's lifetime risk of developing AD, and also indicates the age of onset. This interesting study was carried out by scientists at University of California San Diego School of Medicine and University of California San Francisco.
Alzheimer’s Disease Risk Indicated by Novel Genetic Tool

Aim of the Research

The research team combined genetic information from patients with AD, coupled with known incidence rates from the U.S. population, and evolved a means of instantly calculating the lifetime risk of developing AD at any given age.

"We combined genetic data from large, independent cohorts of patients with AD with epidemiological estimates to create the scoring, then replicated our findings on an independent sample and validated them with known biomarkers of Alzheimer's pathology," said co-first author Rahul S. Desikan, MD, PhD, clinical instructor in the UCSF Department of Radiology & Biomedical Imaging.

Interestingly, and quite unsettlingly, even for those who are normal and don't suffer from dementia, this tool can accurately predict the risk and age of onset.

Says Desikan, "Even if you don't already have dementia, you can find out what is your yearly risk for AD onset, based on your age and genetic information. We think these measures of polygenetic risk, of involving multiple genes, will be very informative for early AD diagnosis, both in determining prognosis and as an enrichment strategy in clinical trials."

Details of the Research

The research team analyzed genetic information from more than 70,000 AD patients, along with normal elderly cohorts, who were a part of numerous research projects, such as the Alzheimer's Disease Genetics Consortium, the National Alzheimer's Coordinating Center and the Alzheimer's Disease Neuroimaging Initiative.

The team analyzed the genome of the volunteers to determine the presence of single nucleotide polymorphisms or SNPs, which represent variations in a single nucleotide (building block of DNA) occurring at specific positions in the genome.

These SNPs influence susceptibility to disease. The scientists looked specifically at the association between specific SNPs and Alzheimer's disease and for APOE status (presence of APOE E4 allele is linked to a greater risk of developing late onset AD).

The research group developed a continuous polygenic hazard (PHS) score based on the genetic analysis to predict age-specific risk of developing AD, then tested it in two separate cohorts or defined groups of people.

Findings of the Study References:

  • Persons in the top PHS quartile developed AD at a significantly younger age and showed the highest annual AD incidence rate.
  • PHS also identified people who were cognitively normal at the time but eventually developed AD.
  • Interestingly, even in persons who were negative for the APOE E4 allele, the most important risk factor for AD genetically, PHS indicated age of onset; persons with high PHS scores developed AD 10-15 years earlier compared to those with a low score.
  • PHS strongly predicted age of AD onset and progression from normal aging to AD, correlating with biomarkers of AD neurodegeneration and neuropathology.
"From a clinical perspective, the polygenic hazard score provides a novel way not just to assess an individual's lifetime risk of developing AD, but also to predict the age of disease onset," said senior author Anders Dale, PhD, director of the Center for Translational Imaging and Precision Medicine and professor in neurosciences, radiology, psychiatry and cognitive science at UC San Diego School of Medicine. "Equally important, continuous polygenic testing of AD genetic risk can better inform prevention and therapeutic trials and be useful in determining which individuals are most likely to respond to therapy."

Possible Limitations of the Study

The authors noted that their study population consists of persons predominantly of European descent, and therefore the results do not indicate AD risk or incidence in other populations such as Afro-Americans or Latinos.

"This limitation is an unfortunate product of available genetic studies. To have good predictive performance, the genetic risk score requires a large amount of data to train, but currently only European cohorts have reached this critical mass," said co-first author Chun Chieh Fan, MD, in the Department of Cognitive Science at UC San Diego.

But "given the genome-wide association studies across ethnic populations that are emerging, the health disparities in the field of genetic prediction will be removed," Fan added.

References:
  1. Rahul S. Desikan, Chun Chieh Fan, Yunpeng Wang, Andrew J. Schork, Howard J. Cabral, L. Adrienne Cupples, Wesley K. Thompson, Lilah Besser, Walter A. Kukull, Dominic Holland, Chi-Hua Chen, James B. Brewer, David S. Karow, Karolina Kauppi, Aree Witoelar, Celeste M. Karch, Luke W. Bonham, Jennifer S. Yokoyama, Howard J. Rosen, Bruce L. Miller, William P. Dillon, David M. Wilson, Christopher P. Hess, Margaret Pericak-Vance, Jonathan L. Haines, Lindsay A. Farrer, Richard Mayeux, John Hardy, Alison M. Goate, Bradley T. Hyman, Gerard D. Schellenberg, Linda K. McEvoy, Ole A. Andreassen, Anders M. Dale. "Genetic assessment of age-associated Alzheimer disease risk: Development and validation of a polygenic hazard score." PLOS Medicine, (2017); 14 (3): e1002258 DOI: 10.1371/journal.pmed.1002258


Source: Medindia

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