- 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
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
Aim of the Research
The research team combined genetic
information from patients with AD, coupled with known incidence rates from the
and evolved a means of instantly
calculating the lifetime risk of developing AD at any given age
‘Single nucleotide polymorphisms (SNPs), a type of DNA sequence variation within a given population, predicts lifetime risk of Alzheimer’s disease and age of onset.’
"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
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
scientists looked specifically at the association between specific SNPs and
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
- 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
"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
- 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: