Summary: A new study reports the genetic risk score may be able to detect those at higher risk for developing Alzheimer’s disease, even during early adulthood.
New research shows that a genetic risk score may detect those at higher risk for Alzheimer’s disease long before symptoms appear, even possibly in healthy young adults, according to a study published in the July 6, 2016, online issue of Neurology.
“The stage of Alzheimer’s before symptoms show up is thought to last over a decade,” said Elizabeth C. Mormino, PhD, with Massachusetts General Hospital in Charlestown, Mass. “Given that current clinical trials are testing whether therapies can slow memory and thinking decline among people at risk for the disease, it is critical to understand the influence of risk factors before symptoms are present.”
For the study, researchers calculated a polygenic risk score, or a numeric score based on whether or not a person has several high-risk gene variants, in 166 people with dementia and 1,026 without dementia. Participants had an average age of 75. Scientists also looked for specific markers of Alzheimer’s disease. The markers included memory and thinking decline, clinical progression of the disease and the volume of the hippocampus (the memory center of the brain).
Researchers also looked at links between the risk score and hippocampus volume in 1,322 healthy, younger participants between the ages of 18 and 35.
The study found that within older people free of dementia, a higher polygenic risk score was associated with worse memory and smaller hippocampus at the start of the study, accounting for 2.3 percent of the total variance in memory and 2.0 percent of the variance in hippocampus volume.
Over the three years of the study, a higher score was also linked to greater longitudinal memory and executive function decline and clinical progression of the disease. Finally, the risk score was associated with overall disease progression, with 15 of 194 participants that were cognitively normal at the start of the study developing mild cognitive impairment or Alzheimer’s disease, and 143 of 332 with mild cognitive impairment at the start of the study developing Alzheimer’s disease after three years. Each standard deviation increase in polygenic risk was associated with a 1.6 times increase in risk of clinical progression.
Within the younger group, a higher risk score was tied to smaller hippocampus volume. For the younger group, the risk score accounted for 0.2 percent of the difference in hippocampus volume between those with high and low risk scores.
“Our study was small and larger numbers of participants will need to be studied to confirm our findings,” said Mormino. “The goal of this type of research is to help physicians better identify those at high risk of dementia so that future preventative treatments may be used as early as possible.”
Funding: The study was supported by the National Institutes of Health.
Source: Michelle Uher – AAN
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Original Research: Abstract for “Polygenic risk of Alzheimer disease is associated with early- and late-life processes” by Elizabeth C. Mormino, Reisa A. Sperling, Avram J. Holmes, Randy L. Buckner, Philip L. De Jager, Jordan W. Smoller, Mert R. Sabuncu, and For the Alzheimer’s Disease Neuroimaging Initiative in Neurology. Published online July 6 2016 doi:10.1212/WNL.0000000000002922
Polygenic risk of Alzheimer disease is associated with early- and late-life processes
Objective: To examine associations between aggregate genetic risk and Alzheimer disease (AD) markers in stages preceding the clinical symptoms of dementia using data from 2 large observational cohort studies.
Methods: We computed polygenic risk scores (PGRS) using summary statistics from the International Genomics of Alzheimer’s Project genome-wide association study of AD. Associations between PGRS and AD markers (cognitive decline, clinical progression, hippocampus volume, and β-amyloid) were assessed within older participants with dementia. Associations between PGRS and hippocampus volume were additionally examined within healthy younger participants (age 18–35 years).
Results: Within participants without dementia, elevated PGRS was associated with worse memory (p = 0.002) and smaller hippocampus (p = 0.002) at baseline, as well as greater longitudinal cognitive decline (memory: p = 0.0005, executive function: p = 0.01) and clinical progression (p < 0.00001). High PGRS was associated with AD-like levels of β-amyloid burden as measured with florbetapir PET (p = 0.03) but did not reach statistical significance for CSF β-amyloid (p = 0.11). Within the younger group, higher PGRS was associated with smaller hippocampus volume (p = 0.05). This pattern was evident when examining a PGRS that included many loci below the genome-wide association study (GWAS)–level significance threshold (16,123 single nucleotide polymorphisms), but not when PGRS was restricted to GWAS-level significant loci (18 single nucleotide polymorphisms).
Conclusions: Effects related to common genetic risk loci distributed throughout the genome are detectable among individuals without dementia. The influence of this genetic risk may begin in early life and make an individual more susceptible to cognitive impairment in late life. Future refinement of polygenic risk scores may help identify individuals at risk for AD dementia.
“Polygenic risk of Alzheimer disease is associated with early- and late-life processes” by Elizabeth C. Mormino, Reisa A. Sperling, Avram J. Holmes, Randy L. Buckner, Philip L. De Jager, Jordan W. Smoller, Mert R. Sabuncu, and For the Alzheimer’s Disease Neuroimaging Initiative in Neurology. Published online July 6 2016 doi:10.1212/WNL.0000000000002922