Study evaluates association between
genetic factors and brain imaging findings in Alzheimer's disease
By investigating the association between genetic loci
related to Alzheimer's disease and neuroimaging measures related to disease risk,
researchers may have uncovered additional evidence that several previously studied
genetic variants are associated with the development and progression of Alzheimer's
disease and also may have identified new genetic risk factors for further study,
according to a report in the June issue of Archives of Neurology, one of the JAMA/Archives
journals.
"The mechanisms underlying Alzheimer's disease onset and progression remain
largely unexplained," the authors write as background information in the
article. Twin studies have suggested that the condition is 60 percent to 80 percent
heritable. Until recently, only one genetic variant-known as APOE-was shown to
influence Alzheimer's disease risk and age at onset. However, new findings from
genome-wide association studies have identified three additional loci that confer
risk of Alzheimer's disease.
Neuroimaging measures-including the volume of hippocampus, amygdala and other
brain structures-also correlate with the risk and progression of Alzheimer's disease.
"The demonstration that recently discovered genetic risk factors for Alzheimer's
disease also influence these neuroimaging traits would provide important confirmation
of a role for these genetic variants and suggest mechanisms through which they
might be acting," the authors write.
Alessandro Biffi, M.D., and Christopher D. Anderson, M.D., of Massachusetts
General Hospital, Boston, and Broad Institute, Cambridge, Mass., and colleagues
studied the associations between genes and neuroimaging results among 168 individuals
with probable Alzheimer's disease, 357 with mild cognitive impairment and 215
who were cognitively normal.
The four loci previously associated with Alzheimer's disease were assessed,
along with six neuroimaging traits linked to Alzheimer's disease. The APOE gene
had the strongest association with clinical Alzheimer's disease, and was associated
with all the neuroimaging traits except one. The other candidate genes showed
a significant cumulative effect on the neuroimaging measures analyzed.
"Our results indicate that APOE and other previously validated loci for
Alzheimer's disease affect clinical diagnosis of Alzheimer's disease and neuroimaging
measures associated with disease," the authors write. "These findings
suggest that sequence variants that modulate Alzheimer's disease risk in recent
genome-wide association studies may act through their influence on neuroimaging
measures."
In addition, the genetic analysis of neuroimaging traits identified two new
target gene locations-BIN1 and CNTN5-of heightened interest for their relationship
with Alzheimer's disease. "Although our results for these loci can only be
considered preliminary, they may help prioritize targets for future genetic studies
and genome-wide association studies in Alzheimer's disease, particularly given
their association with neuroimaging correlates of Alzheimer's disease and disease
status," the authors write. They add that independent evidence for an association
between the BIN1 gene location and Alzheimer's disease emerged in a recent meta-analysis.
"While we have understood the bases for mendelian, early-onset Alzheimer's
disease for nearly two decades, elucidation of the genetic risks for late-onset
disease beyond the apolipoprotein E locus, discovered in 1993, had been painfully
slow until last year," write John Hardy, Ph.D., of University College London
Institute of Neurology, and Julie Williams, Ph.D., of the Medical Research Council
Centre for Neuropsychiatric Genetics and Genomics, Cardiff, Wales, in an accompanying
editorial.
"With the benefit of hindsight, we now have some indication of why no
other risk loci were found during this period; simply, there are no other loci
with similar effect sizes to apolipoprotein E to be found. Now, however, with
the advent of whole-genome associations, we are beginning to find the weaker risk
loci for the disease."
"These findings, and the genome-wide studies that presaged them, mark
a new period of optimism for those of us who study the etiologies of complex diseases
of the nervous system," Drs. Hardy and Williams write. "While the drought
of genetic findings in Alzheimer's disease has lasted a long time, the flood of
new findings have been a reward worth waiting for."
Please see the article for additional information, including author contributions
and affiliations, financial disclosures, funding and support, etc.
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