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Early-Onset Dementia Risk Shaped by Variants in Multiple Genes, Study Finds

NEW YORK – Variants in multiple genes variants can contribute to early-onset dementia risk, according to a new analysis from HudsonAlpha Institute for Biotechnology researchers.

To characterize the landscape of genetic risk factors in the disease, the researchers sequenced the genomes of 32 patients with early-onset dementia. As they reported in the journal Molecular Case Studies last week, the researchers found that more than a quarter of the patients had a pathogenic or likely pathogenic variant within key disease genes like APP, C9orf72, CSF1R, and MAPT. But they also noted that a number of patients had risk alleles of moderate penetrance, often in conjunction with one or two APOE ε4 alleles. This, they said, suggests that multiple moderate-risk variants can, when combined, increase the overall risk of early-onset dementia.

"If we can create a more complete picture of the constellation of risk factors for dementia and observe the ways they interact, it could lead to more effective early tests to identify individuals who may be at high risk for dementia, which is critical because the most effective treatments for these diseases will be those that are administered early, perhaps even preventatively," first author Nicholas Cochran from Hudson Alpha said in a statement.

For their analysis, the researchers recruited patients with early-onset dementia from the Memory Disorders Clinic at the University of Alabama at Birmingham, including early-onset Alzheimer's disease, frontotemporal dementia, and other, unspecified dementias. On average, the patients in their cohort developed dementia at the age of 54 years. Half had a strong family history of dementia, while 37.5 percent had some family history and 12.5 percent had no reported family history.

After sequencing and C9orf72 repeat expansion testing, the researchers found that 28 percent of patients had a highly penetrant variant related to their diagnosis and 22 percent had multiple moderately penetrant risk alleles.

For instance, two siblings in the study with a family history of early-onset Alzheimer's disease who developed dementia in their mid-to-late 40s had a well-established pathogenic variant in APP. Additionally, the researchers uncovered three patients with frontotemporal dementia with a pathogenic expansion in C9orf72.

But those frontotemporal dementia patients also had variants in other genes that could potentially contribute to their disease. One person additionally had an established risk variant in ABCA7, an APOE ε4 allele, and a variant of uncertain significance in PSEN1. This, the researchers noted, was in line with previous studies that had suggested additional alleles could contribute to or possibly ever lower the age of clinical onset in C9orf72 expansion carriers.

Other patients in their cohort, meanwhile, had APOE ε4 alleles in combination with other moderate risk variants. For instance, one patient had two APOE ε4 alleles, a PLD3 variant, a variant of uncertain significance in APP, and a private variant in ABI3. Another patient had one APOE ε4 allele and a SORL1 variant, and yet other patients had APOE ε4 alleles in conjunction with TREM2 or with AKAP9 variants.

Additionally, the researchers found that these disease-linked variants are more common in cases, as compared to a set of population controls, and that unaffected family members fell between the cases and controls.

Overall, the researchers said their findings provide support for an oligogenic model of early-onset dementia.