Genetic risk for Alzheimer’s disease may be related to brain function and hippocampal volume in childhood, suggesting a neurodevelopmental origin of the disease, new research suggests.
“We found that the genetic risk for Alzheimer’s disease is associated with lower performance in memory tasks even decades before the onset of the disease,” Giovanni Salum, MD, PhD, from Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil, told Medscape Medical News.
The possibility of a neurodevelopmental origin opens opportunities for research on Alzheimer’s disease prevention, risk detection, and pathogenesis, he noted.
The study was published online March 2 in the American Journal of Psychiatry.
Novel Study in Children
“Alzheimer’s disease is a highly heritable neurodegenerative disease associated with the apolipoprotein E ε4 (APOE-ε4) allele and with several other single-nucleotide polymorphisms (SNPs). Even though each of these SNPs presents a small effect size, the aggregation of multiple loci may have significant predictive utility,” Salum said.
“Previous studies showed associations between polygenic risk score for Alzheimer’s disease and both memory decline and lower hippocampal volume in adults. Nevertheless, studies investigating this issue in children and adolescents were lacking,” he added.
The researchers studied associations of Alzheimer’s polygenic risk score with cognitive abilities and hippocampal volume in two Brazilian samples of children aged 6 to 14 years old — 364 in a discovery cohort, and 352 in a replication cohort. They quantified genetic risk for Alzheimer’s disease using summary statistics from the International Genomics of Alzheimer’s Project.
In the discovery sample, each 1-unit increase in z-score for Alzheimer’s polygenic risk score significantly predicted a 0.185 decrement in z-score for immediate recall and a 0.282 decrement for delayed recall, the researchers report. Results were similar in the replication sample.
“These associations were not driven solely by the APOE-ε4 allele or by any other SNP separately, but by the aggregated genetic risk,” said Salum.
“The lack of associations with APOE-ε4 may suggest that the impact of this allele on the predisposition to Alzheimer’s disease may be clinically apparent only later in life. It also raises the hypothesis that the effects from SNPs associated with Alzheimer’s disease in early life may influence vulnerability to APOE effects later in life,” the research team writes.
The researchers also observed lower hippocampal volumes bilaterally in children with high polygenic risk scores.
The associations observed in the Brazilian samples fell short of significance in a third replication sample of 1029 Canadian children, who were assessed with a different protocol. “The lack of associations found for the Canadian sample may reflect multiple factors, including the possibility that our significant results represent a type I error,” Salum and colleagues note.
Nonetheless, the findings suggest that “even classical neurodegenerative diseases such as Alzheimer’s disease may have neurodevelopmental roots, like other chronic disorders of adults,” they conclude.
Cognitive Reserve
Medscape Medical News asked Thomas Wisniewski, MD, director of the Center for Cognitive Neurology at NYU Langone Health, New York City, for his thoughts on the study.
“This analysis is certainly interesting,” he said, “and it does dovetail with lots of prior work suggesting that genetic risk factors and one’s predisposition, even at very early points in one’s life, predict your risk of developing cognitive dysfunction, dementia, and Alzheimer’s disease in very late life.”
However, Wisniewski said he’s not convinced that Alzheimer’s disease does have a neurodevelopmental origin. He believes cognitive reserve is “much more likely.
“The pathology of Alzheimer’s disease is extremely common as you get older. If you have a highly resilient brain with good synaptic organization, high level of education, you stimulated your brain, and those sorts of positive factors, you’re able to deal with a given level of AD [Alzheimer’s disese]–related pathology potentially without any clinical symptoms.
“This is more a readout of that phenomenon rather than directly saying that your possibility of getting Alzheimer’s disease is preset at that early age,” Wisniewski said.
The study had no commercial funding. Several authors have disclosed relationships with various pharmaceutical companies, which are listed in the original article.
Am J Psychiatry. Published online March 2, 2018. Abstract
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