Genetic risk factors signal AD susceptibility in the very young
medwireNews: Genetic risk factors for Alzheimer’s disease (AD) appear to have an early effect on the brain and may allow the detection of susceptible young individuals before symptoms are present, findings from two studies in Neurology suggest.
In the first, researchers looked at all six apolipoprotein ε genotypes in 1187 healthy children aged 3–20 years from the cross-sectional Pediatric Imaging Neurocognition and Genetics (PING) study and found differential effects on brain morphometry and function after accounting for covariates such as socioeconomic status, genetic ancestry, scanner device used, gender and age .
“The ε4ε4 and ε2ε4 carriers appear to show the strongest antagonistic pleiotropic effects, with negative influences on brain structures and cognition at younger age, mirroring those in elderly participants and patients with AD”, say Linda Chang (University of Hawaii, Honolulu, USA) and colleagues.
Compared with children with the most common genotype, ε3ε3, those with the ε2ε4 genotype had smaller hippocampi, while those with ε4ε4 genotype and aged younger than 8 years had poorer structural integrity of the hippocampus.
The ε2ε4 children also showed widespread and relatively stable reductions in cortical surface area, and had altered age-related slopes for cortical volume and thickness, as did the ε4ε4 children.
Some of the children with the ε4ε4 genotype had worse performances on working memory and executive function tests, with the youngest ε4ε4 carriers scoring up to 50% lower than others. But the researchers note that the performance of these carriers equalled or bettered that of other children after the age of 8 years old. Among the youngest ε2ε4 carriers, performances on attention tests were impaired.
Commenting on the findings in a related editorial, Rebecca Knickmeyer (University of North Carolina, Chapel Hill, USA) and M Elizabeth Ross (Weill Cornell Medical College, New York, USA) say: “Ultimately, studying APOE polymorphisms in young children may allow us to develop behavioural interventions and pharmaceutical agents that could normalize adverse developmental trajectories, thereby postponing the onset of AD or reducing its severity.”
Supporting these findings, the second study showed the further benefits of looking at the aggregated effects of many risk loci as part of a polygenic risk score (PGRS).
Elizabeth Mormino (Massachusetts General Hospital and Harvard Medical School, Boston, USA) and colleagues analysed the genomes of 166 adults with dementia and 526 without, aged an average of 75 years, and applied a liberally defined computed PGRS from the International Genomics of Alzheimer’s Project genome-wide association study of AD.
The PGRS distinguished between the adults with and without dementia and a high score was indicative of worse memory and a smaller hippocampus at baseline in the adults free of dementia, accounting for 2.3% and 2.0% of the variance in these markers, respectively.
A higher PGRS was also associated with a significantly greater rate of decline in memory and executive function over the 3 years of study and an increase in the risk of progression from healthy to mild cognitive impairment or from mild cognitive impairment to AD.
The researchers note that a high PGRS was associated with β amyloid among 272 of the older participants without dementia who had cerebrospinal fluid data available and this was confirmed in a further sample of 505 individuals.
However, they also found that a high PGRS explained a modest 0.2% of variance in hippocampal volume in a younger sample of 1322 healthy patients aged between 18 and 30 years, when β amyloid accumulation is unlikely. This suggests PGRS exerts an effect via pathways other than β amyloid, the team suggests.
“Overall, these analyses provide evidence that aggregate genetic risk of AD dementia exerts effects that are detectable before the clinical symptoms of dementia are present, even among young adults”, they conclude.
By Lucy Piper
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