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The 129 codon polymorphism of the prion protein gene influences earlier cognitive performance in Down syndrome
Roberto Del Bo1, Giacomo Pietro Comi, Roberto Giorda
1Dipartimento di Scienze Neurologiche, Padiglione Ponti, I. R. C. S. S. Ospedale Maggiore Policlinico, Via F. Sforza, 35, 20122 Milan, Italy. gpcomi@mailserver.unimi.it
Abstract:
Recently, a frequent prion protein gene (PRNP) polymorphism consisting of a methionine (M) for valine (V) substitution at codon 129 has been associated with cognitive impairment in elderly individuals. Down syndrome (DS) is associated with mental retardation and development of Alzheimer-like brain abnormalities. In the present study, we investigated the role of the PRNP polymorphism in 122 relatively young Italian DS patients. Allele frequencies of DS subjects did not differ from those in the general population. However, we found a significantly faster rate of decline in intellectual ability in the subgroup of DS patients carrying at least one V allele compared with the M/M DS subjects. An additive deleterious effect of apolipoprotein E epsilon 4 allele was detected after stratifying by APOE gene status. Our findings provide evidence that variability of the PRNP gene at codon 129 might contribute to accelerating the rate of earlier cognitive decline in DS subjects.
Insights
The prion protein gene (PRNP) polymorphism at codon 129 may accelerate cognitive decline in Down syndrome (DS) individuals. Carrying the V allele, particularly with APOE4, is linked to faster intellectual decline in DS patients.
Area of Science:
- Neurogenetics
- Gerontology
- Developmental Disorders
Background:
- Down syndrome (DS) is linked to intellectual disability and Alzheimer-like brain changes.
- A common prion protein gene (PRNP) polymorphism (M129V) is associated with cognitive impairment in the elderly.
- The role of PRNP M129V polymorphism in cognitive decline in DS patients is not well understood.
Purpose of the Study:
- To investigate the association between the PRNP M129V polymorphism and cognitive decline in Italian Down syndrome patients.
- To explore potential interactions between PRNP M129V and APOE epsilon 4 alleles regarding cognitive trajectory in DS.
Main Methods:
- Genotyping of the PRNP codon 129 polymorphism in 122 Italian DS patients.
- Assessment of allele frequencies in DS subjects compared to the general population.
- Analysis of cognitive decline rates stratified by PRNP genotype and APOE status.
Main Results:
- PRNP codon 129 allele frequencies in DS patients did not differ from the general population.
- DS patients with at least one V allele showed a significantly faster rate of intellectual decline compared to M/M homozygotes.
- An additive negative effect was observed for the apolipoprotein E epsilon 4 (APOE4) allele.
Conclusions:
- PRNP gene variability at codon 129 may accelerate cognitive decline in Down syndrome.
- The M129V polymorphism is a potential genetic modifier of cognitive trajectory in DS.
- This genetic factor may contribute to earlier onset or faster progression of cognitive impairment in DS individuals.