NR AOFN
AU Croes,E.A.; Dermaut,B.; Houwing-Duistermaat,J.J.; van den Broeck,M.; Cruts,M.; Breteler,M.M.; Hofman,A.; van Broeckhoven,C.; van Duijn,C.M.
TI Early cognitive decline is associated with prion protein codon 129 polymorphism
QU Annals of Neurology 2003 Aug; 54(2): 275-6
PT letter
VT
A common polymorphism in the gene encoding the prion protein (PRNP) is known to determine susceptibility to Creutzfeldt-Jakob disease.[AAFZ] This polymorphism at codon 129 encodes for either methionine (M) or valine (V). There is an increasing interest in the role of this protein in other neurodegenerative processes including Alzheimer's disease.[ACHK] Here, we address the question whether genetic variability of the PRNP codon 129 polymorphism plays an (age-dependent) role in cognitive decline.
PRNP codon 129 genotypes were determined in 965 randomly selected participants from a population-based study, the Rotterdam Study.[3] The subjects were sampled in four 10-year age categories (age range, 55-95 years). Cognitive performance was assessed by the Mini-Mental State Examination (MMSE) and the Geriatric Mental State Schedule. Based on Diagnostic and Statistical Manual-III-R criteria, screen-positive persons were further evaluated for the presence of dementia by two neurologists. After a mean follow-up of 6.5+/-0.6 years 418 (43%) participants were reexamined. Reasons for loss to follow-up were death (63%), refusal (33%), and inability to undergo the MMSE (4%).
Genotype and allele frequencies were in Hardy-Weinberg equilibrium (MV, n = 440; MM, n = 435; VV, n = 90; p = 0.16). We found no evidence for a shift in allele frequencies with age. The baseline MMSE scores did not differ between the genotypes.
For the assessment of cognitive decline, all prevalent demented subjects were excluded. In the analyses adjusting for age, sex, education, baseline MMSE, and having the apolipoprotein E4 allele, we found a significantly higher decline in cognitive performance in V homozygous subjects aged 55 to 64 years (p < 0.01) compared with the reference group MV (Fig). We further found more patients with dementia in V homozygotes (p < 0.01). Age at onset was lower in demented PRNP129 VV carriers (MV, 85.4 years; MM, 86.3 years; VV, 84.4 years), but numbers were too low to reach statistical significance.
Previously, significantly lower MMSE scores were observed in V homozygous subjects aged 66 to 71 years [ABHH]. We recently described an increased prevalence of this genotype in patients with early-onset Alzheimer's disease [ANPY]. In line with these findings, here we report a shift in cognitive decline toward early age in carriers of PRNP129 VV. Interestingly, in sporadic Creutzfeldt-Jakob disease patients with genotype VV, the risk for developing the disease is also only significantly increased at early age (<49 years) [AAFZ].
Our data and those of others support the view of an increased susceptibility for neurodegeneration in carriers of the PRNP129 VV genotype early in life.
References
AAFZ Alperovitch A, Zerr I, Pocchiari M, et al. Codon 129 prion protein genotype and sporadic Creutzfeldt-Jakob disease. Lancet 1999; 353: 1673-1674.
ACHK Casadei VM, Ferri C, Calabrese E, et al. Prion protein gene polymorphism and Alzheimer's disease: one modulatory trait of cognitive decline? J Neurol Neurosurg Psychiatry 2001; 71: 279-280.
3. Hofman A, Grobbee DE, de Jong PT, van den Ouweland FA. Determinants of disease and disability in the elderly: the Rotterdam Elderly Study. Eur J Epidemiol 1991; 7: 403-422.
ABHH Berr C, Richard F, Dufouil C, et al. Polymorphism of the prion protein is associated with cognitive impairment in the elderly: the EVA study. Neurology 1998; 51: 734-737.
ANPY Dermaut B, Croes EA, Rademakers R, et al. PRNP Val129 homozygosity increases risk for early-onset Alzheimer's disease. Ann Neurol 2003; 53: 409-412.
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This work was supported by European Union grants (CT98-7022 and CT98-0208, C.M.v.D., C.v.B.).
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Fig. Annual decline in Mini-Mental State Examination (mmse) score in relation to the PRNP codon 129 polymorphism, in three age categories. Age categories 75 to 84 and 85 to 95 years were combined to increase the number.
IN
Schon lange bevor eine andere Arbeitsgruppe bei hinsichtlich der Aminosäure 129 des Prionproteins Valin-homozygoten Menschen im Alter signifikant häufiger kognitiv-neuropsychologische Defizite gefunden hatte [ABHH], suchten die Autoren 965 Menschen (vermutlich Niederländer) zufällig aus (Demenzkranke wurden allerdings aussortiert.) und teilten sie in 4 Altersgruppen mit einer Spanne von jeweils 10 Jahren ein. Außerdem stellten sie mit einem Gentest fest, welche Prionprotein-Allele die Probanden hatten (440 MV, 435 MM, 90 VV). Dann ermittelten sie mit zwei Testverfahren die kognitiven Fähigkeiten. Durchschnittlich sechseinhalb Jahre danach konnten die Autoren ihre Tests bei nur noch 418 (43%) Teilnehmern wiederholen. Die übrigen waren entweder gestorben (63%), weigerten sich (33%), oder konnten einen der Tests nicht mehr durchführen (4%).
Die Autoren fanden eine normale Allelverteilung ohne erkennbare Altersabhängigkeit. Aber bei Menschen mit Valin an der Position 129 aller ihrer Prionproteine fand man signifikant mehr und etwas jüngere Demenzkranke und die kognitiven Fähigkeiten nahmen im Alter von 55-64 Jahren signifikant stärker ab, als bei den heterozygoten. Auch unter Alzheimer-Patienten mit frühem Erkrankungsbeginn fanden die Autoren überproportional viele Val/Val-Homozygote [ANPY].
MH Age of Onset; Aged; Aged, 80 and over; Alleles; Codon/*genetics; Cognition Disorders/*genetics/*psychology; Female; Gene Frequency; Genotype; Human; Male; Middle Aged; Neuropsychological Tests; Polymorphism (Genetics)/*genetics; Prions/*genetics; Support, Non-U.S. Gov't
AD Esther A. Croes, MD, PhD, Jeanine J. Houwing-Duistermaat, PhD, Monique M. B. Breteler, MD, PhD, Albert Hofman, MD, PhD, Cornelia M. van Duijn, PhD - Department of Epidemiology and Biostatistics, Erasmus MC, Rotterdam, The Netherlands und Bart Dermaut, MD, PhD, Marleen van den Broeck, Marc Cruts, PhD, Christine van Broeckhoven, PhD, DSc, Cornelia M. van Duijn, PhD - Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology, University of Antwerp, Antwerp, Belgium
SP englisch
PO USA