Article Text

Prion protein gene polymorphism and Alzheimer's disease: one modulatory trait of cognitive decline?
  1. V M CASADEI,
  2. C FERRI,
  3. E CALABRESE,
  4. L M E GRIMALDI
  1. Neuroimmunology Unit, Department of Neuroscience, San Raffaele Scientific Institute, via Olgettina 58, 20132 Milano, Italy
  2. Department of Neurology, Clinica Santa Maria di Castellanza, San Raffaele Scientific Institute, Milano, Italy
  3. ISI (Institute for Scientific Interchange) Foundation, Torino, Italy
  4. Department of Experimental Pathology, University of Bologna, Bologna, Italy
  5. Neurorehabilitation Unit, IRCCS Santa Maria Nascente, Milano, Italy
  6. Department of Neuroscience AUSL n.2 Caltanissetta
  1. Dr L Grimaldi luigi.grimaldi{at}hsr.it
  1. M FRANCESCHI
  1. Neuroimmunology Unit, Department of Neuroscience, San Raffaele Scientific Institute, via Olgettina 58, 20132 Milano, Italy
  2. Department of Neurology, Clinica Santa Maria di Castellanza, San Raffaele Scientific Institute, Milano, Italy
  3. ISI (Institute for Scientific Interchange) Foundation, Torino, Italy
  4. Department of Experimental Pathology, University of Bologna, Bologna, Italy
  5. Neurorehabilitation Unit, IRCCS Santa Maria Nascente, Milano, Italy
  6. Department of Neuroscience AUSL n.2 Caltanissetta
  1. Dr L Grimaldi luigi.grimaldi{at}hsr.it
  1. F VEGLIA
  1. Neuroimmunology Unit, Department of Neuroscience, San Raffaele Scientific Institute, via Olgettina 58, 20132 Milano, Italy
  2. Department of Neurology, Clinica Santa Maria di Castellanza, San Raffaele Scientific Institute, Milano, Italy
  3. ISI (Institute for Scientific Interchange) Foundation, Torino, Italy
  4. Department of Experimental Pathology, University of Bologna, Bologna, Italy
  5. Neurorehabilitation Unit, IRCCS Santa Maria Nascente, Milano, Italy
  6. Department of Neuroscience AUSL n.2 Caltanissetta
  1. Dr L Grimaldi luigi.grimaldi{at}hsr.it
  1. F LICASTRO
  1. Neuroimmunology Unit, Department of Neuroscience, San Raffaele Scientific Institute, via Olgettina 58, 20132 Milano, Italy
  2. Department of Neurology, Clinica Santa Maria di Castellanza, San Raffaele Scientific Institute, Milano, Italy
  3. ISI (Institute for Scientific Interchange) Foundation, Torino, Italy
  4. Department of Experimental Pathology, University of Bologna, Bologna, Italy
  5. Neurorehabilitation Unit, IRCCS Santa Maria Nascente, Milano, Italy
  6. Department of Neuroscience AUSL n.2 Caltanissetta
  1. Dr L Grimaldi luigi.grimaldi{at}hsr.it
  1. C MARIANI
  1. Neuroimmunology Unit, Department of Neuroscience, San Raffaele Scientific Institute, via Olgettina 58, 20132 Milano, Italy
  2. Department of Neurology, Clinica Santa Maria di Castellanza, San Raffaele Scientific Institute, Milano, Italy
  3. ISI (Institute for Scientific Interchange) Foundation, Torino, Italy
  4. Department of Experimental Pathology, University of Bologna, Bologna, Italy
  5. Neurorehabilitation Unit, IRCCS Santa Maria Nascente, Milano, Italy
  6. Department of Neuroscience AUSL n.2 Caltanissetta
  1. Dr L Grimaldi luigi.grimaldi{at}hsr.it
  1. L M E GRIMALDI
  1. Neuroimmunology Unit, Department of Neuroscience, San Raffaele Scientific Institute, via Olgettina 58, 20132 Milano, Italy
  2. Department of Neurology, Clinica Santa Maria di Castellanza, San Raffaele Scientific Institute, Milano, Italy
  3. ISI (Institute for Scientific Interchange) Foundation, Torino, Italy
  4. Department of Experimental Pathology, University of Bologna, Bologna, Italy
  5. Neurorehabilitation Unit, IRCCS Santa Maria Nascente, Milano, Italy
  6. Department of Neuroscience AUSL n.2 Caltanissetta
  1. Dr L Grimaldi luigi.grimaldi{at}hsr.it

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Although its main biological function is still unknown, the prion protein is involved in normal synaptic function.1Interestingly, the presence of a valine (V), replacing a methionine (M) at codon 129 of the prion protein gene (PRNP), has been associated with poor performance in cognitive tests in a large cohort of aged, non-demented, French people.2 Accordingly, this polymorphic gene represents a suitable candidate for an association with Alzheimer's disease, a dementing disorder characterised by neuronal degeneration and synaptic loss. To assess whether the PRNP V/M codon129 polymorphism—alone or in combination with polymorphisms in the apolipoprotein (APO)E3 and interleukin (IL)-1α4 genes, already shown to be associated with Alzheimer's disease—affects the occurrence or clinical features of the disease, we performed a case-control study in a cohort of Italian patients with sporadic Alzheimer's disease and age matched healthy controls.

Venous blood was collected from 212 Italian patients (130 women, 82 men; mean (SD) age at disease onset 68.3 (8.0) years) affected by clinically probable Alzheimer's disease, according to McKhann's criteria. Patients were also divided into those with early disease onset (⩽65 years; 72 patients; mean (SD) age at disease onset 57.0 (7.5) years), and those with a late onset (>65 years; 140 patients; mean (SD) age at disease onset 73.1 (5.4) years). Blood was also collected from 201 age and ethnicity matched healthy controls (80 women, 121 men; mean (SD) age 67.2 (10.5) years), chosen among the participants in the Italian Longitudinal Study on Aging who were not affected by neurological diseases. At the time of blood collection, we recorded in all subjects a mini mental state examination (MMSE) score (score for inclusion as control subject >24/30) and—only in patients with Alzheimer's disease—the duration of the disease.

The PRNP codon 129 M/V polymorphism was analysed by polymerase chain reaction followed by BsaA1 restriction endonuclease digestion, as previously described.2 To overcome the paucity of VV homozygous subjects (6% in patients with Alzheimer's disease and 10% in healthy controls, table 1), all analyses, except verification of the Hardy-Weinberg equilibrium, were focused on the combination of MV and VV (V+) compared with MM genotypes. APOE ε2–4 and IL-1α -889 T to C polymorphisms were determined as described.3 4 Allele frequency and genotype frequency of PRNP, APOE, and IL-1α polymorphisms were compared by χ2 test in case-control (Alzheimer's disease v healthy controls) and case-case (early onset Alzheimer's diseasev late onset Alzheimer's disease) analyses. The relative risk for Alzheimer's disease conferred by the carriage of PRNP V+ or MM genotypes was estimated by Cochran-Mantel-Haenszel odds ratios (ORs). Age, sex, APOE, and IL-1α adjusted ORs were computed by logistic regression. MMSE scores recorded in V+ and in MM carriers were compared by non-parametric rank sum test and their association with disease duration was assessed by the Spearman correlation coefficient.

Table 1

PRNP 129 genotype and allele frequency in patients with Alzheimer's disease (AD) and healthy controls (HC)

The PRNP allele and genotype frequency did not differ significantly between patients with Alzheimer's disease and controls (allele frequency: p=0.06; 3×2 genotype frequency: p=0.12). The V allele conferred a non-significant OR for Alzheimer's disease of 0.71 (95% confidence interval (95% CI) 0.48–1.06; p=0.09; p for trend of the V allele in Alzheimer's disease=0.04). Moreover, PRNP allele and genotype frequency were not affected by sex (p=0.18 in Alzheimer's disease and 0.28 in controls), APOE ε4, or IL-1α TT carrier status (data not shown). Stratification of the Alzheimer's disease cohort by age at disease onset showed that, although not significantly, V+ genotype carriers were more represented among patients with early onset (47%) than those with late onset disease (37%), resulting in an OR for early onset disease due to the carriage of the V+ genotypes of 1.46 (95% CI 0.85–2.69, p=0.2). However, a Kaplan-Meyer analysis failed to confirm this differential distribution among patients with Alzheimer's disease, indicating that if an association existed, it was small. When we compared patients with early onset and patients with late onset disease with their respective age matched controls, we found that the V+ genotypes were associated with an OR for Alzheimer's disease of 0.92 (95% CI 0.48–1.74; p=0.8) in the younger age group (⩽65 years), and of 0.63 (95% CI 0.38–1.04; p=0.07) in the older age group (>65 years; allele frequency: p=0.03, genotype frequency: p=0.04, table 1).

As expected, MMSE scores showed a negative correlation with duration of Alzheimer's disease (r=−0.38, p=0.0001), but not with PRNP genotypes (p=0.08). Interestingly, despite a comparable education level (mean number of years in school: V+=7.41; MM=7.52) and a similar median MMSE score recorded at the time of blood collection (15.1 in V+ and 15.3 in MM), V+ carriers had a median disease duration 9 months shorter than MM carriers (38v 47 months; p=0.038), possibly indicating a faster deterioration rate in V+ patients.

In conclusion, we failed to detect a significant association between the PRNP codon 129 polymorphism and the occurrence of sporadic Alzheimer's disease in Italy, irrespective of APOE and IL-1α genotype status, age, or sex. Combarros et al recently reported similar results in another southern European population of comparable size.5 However, our results suggest that patients with Alzheimer's disease carrying at least one V allele might have an earlier onset of the disease and a small but significant acceleration in their cognitive decline when compared with MM carriers. This is not a surprise as, in multigenic diseases, selected characteristics of the natural history of the disease seem more prone to be influenced by gene polymorphisms than mere occurrence of disease.

In conclusion, two independent studies have now provided evidence against PRNP as a susceptibility gene for sporadic Alzheimer's disease. Our study, however, suggests a possible modulation of disease activity due to the PRPN codon 129 polymorphism. A longitudinal assessment of a large cohort of patients with Alzheimer's using a full battery of cognitive tests might be necessary to confirm our finding.

Acknowledgments

This work was supported in part by Telethon, Italy, by a grant from Italian Murst (40% and 60%), and by the Associazione per la Ricerca sulle Demenze (ARD). We thank Drs L Caputo, G De Bellis, and I Biunno for caring for patients and assistance in collecting data and Mrs Liliana Zuccherelli for excellent secreterial work.

References

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  • Please note that the authors and their affiliations should appear as follows:

    VM Casadei
    Neuroimmunology Unit, Department of Neuroscience, San Raffaele Scientific Institute, via Olgettina 58, 20132 Milano, Italy

    M Franceschi
    Department of Neurology, Clinica Santa Maria di Castellanza, San Raffaele Scientific Institute, Milano, Italy

    C Ferri
    Neuroimmunology Unit, Department of Neuroscience, San Raffaele Scientific Institute, via Olgettina 58, 20132 Milano, Italy

    F Veglia
    ISI (Institute for Scientific Interchange) Foundation, Torino, Italy

    E Calabrese
    Neuroimmunology Unit, Department of Neuroscience, San Raffaele Scientific Institute, via Olgettina 58, 20132 Milano, Italy

    F Licastro
    Department of Experimental Pathology, University of Bologna, Bologna, Italy

    C Mariani
    Neurorehabilitation Unit, IRCCS Santa Maria Nascente, Milano, Italy

    IME Grimaldi
    IRCCS Oasi Maria Santissima, Troina, Italy; Neuroimmunology Unit, Department of Neuroscience, San Raffaele Scientific Institute, via Olgettina 58, 20132 Milano, Italy

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