Phenotypic heterogeneity in sporadic Creutzfeldt-Jakob disease (sCJD) is well documented, but there is not yet a systematic classification of the disease variants. In a previous study, we showed that the polymorphic codon 129 of the prion protein gene (PRNP), and two types of protease-resistant prion protein (PrP(Sc)) with distinct physicochemical properties, are major determinants of these variants. To define the full spectrum of variants, we have examined a series of 300 sCJD patients. Clinical features, PRNP genotype, and PrP(Sc) properties were determined in all subjects. In 187, we also studied neuropathological features and immunohistochemical pattern of PrP(Sc) deposition. Seventy percent of subjects showed the classic CJD phenotype, PrP(Sc) type 1, and at least one methionine allele at codon 129; 25% of cases displayed the ataxic and kuru-plaque variants, associated to PrP(Sc) type 2, and valine homozygosity or heterozygosity at codon 129, respectively. Two additional variants, which included a thalamic form of CJD and a phenotype characterized by prominent dementia and cortical pathology, were linked to PrP(Sc) type 2 and methionine homozygosity. Finally, a rare phenotype characterized by progressive dementia was linked to PrP(Sc) type 1 and valine homozygosity. The present data demonstrate the existence of six phenotypic variants of sCJD. The physicochemical properties of PrP(Sc) in conjunction with the PRNP codon 129 genotype largely determine this phenotypic variability, and allow a molecular classification of the disease variants.

Phenotypic heterogeneity in sporadic Creutzfeldt‐Jakob disease (sCJD) is well documented, but there is not yet a systematic classification of the disease variants. In a previous study, we showed that the polymorphic codon 129 of the prion protein gene (PRNP), and two types of protease‐resistant prion protein (PrPSc) with distinct physicochemical properties, are major determinants of these variants. To define the full spectrum of variants, we have examined a series of 300 sCJD patients. Clinical features, PRNP genotype, and PrPSc properties were determined in all subjects. In 187, we also studied neuropathological features and immunohistochemical pattern of PrPSc deposition. Seventy percent of subjects showed the classic CJD phenotype, PrPSc type 1, and at least one methionine allele at codon 129; 25% of cases displayed the ataxic and kuru‐plaque variants, associated to PrPSc type 2, and valine homozygosity or heterozygosity at codon 129, respectively. Two additional variants, which included a thalamic form of CJD and a phenotype characterized by prominent dementia and cortical pathology, were linked to PrPSc type 2 and methionine homozygosity. Finally, a rare phenotype characterized by progressive dementia was linked to PrPSc type 1 and valine homozygosity. The present data demonstrate the existence of six phenotypic variants of sCJD. The physicochemical properties of PrPSc in conjunction with the PRNP codon 129 genotype largely determine this phenotypic variability, and allow a molecular classification of the disease variants. Ann Neurol 1999;46:224–233

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We quantified the amount of amyloid ␤-peptide (A␤) immunoreactivity as well as amyloid deposits in a large cohort of transgenic mice overexpressing the V717F human amyloid precursor protein (APP V717F؉/؊ TG mice) with no, one, or two mouse apolipoprotein E (Apoe) alleles at various ages. Remarkably, no amyloid deposits were found in any brain region of APP V717F؉/؊ Apoe ؊/؊ TG mice as old as 22 mo of age, whereas age-matched APP V717F ؉/؊ Apoe ؉/؊ and Apoe ؉/؉ TG mice display abundant amyloid deposition. The amount of A␤ immunoreactivity in the hippocampus was also markedly reduced in an Apoe gene dose-dependent manner (Apoe ؉/؉ > Apoe ؉/؊ Ͼ Ͼ Apoe ؊/؊ ), and no A␤ immunoreactivity was detected in the cerebral cortex of APP V717F؉/؊ Apoe ؊/؊ TG mice at any of the time points examined. The absence of apolipoprotein E protein (apoE) dramatically reduced the amount of both A␤1-40 and A␤1-42 immunoreactive deposits as well as the resulting astrogliosis and microgliosis normally observed in APP V717F TG mice. ApoE immunoreactivity was detected in a subset of A␤ immunoreactive deposits and in virtually all thioflavine-Sfluorescent amyloid deposits. Because the absence of apoE alters neither the transcription or translation of the APP V717F transgene nor its processing to A␤ peptide(s), we postulate that apoE promotes both the deposition and fibrillization of A␤, ultimately affecting clearance of protease-resistant A␤/apoE aggregates. ApoE appears to play an essential role in amyloid deposition in brain, one of the neuropathological hallmarks of Alzheimer's disease.