Current evidence indicating a role of the human
prion protein (PrP) in
amyloid-beta (Aβ) formation or a synergistic effect between Aβ and
prion pathology remains controversial. Conflicting results also concern the frequency of the association between the two
protein misfolding disorders and the issue of whether the
apolipoprotein E gene (
APOE) and the
prion protein gene (PRNP), the major modifiers of Aβ- and PrP-related pathologies, also have a pathogenic role in other
proteinopathies, including tau neurofibrillary degeneration. Here, we thoroughly characterized the
Alzheimer's disease/primary age-related
tauopathy (AD/PART) spectrum in a series of 450 cases with definite sporadic or genetic
Creutzfeldt-Jakob disease (CJD). Moreover, we analyzed: (i) the effect of variables known to affect CJD pathogenesis and the co-occurring Aβ- and tau-related pathologies; (II) the influence of
APOE genotype on CJD pathology, and (III) the effect of AD/PART co-pathology on the clinical CJD phenotype. AD/PART characterized 74% of CJD brains, with 53.3% and 8.2% showing low or intermediate-high levels of AD pathology, and 12.4 and 11.8% definite or possible PART. There was no significant correlation between variables affecting CJD (i.e., disease subtype,
prion strain, PRNP genotype) and those defining the AD/PART spectrum (i.e., ABC score, Thal phase, prevalence of CAA and Braak stage), and no difference in the distribution of
APOE ε4 and ε2 genotypes among CJD subtypes. Moreover, AD/PART co-pathology did not significantly affect the clinical presentation of typical CJD, except for a tendency to increase the frequency of
cognitive symptoms. Altogether, the present results seem to exclude an increased prevalence AD/PART co-pathology in sporadic and genetic CJD, and indicate that largely independent pathogenic mechanisms drive AD/PART and CJD pathology even when they coexist in the same brain.