Apply clinical features, neuroimaging, and biomarkers to improve identification of cases of probable or definite Creutzfeldt–Jakob Disease (CJD) that were initially misdiagnosed as rapidly progressive Alzheimer Disease (AD).

Overlap in the clinical presentation, imaging findings, and laboratory profiles can challenge differentiation of patients with rapidly progressive AD and CJD, contributing to delays in diagnoses and impacting management.

We systematically searched PubMed and Embase using MeSH and EMTREE synonyms for CJD and AD. We included patients with CJD who were initially diagnosed with AD. Clinical features and results from biomarker, imaging, and CJD-specific tests were extracted.

Of 210 articles, 8 articles (10 cases) were included after full-text review. Four cases were female (40%). Age at symptomatic onset ranged from 52 to 82 years. Median survival from symptom onset was 18.5 months (range ~5 months–6 years). Patients were initially diagnosed with amnestic (n=4) or variant presentations of AD (n=6), supported by CSF AD biomarkers in 3 cases (low Aβ42, n=3; elevated ptau181, n=2) and findings on FDG-PET in 6/10 cases. Subsequent testing established prion disease as the cause of impairment, with prominent MRI cortical ribboning or restricted diffusion present in 8/10 cases (80%), RT-QuIC for prions detected in 6/8 cases (75%), CSF total tau >1200 pg/mL in 4/10 cases (40%), and t-tau/ptau181 ratio >14 in 7/10 cases (70%)

CONCLUSION: Patients with CJD may be mistakenly diagnosed with AD, particularly in individuals presenting with CSF biomarker and FDG-PET findings common in AD. These findings emphasize the need to consider the diagnosis of RPD-CJD in patients with elevated t-tau/ptau181 and support evaluation of CJD-specific biomarkers (i.e., RT-QuIC) in patients with suspected rapidly progressive AD.