A Diagnostic Pitfall in the Era of Amyloid‐Targeting Therapy: Creutzfeldt–Jakob Disease Masquerading as Biologically Defined Alzheimer's Disease

1. Introduction

Alzheimer's disease (AD) has entered an era of biological diagnosis based on biomarkers such as amyloid positron emission tomography (PET) [1]. However, mixed pathologies are common in older adults with neurodegenerative dementia, and the presence of AD pathology does not necessarily indicate that AD is the primary cause of cognitive decline. Consequently, reliance on amyloid positivity alone may lead to overlooking other neurodegenerative diseases responsible for the clinical presentation. Here, I report a patient who had been biologically diagnosed with AD based on amyloid‐PET findings but was subsequently diagnosed with Creutzfeldt–Jakob disease (CJD), highlighting a potential diagnostic pitfall in biomarker‐based dementia diagnosis.

2. Case Presentation

2.1. Patient Background

A woman in her late 70s, right‐handed, was referred to my department for consideration of anti‐amyloid β antibody therapy (ATT). Her medical history included hypertension and angina pectoris. She had completed 12 years of education and had been a homemaker. Her mother had developed dementia in her 80s, although the underlying aetiology was unknown. Approximately 30 months before presentation, her family noticed progressive forgetfulness, including repetitive questioning and repeated conversations. Nine months before referral, she visited a memory clinic that specializes in dementia. Brain MRI demonstrated findings considered compatible with AD, and amyloid‐PET showed cortical amyloid deposition (Figure 1). Based on the clinical presentation and positive amyloid‐PET findings, she was diagnosed with biologically defined AD and was considered a candidate for ATT.

FIGURE 1.

Amyloid positron emission tomography demonstrating cortical amyloid deposition.

She was subsequently referred to my department for consideration of ATT and presented to my clinic in year X.

2.2. Presentation at Initial Visit

At the initial visit, the patient scored 24/30 on the MMSE, losing points for temporal orientation (−2), spatial orientation (−2) and delayed recall (−2). The global CDR score was 1.0, with box scores of 2.0 for Memory, 1.0 for Orientation, 1.0 for Judgement and Problem Solving, 1.0 for Community Affairs, 0.5 for Home and Hobbies and 0.0 for Personal Care. Neurological examination revealed no focal neurological deficits. Deep tendon reflexes were normal, pathological reflexes were absent, and no involuntary movements, including myoclonus, were observed. Cerebellar signs, extrapyramidal signs and gait disturbance were also absent.

2.3. Clinical Course

Routine blood tests, including metabolic and inflammatory markers, were unremarkable, and electrocardiography showed no abnormalities. Review of the MRI obtained 3 months before presentation revealed no abnormal hyperintensity on diffusion‐weighted imaging (DWI) (Figure 2A). In contrast, DWI performed at the initial visit demonstrated asymmetric cortical ribboning involving the bilateral temporal cortices, with a predominance in the left hemisphere (Figure 2B). Given the characteristic DWI findings and the absence of clinical, biochemical, or electrophysiological evidence suggestive of encephalitis, encephalopathy, mitochondrial disease or cardioembolic stroke, cerebrospinal fluid (CSF) examination was performed to investigate the possibility of CJD. CSF biomarkers, including 14‐3‐3 protein, abnormal prion protein (PrP^Sc), and total tau, were analysed at Nagasaki University. The 14‐3‐3 protein assay was negative; however, abnormal PrP^Sc was detected by the real‐time quaking‐induced conversion (RT‐QuIC) assay [2], and the total tau level was found to be elevated to 911 pg/mL.

FIGURE 2.

Serial diffusion‐weighted magnetic resonance imaging findings. (A) DWI obtained 3 months before presentation showing no abnormal cortical hyperintensity. (B) DWI obtained at the initial visit demonstrating asymmetric cortical ribboning involving the bilateral temporal cortices, predominantly in the left hemisphere.

Following the CSF findings, electroencephalography was performed. The background rhythm consisted of 8–9 Hz alpha activity predominant in the occipital regions, and no epileptiform discharges or periodic synchronous discharges were observed.

Based on the progressive cognitive decline, characteristic DWI abnormalities, and positive RT‐QuIC findings, CJD was considered the most likely diagnosis despite the absence of typical neurological signs and periodic synchronous discharges on electroencephalography.

At 10 months after the initial visit, her cognitive function had deteriorated rapidly. Her MMSE score had declined from 24/30 to 12/30, MoCA‐J score to 11/30 and FAB score to 11/18. Two months later, anxiety and agitation emerged as behavioural and psychological symptoms of dementia. At 13 months after the initial visit, she developed abnormal behaviours, including attempts to pull out the fungiform papillae of her tongue. At 14 months, neurological examination revealed myoclonus, and electroencephalography demonstrated periodic synchronous discharges (Figure 3). At 15 months after the initial visit, gait ataxia and dystonia of the right upper extremity became apparent. The emergence of these progressive neurological signs, together with the characteristic MRI, CSF RT‐QuIC positivity and electroencephalographic findings, fulfilled the diagnostic criteria for probable CJD.

FIGURE 3.

Electroencephalography obtained 14 months after the initial visit, demonstrating periodic synchronous discharges.

3. Discussion

The present patient was initially diagnosed with AD at a memory clinic because of slowly progressive cognitive decline in late life and positive amyloid‐PET findings and was subsequently referred to my department for consideration of ATT. At the time of the initial visit, the neurological examination was unremarkable and not inconsistent with a diagnosis of AD. However, repeat MRI‐DWI revealed asymmetric cortical ribboning, prompting a re‐evaluation of the diagnosis.

Unlike the typical form of sporadic CJD (sCJD), which is characterized by rapidly progressive dementia and early neurological manifestations, the present patient initially presented with isolated cognitive impairment and lacked characteristic neurological signs.

The prolonged amnestic presentation resembled the slowly progressive cortical phenotype of CJD, although the subsequent clinical course eventually evolved into a more typical CJD phenotype.

An important question raised by this case is whether the patient's entire clinical course was attributable to CJD or whether AD preceded the development of CJD. Amyloid‐PET positivity reflects the presence of cerebral amyloid pathology but does not establish that amyloid pathology is responsible for the clinical symptoms. In the present case, characteristic cortical ribboning became apparent only between 3 months before referral and the initial evaluation, suggesting that the pathological process responsible for the MRI abnormalities became clinically evident during this period. However, because diffusion‐weighted MRI may remain normal during the early stages of slowly progressive CJD, the absence of cortical hyperintensity 3 months earlier does not exclude the possibility that prion disease had already been present.

Overall, the clinical course is most consistent with a slowly progressive form of CJD presenting with prolonged cognitive impairment, supported by the subsequent development of cortical ribboning, rapid cognitive decline, myoclonus, dystonia, gait ataxia, periodic synchronous discharges on electroencephalography, and positive CSF RT‐QuIC findings. Nevertheless, because neither neuropathological examination nor PRNP genetic analysis was available, it remains impossible to determine whether concomitant AD had already been clinically manifest before the onset of CJD or whether cerebral amyloid pathology merely represented an age‐related co‐pathology. Accordingly, the possibility that early symptomatic AD coexisted with, or preceded, CJD cannot be completely excluded.

The unusually prolonged clinical course also raises the possibility of genetic CJD (gCJD), particularly V180I‐associated gCJD, which is the most common genetic prion disease in Japan. V180I‐associated gCJD typically presents in older individuals with slowly progressive cognitive decline, relatively mild neurological manifestations during the early stage, and prolonged disease duration, all of which overlap with the initial presentation of the present patient. Furthermore, in the present case, the subsequent development of myoclonus, gait ataxia, dystonia, periodic synchronous discharges on electroencephalography, and positive CSF RT‐QuIC findings strongly supported the diagnosis of CJD but did not reliably distinguish sCJD from V180I‐associated gCJD. Because PRNP genetic analysis was not performed, V180I‐associated gCJD cannot be completely excluded. Therefore, definitive subclassification of this patient as sCJD or V180I‐associated gCJD was not possible.

Neuropathological studies have demonstrated that AD‐related pathology frequently coexists with CJD, particularly in older individuals. Rossi et al. [3] reported that AD pathology and primary age‐related tauopathy are relatively common co‐pathologies in CJD, although they likely represent independent pathogenic processes. Similarly, Debatin et al. [4] and Jankovska et al. [5] demonstrated that AD‐related pathology and prion pathology may coexist within the same brain. Notably, Debatin et al. reported that sCJD patients with more extensive amyloid‐β deposition tended to have longer disease durations.

This case highlights an important limitation of biomarker‐based diagnosis in the era of disease‐modifying therapies for AD.

Amyloid‐PET positivity strongly suggests the presence of cerebral amyloid pathology; however, it does not necessarily indicate that AD is the primary cause of dementia. Given the high frequency of mixed pathologies in older adults, clinicians should avoid equating biomarker positivity with the principal neurodegenerative process underlying cognitive decline.

4. Conclusion

This case illustrates an important diagnostic pitfall in the era of ATT. Although amyloid‐PET positivity indicates the presence of cerebral amyloid pathology, it does not necessarily indicate that AD is the primary cause of dementia. In the present case, the positive amyloid‐PET finding may have reflected concomitant age‐related AD pathology rather than the principal driver of dementia. Furthermore, the prolonged clinical course highlights the diagnostic challenge of distinguishing slowly progressive CJD from concomitant neurodegenerative disorders in elderly patients. Comprehensive longitudinal assessment integrating clinical findings, serial MRI‐DWI, and biomarker results is essential to avoid diagnostic error and inappropriate therapeutic decision‐making. Clinicians should therefore be aware that biomarker positivity does not always identify the principal neurodegenerative process underlying dementia.

Consent

Written informed consent for publication of this case report and accompanying images was obtained from the patient's legal representative.

Conflicts of Interest

The author declares no conflicts of interest.

Data Availability Statement

The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.