Rapidly progressive dementia, defined by cognitive decline that unfolds over weeks to months rather than years, presents neurologists with one of the most urgent diagnostic challenges in medicine. The two leading causes are prion diseases, most commonly sporadic Creutzfeldt-Jakob disease, and rapidly progressive forms of Alzheimer disease. In typical presentations, the two can be separated with reasonable confidence: prion disease usually announces itself on magnetic resonance imaging with characteristic diffusion-weighted abnormalities, and cerebrospinal fluid tests for prion seeding activity can confirm suspicion. But as the new research demonstrates, a subset of patients slips through these diagnostic nets entirely, presenting with clinical pictures that faithfully reproduce the amnestic syndromes of Alzheimer disease.

The Mayo Clinic team, led by Anas Elgenidi and Gregory S. Day, examined a prospective cohort of 204 patients with rapidly progressive dementia evaluated between February 2020 and June 2026. Among these, five patients, or 2.5 percent, had been diagnosed with clinically probable Alzheimer disease but were ultimately determined to have prion disease. That figure may seem small, but its significance lies in what it reveals about the limits of current diagnostic algorithms. These were not obscure cases buried in ambiguity; they were patients who met accepted criteria for Alzheimer disease and behaved, at least initially, exactly as that diagnosis predicted.

To understand how widespread this phenomenon is, the researchers turned to a systematic review of MEDLINE and Embase, unearthing ten additional published cases. Together with the Mayo cohort, the analysis encompassed fifteen patients with a median age at onset of 59 years, roughly two-thirds of whom were male. The clinical phenotypes these patients displayed mapped remarkably well onto recognized Alzheimer disease variants: just over half presented with an amnestic syndrome dominated by memory loss, about a quarter with a dysexecutive pattern affecting planning and organization, and smaller proportions with primary progressive aphasia, a language-led deterioration, or posterior cortical atrophy, which disrupts visual processing and spatial abilities. In other words, these prion cases were not merely Alzheimer-like in a vague sense; they reproduced specific, named Alzheimer phenotypes with precision.

The technical details of the diagnostic workup reveal where the traditional tools faltered. Diffusion-weighted magnetic resonance imaging, widely regarded as a cornerstone of prion disease diagnosis, was absent in all of the Mayo Clinic cases. In the published cases, the characteristic imaging abnormalities were either absent or equivocal in two patients and, perhaps more troublingly, overlooked in eight. This pattern of missed radiological findings echoes earlier literature showing that MRI changes in Creutzfeldt-Jakob disease are frequently misread or underappreciated, particularly early in the disease course when cortical and basal ganglia changes may be subtle or confined to regions that are not scrutinized routinely.

Cerebrospinal fluid biomarkers added another layer of complexity. In six of nine tested patients, the CSF profile was actually consistent with Alzheimer disease, meaning the amyloid and tau signature that clinicians rely upon to confirm the diagnosis pointed in the wrong direction. Elevated total tau levels, however, emerged as a recurring signal: eleven of thirteen patients showed raised total tau, and in five of nine patients the ratio of total tau to phosphorylated tau 181 was disproportionately elevated. This distinction matters because total tau reflects neuronal injury in a relatively nonspecific fashion, whereas phosphorylated tau is more closely tied to Alzheimer-type pathology. When total tau climbs far out of proportion to phosphorylated tau, the brain is being injured faster and more destructively than Alzheimer disease alone typically explains, and prion disease should enter the differential.

The most definitive diagnostic tool in the study was the real-time quaking-induced conversion assay, or RT-QuIC, a laboratory technique that exploits the prion protein’s infectious misfolding behavior. In the assay, normal recombinant prion protein is exposed to a patient’s cerebrospinal fluid and agitated; if misfolded prions are present, they template the conversion of the normal protein into amyloid fibrils that can be detected with a fluorescent dye, providing a sensitive and specific readout of prion seeding activity. RT-QuIC was positive in the cerebrospinal fluid of nine of twelve patients tested. Across the full cohort, prion disease was ultimately confirmed by neuropathological examination in seven cases, by genetic testing in two, and by RT-QuIC in six, illustrating that no single modality sufficed in every patient.

The median interval between the initial Alzheimer diagnosis and the consideration of prion disease was two months, a delay that, while seemingly brief, is meaningful in a disease measured in months. The stakes are considerable. Prion diseases are uniformly fatal, typically causing death within a year of onset, and there is no established cure, although the field is stirring: an early-phase clinical trial of intrathecally administered prion protein siRNA, a gene-silencing therapy delivered into the spinal fluid, is now enrolling symptomatic patients. Accurate diagnosis also matters for infection control, since prions resist conventional sterilization and demand specialized decontamination protocols in surgical settings, and for genetic counseling, since a proportion of prion disease cases arise from mutations in the prion protein gene with implications for family members.

The timing of this research is particularly consequential given the transformation of Alzheimer therapeutics. With disease-modifying monoclonal antibodies such as lecanemab and donanemab now approved and increasingly deployed, the pressure to confirm an Alzheimer diagnosis early and confidently has never been greater. Blood-based biomarkers are being promoted as accessible confirmatory tests, and CSF profiles are routinely used to anchor clinical decisions. Yet this study demonstrates that a positive Alzheimer biomarker signature does not exclude prion disease, and that patients with rapidly progressive courses deserve scrutiny that goes beyond a single biomarker panel. A patient whose dementia gallops forward while their biomarkers say Alzheimer may, in rare instances, be harboring a prion.

The authors’ central recommendation is pragmatic and easily actionable: disproportionate elevations in cerebrospinal fluid total tau, or an abnormally high ratio of total tau to phosphorylated tau 181, should prompt clinicians to consider prion disease and pursue RT-QuIC testing. Combined with careful re-review of diffusion-weighted MRI, this biomarker-driven vigilance offers a path to catching these mimics earlier. For the vast majority of patients with rapidly progressive dementia, the diagnosis will not be prion disease, and Alzheimer disease itself remains a common and legitimate explanation for swift decline. But for the roughly one in forty patients in this cohort whose illness wore Alzheimer’s mask, the difference between a routine diagnosis and a searching second look was the difference between two entirely different diseases, and the study stands as a reminder that in neurology, the most convincing diagnosis sometimes deserves to be tested against its own biomarkers.

Subject of Research: Prion disease presenting as rapidly progressive Alzheimer disease, diagnosed through CSF tau biomarkers and RT-QuIC assays

Article Title: Prion disease mimicking rapidly progressive Alzheimer disease: case series and systematic review

Article References: Elgenidi, A., Shir, D., Piura, Y. D., Sokol, L. L., Duara, R., Lachner, C., & Day, G. S. (2026). Prion disease mimicking rapidly progressive Alzheimer disease: case series and systematic review. Journal of Neurology, 273(10), Article 565. https://doi.org/10.1007/s00415-026-14087-3

Image Credits: AI Generated

DOI: 10.1007/s00415-026-14087-3

Keywords: prion disease, Creutzfeldt-Jakob disease, Alzheimer disease, rapidly progressive dementia, RT-QuIC, cerebrospinal fluid biomarkers, total tau, phosphorylated tau, diffusion-weighted MRI, differential diagnosis, neurodegeneration, Mayo Clinic