Incident versus prevalent progressive supranuclear palsy: analyses of U.S. Alzheimer's Disease Research Centers data indicate clinical and neuropathological features of a relatively common and underrecognized tauopathy in the aging brain.
In a large multicenter autopsy cohort, PSP pathology was more common than other FTLD-Tau subtypes and was frequently underrecognized, with incident PSP cases (recruited while cognitively normal) differing substantially from 'classic' PSP in clinical presentation, age at death, and neuropathological features.
Key Findings
Results
PSP pathology was found in 3.2% of individuals recruited while cognitively normal, a frequency higher than expected based on prior epidemiology studies estimating prevalence at ~1:10,000.
The full sample comprised 6845 individuals followed longitudinally for 4.0 (±2.9 stdev) approximately yearly visits, with n=297 having eventual autopsy-verified PSP.
Among 1451 participants recruited while cognitively normal (incident group), 3.2% had PSP pathology.
For comparison, only 0.7% of cognitively normal recruits had CBD and 0.1% had Pick's disease.
Participants were not necessarily diagnosed or followed in movement disorder clinics, meaning these represent community-ascertained cases.
Data were aggregated from 38 U.S. Alzheimer's Disease Research Centers (ADRCs) via the NACC Neuropathology Data Set.
Results
PSP pathology was more common than other FTLD-Tau subtypes among individuals recruited with dementia or clinical PSP.
Among those with dementia or PSP at recruitment (n=4310), 4.5% had PSP pathology.
In the same prevalent group, 3.3% had corticobasal degeneration (CBD) and 3.0% had Pick's disease.
PSP pathology thus exceeded both CBD and Pick's disease in prevalence within this cohort.
This pattern held across both incident and prevalent recruitment groups.
Results
Incident PSP cases (recruited while cognitively normal) died significantly older than prevalent PSP cases (recruited with dementia or clinical PSP).
Incident PSP cases died at an average age of 89.5 years.
Prevalent PSP cases died at an average age of 76.3 years.
This represents a difference of approximately 13 years in mean age at death between the two groups.
This age difference suggests incident PSP may represent a later-onset or more slowly progressing form of the disease.
Results
Incident PSP pathology cases were less likely to manifest stereotypical PSP clinical features but more likely to have parkinsonism.
Incident PSP cases differed from 'classic' PSP in their clinical presentation.
Stereotypical PSP clinical features were less common in those recruited while cognitively normal.
Parkinsonism was more frequently observed in incident versus prevalent PSP cases.
This suggests that cognitively normal individuals who later develop PSP pathology may present atypically during life, contributing to underrecognition.
Results
Digital pathology analyses revealed that PSP tau pathology was more severe overall in prevalent PSP compared to incident PSP.
Analyses were performed on a convenience sample of 23 individuals with PSP pathology from the University of Kentucky ADRC.
HALO software and AI-based analytic modules were used for digital pathology quantification.
Within the putamen, incident cases had a higher proportion of tufted astrocytes and a lower proportion of neurofibrillary tangles (NFTs) compared to prevalent cases.
Greater overall tau pathology burden in prevalent cases is consistent with their more severe or classic clinical presentation.
Conclusions
PSP pathology was more common than other FTLD-Tau subtypes across both incident and prevalent recruitment strata in this large multicenter autopsy cohort.
The study included n=297 autopsy-verified PSP cases across 6845 total participants.
PSP exceeded CBD and Pick's disease in frequency in both cognitively normal recruits and those recruited with dementia.
The NACC dataset spans 38 U.S. ADRCs, providing broad geographic and clinical representation.
The authors conclude PSP is a 'relatively common and underrecognized tauopathy in the aging brain.'
What This Means
This research suggests that a brain disease called progressive supranuclear palsy (PSP) — a condition caused by abnormal protein buildups in the brain — is much more common in older adults than previously thought. Scientists analyzed brain autopsy data from nearly 7,000 people enrolled at 38 research centers across the United States. They found that about 3.2% of people who joined the study while still mentally healthy eventually showed PSP-related changes in their brains at autopsy, far more than the roughly 1-in-10,000 prevalence estimate typically cited. PSP was also more common than related brain diseases like corticobasal degeneration and Pick's disease.
The study also found that people who developed PSP without showing obvious symptoms early on ('incident' cases) looked very different from the 'classic' PSP patient. They tended to live much longer — dying around age 89 on average compared to age 76 for those who had obvious PSP symptoms when they enrolled. They were also less likely to show the well-known signs of PSP and more likely to show general movement problems like parkinsonism. Brain tissue analysis from a subset of 23 cases showed that the protein abnormalities in the brain were less severe in these incident cases, particularly in a brain region called the putamen.
This research suggests that PSP is frequently going unrecognized during life, especially in older adults who may not show the textbook symptoms. Many people with PSP-related brain changes may be living with subtle or atypical symptoms that are attributed to aging or other conditions. These findings highlight a need to reconsider how PSP is identified and studied, particularly among older populations who may have a milder or slower-progressing form of the disease.
Cushing B, Shahidehpour R, Abner E, Jicha G, Neltner J, Breig M, et al.. (2026). Incident versus prevalent progressive supranuclear palsy: analyses of U.S. Alzheimer's Disease Research Centers data indicate clinical and neuropathological features of a relatively common and underrecognized tauopathy in the aging brain.. Acta neuropathologica. https://doi.org/10.1007/s00401-026-03100-8