Work

Amyloid and Tau Neuropathologic Stage, Coexisting Brain Disease, and Cognitive Status in a Population-Based Autopsy Cohort

Year: 2026

Type: preprint

Abstract: Importance Interpreting an amyloid or tau biomarker result requires knowing how often the target pathology is present in the tested population, whether a single marker characterizes the joint amyloid-tau state, and whether the detected pathology explains the patient symptoms. Population-based autopsy data addressing these questions are scarce, and recent population-scale prevalence estimates rest on biomarkers rather than ground-truth tissue examination. Objective To estimate stage-resolved, age- and sex-specific frequencies of amyloid and tau neuropathology in an unselected, admixed, autopsy population and to evaluate their clinical expression in relation to coexisting neuropathology. Design Setting and Participants Cross-sectional clinicopathologic study of decedents accrued from 2004 through 2025 at the Biobank for Aging Studies of the University of Sao Paulo, sampled through the centralized Sao Paulo municipal autopsy service, which performs approximately 15 000 autopsies annually and verifies about 16% of deaths in the city. Eligible decedents were aged 18 years or older with complete amyloid, tau, Clinical Dementia Rating (CDR), and coexisting pathology assessments. Exposures Age, sex, Thal amyloid phase, Braak neurofibrillary tangle stage, Consortium to Establish a Registry for Alzheimer Disease (CERAD) neuritic plaque score, and contributing coexisting neuropathology. Main Outcomes and Measures The complete Thal phase by Braak stage distribution; age- and sex-specific frequency of pathology in the biomarker-detectable range, prespecified as Thal phase 3 to 5 together with Braak stage IV to VI; and associations with CDR and CDR Sum of Boxes (CDR-SB). Results Among 2711 decedents (mean [SD] age, 73.4 [14.4] years; range, 23 to 111 years; 1340 [49.4%] female), 531 (19.6%) met both thresholds, 270 (10.0%) the amyloid threshold only, 207 (7.6%) the tau threshold only, and 1703 (62.8%) neither. Frequency of the combined state rose from 0% at ages 23 to 50 years to 5.5% at 61 to 70, 14.5% at 71 to 80, 36.5% at 81 to 90, and 45.9% at 91 to 111 years. The proportion with CDR greater than 0 increased monotonically across Braak stages, from 88 of 541 (16.3%) at stage 0 to 155 of 179 (86.6%) at stage VI. When the combined amyloid-tau state was cross-classified with contributing coexisting pathology, CDR greater than 0 was present in 225 of 1467 participants (15.3%) with neither, 204 of 349 (58.5%) with coexisting pathology alone, 216 of 339 (63.7%) with combined amyloid-tau pathology alone, and 165 of 192 (85.9%) with both. In a multivariable model of CDR-SB, contributing coexisting pathology had the largest unique adjusted contribution (partial R 2 , 0.088; 95% CI, 0.064-0.114), and Braak stage had the largest share of total explained variance (Lindeman, Merenda, and Gold contribution, 0.115). Conclusions and Relevance Amyloid and tau pathology within the range detected by current biomarkers was uncommon before age 70 and discordant in 17.6% of decedents. Contributing coexisting brain disease, which amyloid and tau biomarkers do not detect, accompanied cognitive impairment as often as advanced Alzheimer disease pathology did. These tissue-based frequencies can inform the interpretation of positive and negative biomarker results. Key Points Question Among people with amyloid and tau neuropathology at levels expected to be detectable by current biomarkers, how often is cognitive impairment present, and how does coexisting brain disease affect this relationship? Findings In this cross-sectional study of 2711 autopsies from a population-based cohort aged 23 to 111 years, 19.6% had neuropathology meeting both amyloid and tau thresholds expected to be detectable by current biomarkers, rising from 0% before age 51 to 45.9% after age 90. Contributing coexisting brain disease alone was accompanied by impairment in 58.5% of participants, nearly as often as amyloid and tau pathology alone (63.7%). Meaning Age-specific neuropathologic frequencies provide an autopsy-derived context for interpreting the predictive value of Alzheimer disease biomarkers, while coexisting brain disease was a major contributor to cognitive impairment beyond amyloid and tau pathology.

Source: medRxiv

DOI: 10.64898/2026.10.20.26365945