Primary age-related tauopathy

Abstract

Primary age-related tauopathy (PART) was proposed in 2014 as a neuropathological term to describe patients with Alzheimer's-type medial temporal lobe neurofibrillary degeneration in the absence of significant β-amyloid pathology. Over the past decade, this designation has gained widespread adoption, helping to clarify the interpretation of biomarker profiles, delineate early-stage tauopathy in aging, and differentiate non-Alzheimer tauopathies from aging and classical Alzheimer disease. This review revisits PART ten years following its conception, critically evaluating its neuropathological features, clinical correlates, molecular underpinnings, and current limitations. We synthesize recent advances in neuroimaging, biomarkers, genetics, and epidemiology, explore the relationship between PART and other age-associated neurodegenerative processes, and propose revisions to the original PART criteria. While PART has served as a valuable framework for studying tau pathology in aging, key questions remain regarding its pathogenesis, clinical significance, and relationship to the broader spectrum of tauopathies. We highlight major gaps in knowledge and outline priorities for future research aimed at defining the mechanisms, biomarkers, and clinical criteria that will determine whether PART represents a distinct disease or a universal feature of human brain aging.

Keywords: Aging; Alzheimer’s disease neuropathologic change (ADNC); CA1 hippocampal subfield; Cognitive reserve; Cornu ammonis 2 (CA2) hippocampal subfield; Limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC); Primary age-related tauopathy (PART); Resilience.

Fig. 1

The Alzheimer disease neuropathologic change (ADNC) and primary age-related tauopathy (PART) spectrum. This figure is partially adapted from Montine et al. 2012 [178]

Fig. 2

Representative hyperphosphorylated tau (p-tau, AT8) and β-amyloid (Aβ, 6E10) immunohistochemistry of hippocampi from subjects with definite primary age-related tauopathy (PART), possible PART, and Alzheimer disease neuropathologic change (ADNC). Scale bars = 4 mm. This figure is derived from Walker et al. 2021 [285] and is used with permission

Fig. 3

Representative pathology in definite primary age-related tauopathy (PART). There are p-tau-positive (AT8) neurofibrillary tangles in the pigmented locus coeruleus (LC) neurons in sagittal orientation of the pons (a, b), as well as neurofibrillary tangles in the pyramidal neurons of the CA2 hippocampal subregion and entorhinal cortex (Ent) with relative sparing of the transentorhinal cortex (TE), entorhinal layer 2 pre-α clusters, and CA1 hippocampal subregion (c–f). Significant neuronal death, neurofibrillary tangles, and extracellular “ghost tangles” may be largely confined to the CA2 subregion (g, h). Neurofibrillary tangles are immunoreactive for both 3R-tau (i) and 4R-tau (j). Scale bars = 4 mm in panels a and c, 300 µm in panels b, d, e, and f, 100 µm in panels g and h, and 500 µm in panels i and j. Portions of this figure are derived from Walker et al., 2021 [285] and are used with permission

Fig. 4

Neuroradiology of primary age-related tauopathy (PART). a Representative axial, sagittal, and coronal T1-weighted MRI images of a 78-year-old male with PART, demonstrating modest atrophy in the hippocampus and surrounding temporal lobe structures. b Cortical and subcortical volume differences in PART and Alzheimer disease neuropathologic change (ADNC); yellow represents brain regions with significantly higher relative volume in PART/lower relative volume in ADNC; only significant values are shown after false discovery rate (FDR) correction. Part a of this figure is derived from Quintas-Neves et al. 2019 [209] and part b is derived from Almeida et al., 2025 [9]; used with permission under Creative Commons licenses (https://creativecommons.org/licenses/by/4.0/)

Fig. 5

Mean cognitive trajectories with 95% confidence intervals (expressed as Clinical Dementia Rating^® Sum of Boxes [CDR-SB]) for individual and mixed pathologies over the final 12 years of life. a Subjects with isolated Alzheimer disease neuropathologic change (ADNC) have significantly worse overall cognition as well as rate of progression compared to control subjects with no/minimal pathology and subjects with isolated primary age-related tauopathy (PART). b PART subjects with comorbid limbic predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC), Lewy body disease (LBD), and cerebrovascular disease (CVD) have significantly worse overall cognition and rate of progression compared to subjects with isolated PART. Graphs were generated using data analyzed in Maldonado-Díaz et al. 2024 [159] and Almeida et al. 2025 [8] from the National Alzheimer’s Coordinating Center (NACC) dataset (https://naccdata.org/)