Primary Age-Related Tauopathy (PART)

Primary age-related tauopathy (PART) refers to the neuropathologic finding of medial temporal–predominant Alzheimer disease (AD)–type neurofibrillary tangles (NFTs) in the absence of significant amyloid-beta (Aβ) plaque accumulation. First formally defined by consensus in 2014, PART encompasses a continuum from the near-ubiquitous medial temporal NFT deposition seen in cognitively normal older adults to the less common entity historically termed “tangle-predominant dementia.” Approximately 20% of centenarians display hippocampal NFTs without Aβ plaques, and it remains debated whether PART represents a truly distinct disease entity or an early, amyloid-independent stage on the AD spectrum. Accurate recognition of PART is essential for clinical decision-making, particularly with the emergence of anti-amyloid therapies that would be inappropriate for patients whose pathology lacks a significant amyloid component.

Definition and Diagnostic Criteria

The 2014 consensus workgroup established PART as a formal neuropathologic entity to standardize what had previously been described as tangle-predominant dementia, tangle-only dementia, and neurofibrillary tangle–predominant senile dementia. The criteria require AD-type NFTs in the medial temporal lobe with absent or minimal Aβ plaques:

The distinction between “definite” (Thal phase 0) and “possible” (Thal phase 1–2) acknowledges the difficulty in determining whether sparse Aβ represents incipient AD or is coincidental. In either case, neuritic plaques are absent or extremely sparse and neocortical tau spread is limited.

Neuropathology

The defining histologic feature is hyperphosphorylated 3R and 4R tau aggregated into paired helical filament structures within neurons — identical to AD NFTs in both tau isoform composition and ultrastructure. Despite this shared biochemistry, several neuropathologic distinctions from AD exist:

• Regional distribution: NFTs predominantly in the medial temporal lobe (entorhinal cortex, hippocampus, subiculum), with possible extension to the basal forebrain, brainstem nuclei, and olfactory regions
• Limited neocortical spread: Advanced cases (Braak III–IV) may extend to lateral temporal and cingulate cortex, but significant neocortical involvement is absent
• Absence of neuritic plaques: PART lacks the dense-core neuritic plaques surrounded by dystrophic neurites that characterize AD
• Braak cap at stage IV: Progression to stages V–VI (widespread neocortical NFTs) occurs in AD, not in PART
• Less frequent TDP-43 copathology: ~25% of PART cases show coexisting TDP-43 accumulation, compared with higher rates in AD

Some imaging studies have confirmed the presence of distinct spatial and temporal patterns of tau deposition in AD compared with amyloid-negative settings and have suggested that at least moderate levels of cortical amyloid burden are necessary for detectable tau burden beyond the entorhinal cortex. This observation further supports the biological separation of PART from AD, as PART tau remains confined to medial temporal structures in the absence of amyloid.

Clinical Features

There are no established criteria for a clinical diagnosis of PART. One fundamental barrier is that the majority of individuals with pathologically definite PART — approximately 70% in one large autopsy cohort — have no evident cognitive syndrome at the time of death. In these individuals, medial temporal NFTs represent an incidental finding of aging.

When symptomatic, PART has a recognizable profile:

• Mild, slowly progressive, amnestic-predominant cognitive impairment
• Later age of onset, lesser degree of impairment, and longer overall lifespan than AD
• Very slow rate of functional decline — the slowest progression among common neurodegenerative etiologies
• Cognitive symptoms emerge only at Braak stages III and IV, where NFT burden extends beyond the entorhinal cortex into the hippocampus proper

Recent analyses suggest nonamnestic deficits may be more frequent than previously thought. Deficits on Trail Making Test A (processing speed) and Trail Making Test B (task switching) have been reported as selectively affected in PART compared with AD. Braak stage alone may not fully characterize the phenotypic spectrum, with disruptions to larger-scale functional brain networks proposed as an additional mechanism.

PART vs Alzheimer Disease vs LATE

Whether PART represents a truly distinct disease or falls within the biologic spectrum of AD remains one of the most actively debated questions in neuropathology:

• Arguments for PART as part of AD: Identical tau isoforms (3R/4R), identical paired helical filament ultrastructure, similar regional initiation in the medial temporal lobe, and the observation that both share the same Braak staging system
• Arguments for PART as distinct: Divergent APOE genetics, different demographic profiles (PART peaks in the oldest old), absence of neuritic plaques, lower maximum Braak stage, milder clinical course, and evidence that moderate cortical amyloid is required for detectable tau spread beyond the entorhinal cortex

The aggregate evidence increasingly supports PART as a clinically and mechanistically separate entity, though additional research is needed to fully resolve this question.

Biomarkers

Definite PART currently requires postmortem neuropathology. However, several modalities may provide supportive evidence:

• MRI: Hippocampal atrophy is observed but nonspecific — also seen in limbic-predominant AD, LATE, argyrophilic grain disease, and temporal-predominant FTLD
• FDG-PET: Medial temporal hypometabolism reflecting focal neurodegeneration; overlaps with multiple medial temporal pathologies
• Amyloid PET: A negative amyloid PET is critical — it excludes AD and raises pretest probability for PART or LATE
• First-generation tau PET (flortaucipir): Most studies have not demonstrated reliable PART tau detection; off-target binding confounds results
• Newer tau PET (¹⁸F-RO948): 2023 data showed higher medial temporal tau signal with advancing age even in amyloid PET–negative individuals, suggesting detection of amyloid-independent tau consistent with PART
• Fluid biomarkers: CSF p-tau may be elevated but is not specific for amyloid status; plasma p-tau217 (high specificity for amyloidosis) could theoretically help distinguish PART from AD but requires validation

Relationship to LATE and Hippocampal Sclerosis

PART, LATE, and hippocampal sclerosis all preferentially affect the medial temporal lobe and can present with amnestic cognitive impairment in older adults. They share considerable demographic and clinical overlap but are neuropathologically distinct:

• PART: Defined by tau NFTs; TDP-43 is present in ~25% of cases as a copathology
• LATE: Defined by TDP-43 proteinopathy (stages 1–3: amygdala → hippocampus → middle frontal gyrus); tau NFTs frequently coexist
• Hippocampal sclerosis: Defined by neuronal loss and gliosis in the CA1 region and subiculum; associated with TDP-43 pathology (LATE) in up to 90% of cases

In PART cases with coexisting TDP-43, the TDP-43 is independently associated with greater medial and anterior temporal atrophy on MRI. This suggests that some of the brain atrophy and cognitive impairment attributed to PART may be driven by the copathology rather than tau alone, underscoring the complexity of medial temporal neurodegeneration in the oldest old.

Therapeutic Implications

The emergence of anti-amyloid monoclonal antibodies (lecanemab, donanemab) for early symptomatic AD has heightened the clinical importance of distinguishing PART from AD. With new disease-modifying therapies for AD, high-confidence etiologic diagnoses are critical to maximize treatment benefits for those eligible and minimize unnecessary treatment-related complications in individuals with non-AD diagnoses.

• Anti-amyloid therapies target Aβ plaques, which are absent or minimal in PART — no therapeutic benefit would be expected
• Treatment carries risk of amyloid-related imaging abnormalities (ARIA), including edema and microhemorrhages — this represents unnecessary harm in a patient without significant amyloid burden
• As many as 15–20% of individuals diagnosed clinically with probable AD dementia lack biological evidence for the disease, highlighting the frequency of non-AD etiologies including PART
• Cholinesterase inhibitors and memantine, while indicated for AD, have no proven efficacy in isolated PART
• Future tau-targeted therapies (tau immunotherapy, tau aggregation inhibitors, antisense oligonucleotides) could potentially be relevant to PART, but none have yet demonstrated clinical efficacy in this population

Etiologic Considerations in Amnestic Syndromes

+ = rarely; ++ = sometimes; +++ = often; ++++ = very often; – = typically absent; N/A = not applicable. AD = Alzheimer disease; AGD = argyrophilic grain disease; DLB = dementia with Lewy bodies; FTLD = frontotemporal lobar degeneration; HS = hippocampal sclerosis; LATE = limbic-predominant age-related TDP-43 encephalopathy.

References

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