Primary Age-related Tauopathy Research Articles

PRMT3-Mediated H4R3me2a Promotes Primary Age-Related Tauopathy by Driving Tau Hyperphosphorylation in Neuron.

Primary age-related tauopathy (PART) and Alzheimer's disease (AD) both exhibit 3R/4R hyperphosphorylated tau-positive neurofibrillary tangles (NFTs) within the hippocampal-entorhinal system. Notably, PART patients show a higher degree of tau hyperphosphorylation in the entorhinal cortex (EC) than AD, yet the molecular mechanisms driving Aβ-independent tau hyperphosphorylation in PART remain poorly understood. Herein, through transcriptomic profiling of postmortem EC tissues and in vitro and in vivo functional validation, the present study identifies protein arginine methyltransferase 3 (PRMT3) as a critical driver of tau hyperphosphorylation. Mechanistically, PRMT3-mediated tau hyperphosphorylation is dependent on asymmetric dimethylation of histone H4 at arginine 3 (H4R3me2a), which upregulates miR-448. Elevated miR-448 specifically targets and suppresses IGF1R, leading to downstream GSK3β activation and subsequent tau hyperphosphorylation through PI3K/AKT/GSK3β signaling. Treatment with SGC707, a selective PRMT3 inhibitor, effectively reduces tau hyperphosphorylation and demonstrates therapeutic promise for PART and potentially other tauopathies. Collectively, this study defines the PRMT3/H4R3me2a/miR-448 axis as a critical regulatory pathway in tau hyperphosphorylation within PART, underscoring the potential of PRMT3 inhibition as a targeted therapeutic strategy for tauopathies.

Layer-Dependent Effect of Aβ-Pathology on Cortical Microstructure With ExVivo Human Brain Diffusion MRI at 7 Tesla.

The laminar-specific distributions of Aβ and Tau deposition in the neocortex of Alzheimer's disease (AD) have been established. However, direct evidence about the effect of AD pathology on cortical microstructure is lacking in human studies. We performed high-resolution T2-weighted and diffusion-weighted MRI (dMRI) on 15 exvivo whole-hemisphere specimens, including eight cases with low AD neuropathologic change, three cases with primary age-related tauopathy (PART), and four healthy controls (HCs). Using the diffusion tensor model, we evaluated microstructure patterns in six layers of gray matter cortex and performed MRI-histology correlation analysis across cortical layers. Aβ-positive cases exhibited higher diffusivity than Aβ-negative cases (PART and HC) in selected cortical regions, particularly in the inferior frontal cortex. Both Aβ/Tau depositions and dMRI-based microstructural markers demonstrated distinct cortical layer-dependent and region-specific patterns. A significant positive correlation was observed between increased diffusivity and Aβ burden across six cortical layers but not with Tau burden. Furthermore, the mean diffusivity in layer V of the inferior frontal cortex significantly increased with the Amyloid stage. Our findings demonstrate a layer-dependent effect of Aβ pathology on cortical microstructure of the human brain, which may be used to serve as a marker of low AD neuropathologic change.

Essential Tremor with Tau Pathology Features Seeds Indistinguishable in Conformation from Alzheimer’s Disease and Primary Age-related Tauopathy (S21.006)

Essential Tremor with Tau Pathology Features Seeds Indistinguishable in Conformation from Alzheimer’s Disease and Primary Age-related Tauopathy (S21.006)

Alzheimer mimicry: LATE and PART.

Alzheimer's disease (AD) is the main cause of dementia and accounts for 60% of dementia syndromes in people older than 75years. The correct classification of AD and non-AD cases is mandatory to study disease mechanisms or new treatment possibilities. A typical clinical picture of AD consists of a progressive cognitive decline, with primary memory impairment. Structural, functional, and molecular brain imaging, along with CSF biomarkers of amyloid pathology, neurodegeneration, and the presence of a vulnerability-associated APOE genotype, support the diagnosis of AD. Use of biomarkers have led to the identification of individuals with mild cognitive impairment who are amyloid-negative addressing a conceptually separate clinical entity named suspected non-Alzheimer disease pathophysiology (SNAP). Clinical presentation and progression of SNAP can mimic AD which makes the final diagnosis and possible treatment uncertain in up to 30% of cases in clinical centers that are not using biomarkers. These non-AD pathologies are common with advancing age both in cognitively impaired and clinically normal elderly people and include Argyrophilic Grain Disease (ARG), Tangle Predominant Dementia and TDP-43 proteinopathy. The terms Primary age-related tauopathy (PART) and Limbic-dominant TDP-43 age-related encephalopathy (LATE) have been proposed as the most common and useful biological and emerging clinical construct to describe this phenomenon in > 80years old individuals. Current evidence underlines the limitations of existing diagnostic tools, which remain inadequate for fully capturing the complexities of these conditions. Addressing these diagnostic ambiguities is crucial for assigning accurate diagnoses, reducing frequent misdiagnoses of AD, and implementing appropriate therapeutic strategies for elderly patients with mild cognitive impairment and dementia.

Very Late-Onset Neurodegeneration with Brain Iron Accumulation Associated with Mild Chorea: A Clinicopathological Case.

Neurodegeneration with Brain Iron Accumulation (NBIA) rarely manifests after the age of 50 years. The phenotype in these cases is most often parkinsonism. To present the case with the oldest age of NBIA onset reported so far. Clinico-pathological case. A female patient presented at 84 years of age with wobbling of the head that had started approximately 2 years ago. Choreiform movements of the head and upper body were observed and these abated when she focused on doing something else or lay down but started again when she was talking or moving. There were no cerebellar signs, abnormal reflexes or sensory disturbance. Cognitive screening tests were abnormal but significant cognitive symptoms absent. Magnetic Resonance Imaging (MRI) showed extensive iron accumulation in the basal ganglia and upper pons. Extensive analyses yielded no genetic diagnosis. She died suddenly 19 months after her first appointment. In neuropathological analysis the basal ganglia, especially the lenticular nuclei, were macroscopically darker than normal with notable iron accumulation in the arterial walls in these areas. Prominent axonal ballooning was observed especially in the internal globus pallidus. Globus pallidus displayed iron accumulation, observed to a slightly lesser extent also in the substantia nigra pars reticulata. The neuropathological phenotype resembled classical pantothenate kinase-associated neurodegeneration (PKAN). Concomitant beta-amyloid, hyperphosphorylated tau protein (consistent with primary age-related tauopathy, or PART) and TDP-43 (consistent with LATE-NC) pathologies were also evident. NBIA may manifest at a very advanced age with a mild phenotype, likely influenced by coexisting neuropathology.

Transcriptional signatures of hippocampal tau pathology in primary age-related tauopathy and Alzheimer's disease.

Transcriptional signatures of hippocampal tau pathology in primary age-related tauopathy and Alzheimer's disease.

Early Alzheimer’s Disease with frequent neuritic plaques harbors neocortical tau seeds distinct from primary age-related tauopathy

Tau neurofibrillary tangles (NFTs) in the presence of amyloid-β (Aβ) plaques are required for the diagnosis of Alzheimer’s Disease (AD) and closely track with cognitive impairment, yet cognitively normal aged individuals frequently exhibit NFTs arising from tau seed accumulation. This may suggest that not all tau species are equally pathogenic and raises the question of whether unidentified tau modifications augment tau seeding activity and neurodegeneration in AD. We investigated how biochemical modifications of tau relate to clinicopathological outcomes in a cohort of 38 patients with Braak-matched AD neuropathologic change (ADNC) or primary age-related tauopathy (PART), a 3R/4R tauopathy with identical tau filament core structure to ADNC but with little to no Aβ deposition. We comprehensively measured tau histologic density, seeding activity using real-time quaking induced conversion (RT-QuIC) seed amplification assays, and select post-translational modifications (PTMs) (i.e. pT217, pS202/T205, & C-terminal epitopes) in hippocampus and neocortex. Even in cases without overt neocortical tau neuropathology, substantial hippocampal and neocortical tau seeding occurred in both PART and ADNC and predicted region-specific cognitive performance and longitudinal decline. Notably, tau seeding and PTM profiles were associated with Aβ neuritic plaque density and differentiated ADNC from PART in neocortex. Our data indicate that tau seed modifications meaningfully relate to disease trajectory, potentially explaining the more severe cognitive dysfunction observed in late-stage AD versus PART.

Neuropathological comorbidity, genetics and cognition in a Chinese community-based autopsy cohort.

Neurodegenerative comorbidities are common and critical, yet data specific to the Chinese population remains limited. The study aims to investigate the prevalence and associations of neuropathologic changes and comorbidities, and their correlation with genetics and cognition in a community-dwelling autopsy cohort in China. Datasets of 610 participants were obtained from the National Human Brain Bank for Development and Function at the Chinese Academy of Medical Sciences/Peking Union Medical College. Neuropathological changes analysed included Alzheimer's disease neuropathological change (ADNC) (n = 331); α-synucleinopathies (n = 124) with 120 Lewy body disease (LBD) and 4 multiple system atrophy; limbic-predominant age-related TDP-43 encephalopathy neuropathologic changes (LATE-NC) (n = 341); primary age-related tauopathy (PART) (n = 231); argyrophilic grain disease (AGD) (n = 107); age-related tau astrogliopathy (ARTAG) (n = 144); cerebral amyloid angiopathy (CAA) (n = 183); hippocampus sclerosis (HS) (n = 46). Frontotemporal lobar degeneration, amyotrophic lateral sclerosis, and amygdala-predominant LBD are rare. Descriptive statistics and logistic regression models were used to assess the neuropathological associations. Increased age at death was correlated with increased severity in ADNC, LBD, and LATE-NC, as well as with a higher number of comorbidities. APOE ε4 allele frequency in the present autopsy cohort was 13.63%. The presence of the APOE ε4 allele was linked to an advanced ADNC stage and increased comorbidities. The co-pathology prevalence varied by pathologies, with notable increases in specific subgroups: within the ADNC subgroups, LBD, LATE-NC, CAA, and HS were more frequent in advanced stages; in the LATE-NC subgroups, ADNC, CAA, and ARTAG increased, while PART decreased in higher LATE-NC stages. PART cases presented the highest proportion of pure pathology (37.2%) compared to other groups. Advanced ADNC stages were significantly associated with higher LATE-NC stages, and vice versa. Neocortical LBD was correlated with elevated ADNC levels, and higher LATE-NC stages were associated with worsening LBD pathology. High level ADNC, neocortical LBD, and stage 3 of LATE-NC were identified as independent predictors of severe cognition status. Our study suggests that older age at death and APOE ε4 presence are the risk factors for neuropathologic comorbidities in Chinese people. The findings underscore the importance of considering comorbid neurologic diagnoses and therapies in clinical practice.

Tau PET Imaging With [18F]MK-6240: Limited Affinity for Primary Tauopathies and High Specificity for Alzheimer's Disease.

Second-generation tau-PET tracers like [18F]MK-6240 are increasingly used both for diagnosing and quantifying Alzheimer's Disease (AD) tauopathy. However, while [18F]MK-6240 tau-PET has demonstrated excellent sensitivity for AD tauopathy, data assessing its specificity and binding in non-AD tauopathies are still scarce. Participants were assigned to exclusive categorical diagnoses based on their amyloid (Aβ) and cognitive status. We quantified mesiotemporal (MTL) and neocortical [18F]MK-6240 tau-PET signal in 28 Aβ- cognitively impaired (CI) patients presenting various non-AD neurodegenerative disorders. Tau-PET quantifications were compared with Aβ- cognitively unimpaired (CU) subjects (n = 51) and Aβ+ CI patients (n = 77). Among the 28 Aβ- impaired subjects, only five presented significant and isolated mesiotemporal signal, most of them being suspected of primary age-related tauopathy (PART). Only two Aβ- impaired patients (7%) presented positive neocortical signal, both being diagnosed with fronto-temporal degeneration (FTD). The Tau-PET results of all the remaining Aβ- patients were comparable to the CU population, including eight other FTD patients. Importantly, 4R-only tauopathies (CBD and PSP) and sv-PPA were negative. [18F]MK-6240 tau-PET has a special affinity for tauopathies involving 3R/4R paired helical filaments: AD, PART (Aβ- subjects with MTL-restricted tau-PET signal) and some forms of FTD while most primary tauopathies do not exhibit significant cortical signal. Positive neocortical scans are therefore highly specific for AD tauopathy. Based on those and previous results, we propose a diagnostic flowchart for MCI subjects suspected of AD or another tauopathy which may significantly reduce the need for amyloid PET or CSF measurement.

Essential tremor with tau pathology features seeds indistinguishable in conformation from Alzheimer’s disease and primary age-related tauopathy

Neurodegenerative tauopathies are characterized by the deposition of distinct fibrillar tau assemblies, whose rigid core structures correlate with defined neuropathological phenotypes. Essential tremor (ET) is a progressive neurological disorder that, in some cases, is associated with cognitive impairment and tau accumulation. In this study, we explored tau assembly conformation in ET patients with tau pathology using cytometry-based tau biosensor assays. These assays quantify the tau seeding activity present in brain homogenates by detecting the conversion of intracellular tau-fluorescent protein fusions from a soluble to an aggregated state. Pathogenic tau assemblies exhibit seeding barriers, where a specific assembly structure cannot serve as a template for a native monomer if the amino acid sequences are incompatible. We recently leveraged this species barrier to define tauopathies systematically by substituting alanine (Ala) into the tau monomer and measuring its incorporation into seeded aggregates within biosensor cells. This Ala scan precisely classified the conformation of tau seeds from various tauopathies. In this study, we analyzed 18 ET patient brains with tau pathology, detecting robust tau seeding activity in 9 (50%) of the cases, predominantly localized to the temporal pole and temporal cortex. We further examined 8 of these ET cases using the Ala scan and found that the amino acid requirements for tau monomer incorporation into aggregates seeded from ET brain homogenates were identical to those of Alzheimer’s disease (AD) and primary age-related tauopathy (PART), and distinct from other tauopathies, such as corticobasal degeneration (CBD), chronic traumatic encephalopathy (CTE), and progressive supranuclear palsy (PSP). These findings indicate that in a pathologically confined subset of ET cases with significant tau pathology, tau assembly cores are identical to those seen in AD and PART. This could facilitate more precise diagnosis and targeted therapies for ET patients presenting with cognitive impairment.

Morphological substrate of chronic schizophrenia in elderly patients: a clinicopathological study.

Objective: Patients with schizophrenia are at a higher risk of developing dementia, but the basis of cognitive impairment is a matter of discussion. Conflicting results regarding the association of schizophrenia with Alzheimer disease (AD) may partly be attributable to the inclusion of non-AD lesions, which few clinicopathological studies have considered. Therefore, a re-evaluation of an autopsy cohort of elderly schizophrenics published previously [1] was performed. Material & methods: Among 99 consecutive autopsy cases of patients who met the DSM-5 and ICD.10 criteria for schizophrenia (mean age 69.5 ± 8.25 years), 56 showed moderate to severe dementia. All brains were blindly examined using the current criteria for AD and looking for concomitant lesions. They were compared with the frequency of AD in an autopsy series of 1.750 aged demented individuals Results: Four cases revealed the features of definite AD, five probable AD, and three aged 82-89 years were classified as primary age-related tauopathy (PART). Two cases were a cortical type of dementia with Lewy bodies (DLB), one Lewy body disease of brainstem type; six showed hippocampal sclerosis, 14 argyrophilic grain disease (AGD), and one progressive supranuclear palsy (PSP). Other co-pathologies were frequent lacunes in basal ganglia, moderate cerebral amyloid angiopathy, minor development anomalies in the entorhinal cortex, Fahr's disease, metastatic tumors, and acute or old cerebral infarctions (n = 4 each). Definite AD was seen in 48 % of the age-matched demented control group. Conclusions: In this cohort of elderly schizophrenic patients, only 7.6 % fulfilled the neuropathological criteria of definite or probable AD and 3.6 % of PART compared to 6 % to 13.7 % typical and atypical AD in the literature, whereas a considerable number of cases showed non-AD co-pathologies. This is in line with other studies showing that the frequency of AD in elderly schizophrenics may be equal to or less than in age-matched controls. Further studies are needed to elucidate the mechanisms of cognitive decline in schizophrenia.

Spatial proteomic differences in chronic traumatic encephalopathy, Alzheimer's disease, and primary age-related tauopathy hippocampi.

Spatial proteomic differences in chronic traumatic encephalopathy, Alzheimer's disease, and primary age-related tauopathy hippocampi.

Current Status and Future Perspective of Seoul National University Hospital-Dementia Brain Bank with Concordance of Clinical and Neuropathological Diagnosis.

This paper introduces the current status of Seoul National University Hospital Dementia Brain Bank (SNUH-DBB), focusing on the concordance rate between clinical diagnoses and postmortem neuropathological diagnoses. We detail SNUH-DBB operations, including protocols for specimen handling, induced pluripotent stem cells (iPSC) and cerebral organoids establishment from postmortem dural fibroblasts, and adult neural progenitor cell cultures. We assessed clinical-neuropathological diagnostic concordance rate. Between 2015 and September 2024, 162 brain specimens were collected via brain donation and autopsy. The median donor age was 73 years (1-94) with a male-to -female ratio of 2:1. The median postmortem interval was 9.5 hours (range: 2.5-65). Common neuropathological diagnoses included pure Lewy body disease (10.6%), Lewy body disease (LBD) with other brain diseases (10.6%), pure Alzheimer's disease-neuropathological change (ADNC) (6.0%), ADNC with other brain diseases (10.7%), vascular brain injury (15.2%), and primary age-related tauopathy (7.3%). APOE genotype distribution was following: ε3/ε3: 62.3%, ε2/ε3: 9.6%, ε2/ε4: 3.4%, ε3/ε4: 24.0%, and ε4/ε4: 0.7%. Concordance rates between pathological and clinical diagnoses were: ADNC/AD at 42.4%; LBD at 59.0%; PSP at 100%; ALS at 85.7%; Huntington's disease 100%. The varying concordance rates across different diseases emphasize the need for improved diagnostic criteria and biomarkers, particularly for AD and LBD. Tissues have been distributed to over 40 national studies. SNUH-DBB provides high-quality brain tissues and cell models for neuroscience research, operating under standardized procedures and international guidelines. It supports translational research in dementia and neurodegenerative diseases, potentially advancing diagnostic and therapeutic strategies.

Lewy body co-pathology in Alzheimer's disease and primary age-related tauopathy contributes to differential neuropathological, cognitive, and brain atrophy patterns.

Alzheimer's disease (AD) co-pathology with Lewy bodies (LB) is frequent and influences clinical manifestations and outcomes. Its significance in primary age-related tauopathy (PART) is unknown. We investigated the influence of LB on cognition and brain atrophy in AD and PART. We performed a retrospective cohort study in a large sample of autopsied participants with AD neuropathological change (ADNC) with and without LB and PART with and without LB, with corresponding ante mortem magnetic resonance imaging (MRI) data from the National Alzheimer's Coordinating Center dataset. LB co-pathology worsened cognitive impairment in both PART and ADNC. On longitudinal follow-up, LB impacted cognitive decline in multiple domains. Additionally, LB influenced brain atrophy on MRI across groups and LB regional staging was different in PART and ADNC, accompanying tauopathy progression. These results suggest that LB co-pathology is associated with divergent patterns of cognitive impairment, brain atrophy, and regional pathological distribution in PART and AD. Lewy body (LB) co-pathology is frequent in Alzheimer's disease (AD) with important clinical implications. LB co-pathology is also present in primary age-related tauopathy (PART), but its significance is still understudied. In PART and AD, LB leads to higher cognitive impairment and brain regional atrophy. In PART and AD, LB tends to accompany neurofibrillary tangle progression, suggesting amyloid pathology might be a trigger for regional pathology progression.

Amyloid-β oligomers increase the binding and internalization of tau oligomers in human synapses.

In Alzheimer's disease (AD), the propagation and spreading of CNS tau pathology closely correlates with cognitive decline, positioning tau as an attractive therapeutic target. Amyloid beta (Aβ) has been strongly implicated in driving tau spread, whereas primary tauopathies such as primary age-related tauopathy (PART)-which lack Aβ pathology-exhibit limited tau spread and minimal-to-no cognitive decline. Emerging evidence converges on a trans-synaptic mechanism of tau spread, facilitated by the transfer of misfolded tau aggregates (e.g. soluble oligomers). However, it is unclear whether Aβ oligomers modulate the binding and internalization of tau oligomers in human synapses. Our translationally focused paradigms utilize post-mortem brain specimens from Control, PART, and AD patients. Synaptosomes isolated from the temporal cortex of all three groups were incubated with preformed recombinant tauO (rtauO), ± preformed recombinant AβO (rAβO), and oligomer binding/internalization was quantified via flow cytometry following proteinase K (PK) digestion of surface-bound oligomers. TauO-synapse interactions were visualized using EM immunogold. Brain-derived tau oligomers (BDTO) from AD and PART PBS-soluble hippocampal fractions were co-immunoprecipitated and analyzed via mass spectrometry to compare synaptic tauO interactomes in primary and secondary tauopathies, thereby inferring the role of Aβ. AD synaptosomes, enriched in endogenous Aβ pathology, exhibited increased rtauO internalization compared to PART synaptosomes. This observation was mirrored in Control synaptosomes, where recombinant rAβO significantly increased rtauO binding and internalization. PK pre-treatment abolished this effect, implicating synaptic membrane proteins in AβO-mediated tauO internalization. While both PART and AD BDTO were broadly enriched in synaptic proteins, AD BDTO exhibited differential enrichment of endocytic proteins across pre- and post-synaptic compartments, whereas PART BDTO showed no significant synaptic enrichment. This study demonstrates that Aβ oligomers enhance tau oligomer binding and drive its internalization through synaptic membrane proteins. These findings offer novel mechanistic insights underlying pathological tau spreading directly within human synapses and emphasize the therapeutic potential of targeting Aβ-tau interactions.

Shared and Distinct Epigenetic Profiles in Primary Age‐Related Tauopathy and Alzheimer’s Disease: Insights into Tangle Formation and Spread

AbstractBackgroundAlzheimer’s disease (AD) is characterized by neocortical dissemination of neurofibrillary tangles (NFTs) while primary age‐related tauopathy (PART) has NFTs largely confined to the hippocampus and adjacent structures. Thus, PART and AD represent two extremes of a spectrum of NFT spread. We investigated epigenetic mechanisms of interindividual variation in NFT spread.MethodWe evaluated DNA methylation (DNAm) in frontal cortex by Infinium EPIC BeadChip array in the multi‐center PART Working Group cohort (PWG, N = 398), controlling for age, sex, and batch effects. Using SeSAMe and a false discovery rate of p<0.05, we identified differentially methylated positions (DMPs) associated with PART pathology quantitated from immunohistochemically‐stained sections. To assess amyloid effects, we compared this set with DMPs associated with neuritic amyloid plaque using the CERAD score. We identified novel DMPs not previously implicated in AD. We validated our findings in the Religious Orders Study and Memory and Aging Project cohort (ROSMAP, N = 707). We then related DMPs to differential expression of linked genes and performed enrichment analyses using KnowYourCG.ResultWe identified DMPs associated with NFTs [PWG: 8 novel / 8 total; ROSMAP: 31 novel / 68 total]. In the PWG cohort, of the 550 total [539 novel] DMPs that associated with CERAD score, there was no overlap with NFT‐associated DMPs. In the ROSMAP cohort, 57 total [3 novel] DMPs are associated with both NFTs and diagnosis of PART vs. AD and are linked to genes related to T‐cells and axonal transport. In contrast, the 11 total [10 novel] DMPs associated with NFTs alone are linked to genes related to synaptic signaling, heparin sulfate proteoglycan biosynthesis, and microtubule architecture.ConclusionDNA methylation distinguishes PART and AD brain. We identify tau‐specific DMPs that account for variance in NFT burden among aging individuals, both in the absence and presence of amyloid plaques in PART and AD, respectively. In PART, tau‐DMPs are fully orthogonal to the set of amyloid‐DMPs. In contrast, in AD, the tau‐DMPs have both amyloid‐associated and amyloid‐independent subsets with separate gene enrichment profiles. Therefore, distinct epigenetic events may drive pathology within the limbic system compared to those that drive tau spread to neocortex.

LATE, Hippocampal Sclerosis, and Primary Age-related Tauopathy

ABSTRACT OBJECTIVE Although Alzheimer disease (AD) is the most common neurodegenerative cause of dementia, neurologists must be aware of other etiologies that can mimic the amnestic-predominant syndrome and medial temporal brain involvement typically associated with AD. This article reviews recent updates surrounding limbic-predominant age-related transactive response DNA-binding protein 43 (TDP-43) encephalopathy (LATE), hippocampal sclerosis, and primary age-related tauopathy. LATEST DEVELOPMENTS LATE neuropathologic change occurs in approximately 40% of autopsied older adults, including occurrences in isolation in some older individuals with amnestic cognitive impairment. LATE neuropathologic change is often, but not always, associated with hippocampal sclerosis (neuronal loss and gliosis in the hippocampus and associated structures) and frequently coexists with AD and other neurodegenerative pathologies. Although there is no direct clinical biomarker for TDP-43 pathology, recent studies suggest that a clinical diagnosis of LATE can be achieved through the integration of multiple data points. Primary age-related tauopathy refers to the pathologic finding (in some cognitively unimpaired older adults as well as some individuals with cognitive impairment) of medial temporal–predominant neurofibrillary tangles in the absence of amyloid-β (Aβ) plaques. Recent consensus frameworks have attempted to resolve ambiguities of nomenclature and diagnosis for these entities, and efforts toward in vivo biomarkers are ongoing. ESSENTIAL POINTS LATE, with or without hippocampal sclerosis, and primary age-related tauopathy belong in the differential diagnosis (along with AD, argyrophilic grain disease, and other disorders) for slowly progressive amnestic-predominant cognitive impairment, particularly in individuals older than 75 years. Accurate recognition of clinical and diagnostic test features supportive of these non-AD entities is vital to optimize patient counseling, therapeutic selection, and novel biomarker development.

Characterization of plasma biomarkers of individuals with amyloid‐independent increased tau positron‐emission tomography uptake

AbstractBackgroundIncreased uptake on Tau positron‐emission tomography (PET) is sometimes observed in the absence of amyloid β accumulation. This A‐T+ PET profile might represent primary age‐related tauopathy (PART), an amyloid β‐independent 3R/4R tauopathy observed in aging brains. Although A‐T+ individuals have been shown to follow a different cognitive trajectory compared to A‐T‐ and A+T+ individuals, it remains unknown how they differ in terms of plasma biomarkers. Here, we aim to characterize the plasma biomarkers of A‐T+ individuals.MethodThis is a cross‐sectional study with data from the Translational Biomarkers in Aging and Dementia (TRIAD) cohort. Participants were classified into four categories based on their amyloid β ([18F]AZD4694) and Tau ([18F]MK6240) PET status (A‐T‐, A+T‐, A+T+ and A‐T+). Plasma biomarkers phosphorylated tau (p‐tau)181, p‐tau217, p‐tau231, total tau (t‐tau), neurofilament light (NfL) and GFAP were compared using the Kruskal‐Wallis test with post hoc Benjamini‐Hochberg (BH) correction. Discriminative performance was assessed using the area under the receiver operating characteristic curve (AUROC).ResultAmong the total 468 participants, 64 (13.7%) had A‐T+ PET status. The A‐T+ PET participants had a mean age 66.9 years (SD: 12.8), with 62.5% women and 39.1% showing cognitive impairment. Plasma p‐tau181, p‐tau217, p‐tau231 and GFAP were significantly higher in A+T+ individuals compared to A‐T+ (all p < 0.001). On the other hand, plasma p‐tau181 and 217 were significantly different between A‐T‐ vs A‐T+ (p<0.05), but not p‐tau231 and plasma GFAP. No significant differences were found in t‐tau or NfL regarding A‐T‐. Plasma p‐tau217 and plasma GFAP had the highest discriminative accuracies for A‐T+ vs A+T+ (AUROC: 0.860 and 0.836 respectively).ConclusionOur data suggest that individuals with an A‐T+ PET status exhibit a different plasma biomarker profile than those with A+T+ and A‐T‐ status. Further characterization of fluid biomarkers could help identify this group of individuals and facilitate the differential diagnosis of adults with cognitive impairment. Furthermore, our results lend support to the use of plasma biomarkers for identifying amyloid β PET positivity.

Spatial Pattern of Medial Temporal Lobe Cross‐Sectional and Longitudinal Structural Change in Cognitively Normal Individuals

AbstractBackgroundThe medial temporal lobe's (MTL) early involvement in tau pathology makes it a key focus in the development of preclinical Alzheimer’s disease (AD) biomarkers. ROI analyses in prior studies reported significant MTL structural differences in cognitively normal individuals with and without β‐amyloid (A+/‐CN). Pointwise analysis, offering spatial information of early neurodegeneration, has potential to pinpoint “signature regions” of pathological change, but has been underexplored in the MTL. This study employs a specialized pointwise analysis pipeline to examine the spatial pattern of MTL structural change in subgroups dichotomized by both β‐amyloid and tau status in a large cohort of CN individuals.MethodsA dataset of 3036 CN (A‐/A+: 1270/1558, Table 1) individuals from ADNI, HABS, A4 and ABC were analyzed. We extracted MTL regional thickness maps from MRI using tailored pipelines, ASHS‐T1 and CRASHS. For participants with prospective longitudinal MRI (five years follow‐up), regional maps of longitudinal atrophy rate were extracted using SkelDBM. Subjects with cross‐sectional tau PET available (N=563) were further divided into A and T subgroups by tracer uptake. General linear modeling was performed on each surface point to investigate cross‐sectional and longitudinal MTL structural group differences (detailed in Figure 1) and their correlation with MTL tau burden in All/A+/A‐ CN. Age and sex were covariates and cluster‐level multiple comparison correction was performed.ResultsA+CN demonstrated a significantly faster atrophy rate than A‐CN across the whole MTL, primarily driven by A+T+CN individuals (Figure 1‐b). Notably, A‐T+CN showed significantly faster atrophy rate in the entorhinal cortex (ERC) and Brodmann area 35 (BA35), the earliest sites of tau pathology (Figure 1‐b, second column). Figure 2‐b displays an MTL‐wise significant correlation between atrophy rate and tau in All/A+/A‐ CN. In both analyses, cross‐sectional effects are consistently weaker than longitudinal ones, but have some significant clusters in ERC and BA35.ConclusionsPointwise analysis revealed extensive tau‐associated accelerated neurodegeneration in the MTL in preclinical AD. Furthermore, accelerated atrophy was observed in early Braak regions in A‐CN with evidence of tau pathology, potentially driven by primary age‐related tauopathy (PART). These pointwise longitudinal MTL measures provide sensitive measures that may allow for disease monitoring in preclinical AD.

Spatial transcriptomic of hippocampal subfield‐specific pathology in Alzheimer’s disease and Primary Age‐Related Tauopathy (PART)

Spatial transcriptomic of hippocampal subfield‐specific pathology in Alzheimer’s disease and Primary Age‐Related Tauopathy (PART)