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Compelling experimental evidence suggests that microglial activation is involved in the spread of tau tangles over the neocortex in Alzheimer’s disease (AD). We tested the hypothesis that the spatial propagation of microglial activation and tau accumulation colocalize in a Braak-like pattern in the living human brain. We studied 130 individuals across the aging and AD clinical spectrum with positron emission tomography brain imaging for microglial activation ([ 11 C]PBR28), amyloid-β (Aβ) ([ 18 F]AZD4694) and tau ([ 18 F]MK-6240) pathologies. We further assessed microglial triggering receptor expressed on myeloid cells 2 ( TREM2 ) cerebrospinal fluid (CSF) concentrations and brain gene expression patterns. We found that [ 11 C]PBR28 correlated with CSF soluble TREM2 and showed regional distribution resembling TREM2 gene expression. Network analysis revealed that microglial activation and tau correlated hierarchically with each other following Braak-like stages. Regression analysis revealed that the longitudinal tau propagation pathways depended on the baseline microglia network rather than the tau network circuits. The co-occurrence of Aβ, tau and microglia abnormalities was the strongest predictor of cognitive impairment in our study population. Our findings support a model where an interaction between Aβ and activated microglia sets the pace for tau spread across Braak stages. Microglial activation and tau accumulation propagate together in patients with Alzheimer’s disease, suggesting an interaction that determines disease progression.

Alzheimer’s disease (AD) is a brain network disorder where pathological proteins accumulate through networks and drive cognitive decline. Yet, the role of network connectivity in facilitating this accumulation remains unclear. Using in-vivo multimodal imaging, we show that the distribution of tau and reactive microglia in humans follows spatial patterns of connectivity variation, the so-called gradients of brain organization. Notably, less distinct connectivity patterns (“gradient contraction”) are associated with cognitive decline in regions with greater tau, suggesting an interaction between reduced network differentiation and tau on cognition. Furthermore, by modeling tau in subject-specific gradient space, we demonstrate that tau accumulation in the frontoparietal and temporo-occipital cortices is associated with greater baseline tau within their functionally and structurally connected hubs, respectively. Our work unveils a role for both functional and structural brain organization in pathology accumulation in AD, and supports subject-specific gradient space as a promising tool to map disease progression. In Alzheimer’s disease, the role of connectivity in facilitating pathology accumulation remains unclear. Using in-vivo neuroimaging, the authors show that tau and reactive microglia follow connectome gradients, underlying cognitive decline.

Introduction Cerebrospinal fluid (CSF) tau biomarkers are reliable diagnostic markers for Alzheimer’s disease (AD). However, their strong association with amyloid pathology may limit their reliability as specific markers of tau neurofibrillary tangles. A recent study showed evidence that a ratio of CSF C-terminally truncated tau (tau368, a tangle-enriched tau species), especially in ratio with total tau (t-tau), correlates strongly with tau PET tracer uptake. In this study, we set to evaluate the performance of the tau368/t-tau ratio in capturing tangle pathology, as indexed by a high-affinity tau PET tracer, as well as its association with severity of clinical symptoms. Methods In total, 125 participants were evaluated cross-sectionally from the Translational Biomarkers of Aging and Dementia (TRIAD) cohort (21 young, 60 cognitively unimpaired [CU] elderly [15 Aβ+], 10 Aβ+ with mild cognitive impairment [MCI], 14 AD dementia patients, and 20 Aβ− individuals with non-AD cognitive disorders). All participants underwent amyloid and tau PET scanning, with [ 18 F]-AZD4694 and [ 18 F]-MK6240, respectively, and had CSF measurements of p-tau181, p-tau217, and t-tau. CSF concentrations of tau368 were quantified in all individuals with an in-house single molecule array assay. Results CSF tau368 concentration was not significantly different across the diagnostic groups, although a modest increase was observed in all groups as compared with healthy young individuals (all P < 0.01). In contrast, the CSF tau368/t-tau ratio was the lowest in AD dementia, being significantly lower than in CU individuals (Aβ−, P < 0.001; Aβ+, P < 0.01), as well as compared to those with non-AD cognitive disorders ( P < 0.001). Notably, in individuals with symptomatic AD, tau368/t-tau correlated more strongly with [ 18 F]-MK6240 PET SUVR as compared to the other CSF tau biomarkers, with increasing associations being seen in brain regions associated with more advanced disease (isocortical regions > limbic regions > transentorhinal regions). Importantly, linear regression models indicated that these associations were not confounded by Aβ PET SUVr. CSF tau368/t-tau also tended to continue to become more abnormal with higher tau burden, whereas the other biomarkers plateaued after the limbic stage. Finally, the tau368/t-tau ratio correlated more strongly with cognitive performance in individuals with symptomatic AD as compared to t-tau, p-tau217 and p-tau181. Conclusion The tau368/t-tau ratio captures novel aspects of AD pathophysiology and disease severity in comparison to established CSF tau biomarkers, as it is more closely related to tau PET SUVR and cognitive performance in the symptomatic phase of the disease.

Background Females represent approximately 70% of the Alzheimer’s disease (AD) cases and the literature has proposed a connection between the decreased estrogen levels during menopause and an increased AD risk. Previous investigations have predominantly focused on assessing how hormone therapy (HT) affects the likelihood of AD development and cognitive deterioration. However, as the research framework has shifted toward a biomarker-defined AD and alterations in specific biomarkers could take place years before cognitive decline becomes discernible, it is crucial to examine how HT influences AD biomarkers. The main goal of this study was to evaluate the impact of HT on AD biomarker-informed pathophysiology in both cognitively unimpaired (CU) and cognitively impaired (CI) post-menopausal females across the aging and AD spectrum. Methods This cross-sectional study included post-menopausal females without HT history (HT-) and with HT (HT+) at the time of PET imaging assessment from two cohorts: the Translational Biomarkers in Aging and Dementia (TRIAD) cohort, and the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Participants underwent magnetic resonance imaging (MRI), positron emission tomography (PET) and biofluid collection. Voxel-based t-tests were performed to assess the differences in amyloid-β (Aβ) and tau neurofibrillary tangles (NFTs) loads between HT- and HT + females. Linear regression models with interaction terms were also conducted to examine the interactive effects of HT and Aβ-PET on regional tau-PET. Results HT + females demonstrated significantly lower tau-PET standardized uptake value ratio (SUVR) in Braak I-II ROIs ( P  < 0.05, Hedges’ g = 0.73), Braak III-IV ROIs ( P  < 0.0001, Hedges’ g = 0.74) and Braak V-VI ROIs ( P  < 0.0001, Hedges’ g = 0.69) compared to HT- females. HT + females also showed significantly lower CSF p-tau 181 ( P  < 0.001) and plasma p-tau 181 ( P  < 0.0001) concentrations. Additionally, results from multivariate linear regression models indicated that HT interacts with cortical Aβ and is associated with lower regional NFT load. Conclusions Overall, findings from this observational study suggest that HT is associated with lower tau neuroimaging and fluid biomarkers in postmenopausal females. Due to the close link between tau and cognition, this study highlights the need for large randomized controlled trials designed to systemically study the influences of HT on AD biomarkers and disease progression.

The choroid plexus (CP), a critical structure for cerebrospinal fluid (CSF) production, has been increasingly recognized for its involvement in Alzheimer's disease (AD). Accurate segmentation of CP from magnetic resonance imaging (MRI) remains challenging due to its irregular shape, variable MR signal, and proximity to the lateral ventricles. This study aimed to develop and evaluate a region-informed Gaussian Mixture Model (One-GMM) for automatic CP segmentation using anatomical priors derived from FreeSurfer (FS) software and compare it with manual, FS, and one previous GMM-based (Two-GMM) methods. T1-weighted (T1w) and T2-fluid-attenuated inversion recovery (FLAIR) MRI scans were acquired from 38 participants [19 cognitively normal (CN)], 11 with mild cognitive impairment (MCI), and 8 with AD. Manual segmentations served as ground truth. A GMM was applied within an anatomically constrained region combining the lateral ventricles and CP derived from FS reconstruction. The segmentation accuracy was assessed using the dice similarity coefficient (DSC), the 95th percentile Hausdorff distance (HD95), and volume difference percentage (VD%). Results were compared with those from FS and one previous GMM method-based segmentations across diagnostic groups. The region-informed One-GMM achieved significantly higher accuracy compared to FS and Two-GMM, with a mean DSC of 0.82 ± 0.05 for One-GMM versus 0.24 ± 0.11 for FS (   <  0.001), and 0.66 ± 0.10 for Two-GMM (  < 0.001), lower HD95 (One-GMM: 6.06 ± 10.32 mm vs. FS: 26.21 ± 7.32 mm vs. Two-GMM: 10.58 ± 6.47 mm), and comparable volume difference (One-GMM: 20.97 ± 9.53% vs. FS: 24.32 ± 28.13% vs. Two-GMM: 24.27 ± 22.10,  = 0.87). Segmentation accuracy of our proposed method was consistent across all diagnostic groups. Clinical analysis showed that there is no diagnostic group difference in CP volume obtained from manual, FS, Two-GMM, and our proposed One-GMM methods. In the whole cohort, there are also no age and sex effects of CP volume with all methods. Restricting to the CN group, CP volume from both manual (  = 0.03), Two-GMM (  < 0.01) and the proposed One-GMM (  = 0.05), methods show an aging effect, but not for the FS segmented CP volume (  = 0.22). A region-informed One-GMM method significantly improved CP segmentation accuracy over FS, providing a practical and accessible tool for CP quantification in AD and other research studies. Within this small cohort, no diagnostic group difference in CP volume was observed. An aging effect of CP volume was found within the CN group.

Background Neuropsychiatric symptoms (NPS) are frequent in aging and Alzheimer's disease (AD). Here we study the relationship between NPS and AD pathologies in vivo. Method Two hundred and twenty‐one individuals from the TRIAD cohort (143 cognitively unimpaired, 52 mild cognitive impairment, and 26 AD) underwent [18F]MK6240‐tau‐positron emission tomography (PET), [18F]AZD4694‐amyloid‐PET, magnetic resonance imaging, and neuropsychological evaluations. Spearman correlations and voxel‐based regression models evaluated the relationship between Neuropsychiatric Inventory Questionnaire (NPI‐Q) scores, and tau‐PET, amyloid‐PET, and voxel‐based morphometry. Results Fifty percent of individuals presented NPS; these correlated with tau, not amyloid beta or neurodegeneration. Associations between NPI‐Q score and tau‐PET were stronger in the parietal association area, superior frontal, temporal, and medial occipital lobes. NPI‐Q domains associated with distinct patterns of tau uptake. Conclusions NPS are predominantly related to tau in aging and dementia. Regions affected are part of the behavioral circuits, and vulnerable to early AD pathology. Domain‐specific analyses showed NPS are related to the AD pathophysiological processes in a symptom‐specific manner.

[18F]AZD4694 is an amyloid beta (Aβ) imaging agent used in several observational studies and clinical trials. However, no studies have yet published data on longitudinal Aβ accumulation measured with [18F]AZD4694. We assessed 146 individuals who were evaluated with [18F]AZD4694 at baseline and 2-year follow-up. We calculated annual rates of [18F]AZD4694 change for clinically defined and biomarker-defined groups. Cognitively unimpaired (CU) older adults displayed subtle [18F]AZD4694 standardized uptake value ratio (SUVR) accumulation over the follow-up period. In contrast, Aβ positive CU older adults displayed higher annual [18F]AZD4694 SUVR increases. [18F]AZD4694 SUVR accumulation in Aβ positive mild cognitive impairment (MCI) and dementia was modest across the neocortex. Larger increases in [18F]AZD4694 SUVR were observed in CU individuals who had abnormal amyloid positron emission tomography levels at baseline. [18F]AZD4694 can be used to monitor Aβ levels in therapeutic trials as well as clinical settings, particularly prior to initiating anti-amyloid therapies.

Objective To investigate the relationship between the topography of amyloid‐β plaques, tau neurofibrillary tangles, and the overlap between the two, with cognitive dysfunction in individuals without dementia. Methods We evaluated 154 individuals who were assessed with amyloid‐β PET with [18F]AZD4694, tau‐PET with [18F]MK6240, structural MRI, and neuropsychological testing. We also evaluated an independent cohort of 240 individuals who were assessed with amyloid‐β PET with [18F]Florbetapir, tau‐PET with [18F]Flortaucipir, structural MRI, and neuropsychological testing. Using the VoxelStats toolbox, we conducted voxel‐wise linear regressions between amyloid‐PET, tau‐PET, and their interaction with cognitive function, correcting for age, sex, and years of education. Results In both cohorts, we observed that tau‐PET standardized uptake value ratio in medial temporal lobes was associated with clinical dementia rating Sum of Boxes (CDR‐SoB) scores independently of local amyloid‐PET uptake (FWE corrected at p < 0.001). We also observed in both cohorts that in regions of the neocortex, associations between neocortical tau‐PET and clinical function were dependent on local amyloid‐PET (FWE corrected at p < 0.001). Interpretation In medial temporal brain regions, characterized by the accumulation of tau pathology in the absence of amyloid‐β, tau had direct associations with cognitive dysfunction. In brain regions characterized by the accumulation of both amyloid‐β and tau pathologies such as the posterior cingulate and medial frontal cortices, tau’s relationship with cognitive dysfunction was dependent on local amyloid‐β concentrations. Our results provide evidence that amyloid‐β in Alzheimer’s disease influences cognition by potentiating the deleterious effects of tau pathology.

Clinical adoption of blood-based biomarkers for Alzheimer's disease (AD) requires real-world validation. The CliPAD study aims to assess the clinical utility of plasma phosphorylated-tau (p -tau) biomarkers by evaluating their diagnostic performance, concordance with amyloid-β (Aβ) PET imaging, and impact on treatment decisions in routine care. CliPAD is an observational study enrolling up to 200 participants (ages 40-90) referred through UPMC clinics. Eligible individuals have objective cognitive impairment. The study visit includes blood sampling and rapid cognitive testing (MoCA), with questionnaires (NPI-Q, AD8, FAS) completed by a study partner. Clinical plasma p -tau assays (Lucent p -tau181, Lucent p -tau217, ALZpath p -tau217) are performed in CLIA-certified laboratories and results are returned to the referring clinician. Post-assay medical care is monitored to evaluate impacts on clinical management. Optional follow-ups occur at 12, 24, and 36 months. Seventy-eight referrals were received from 14 clinicians within the UPMC Neurology and Geriatric Medicine departments. N=52 participants (mean age: 70.8 ± 11.6 years; MoCA score: 18.3 ± 6.6) are currently enrolled. At referral, primary etiology is recorded as high or low likelihood of AD per clinical opinion of the referring provider (Figure 1A). Figure 1B shows the frequency of positive, intermediate, and negative across p -tau assays. The p -tau217 results show a stronger correlation (r=0.9525) compared to p -tau217 (Lucent) and p -tau181 (r=0.7576) (Figures 1D, E). Discordance between p -tau217 assays was greater in individuals the low-likelihood AD group (Figure 1C). To date, N=11 participants have undergone Aβ PET imaging post assay results. Currently, N = 7 are receiving anti-amyloid therapy (N =6 Leqembi, N=1 Kisunla), all with concordant positive p -tau assays. Additionally, N=10 have been referred for Aβ PET imaging; N=6 demonstrated concordant assay results, while N=4 exhibited discordances. Pending Aβ PET imaging results, ant-amyloid treatment may be recommended. The greater discordance between p -tau217 assays in the low-likelihood AD group (Figure 1C) highlights the complexity of application of these biomarkers in clinical practice. These findings emphasize the need for further research in clinical settings to refine their use for accurate diagnosis and informed treatment decisions.

Gold-standard diagnosis of Alzheimer’s disease (AD) relies on histopathological staging systems. Using the topographical information from [ 18 F]MK6240 tau positron-emission tomography (PET), we applied the Braak tau staging system to 324 living individuals. We used PET-based Braak stage to model the trajectories of amyloid-β, phosphorylated tau (pTau) in cerebrospinal fluid (pTau 181 , pTau 217 , pTau 231 and pTau 235 ) and plasma (pTau 181 and pTau 231 ), neurodegeneration and cognitive symptoms. We identified nonlinear AD biomarker trajectories corresponding to the spatial extent of tau-PET, with modest biomarker changes detectable by Braak stage II and significant changes occurring at stages III–IV, followed by plateaus. Early Braak stages were associated with isolated memory impairment, whereas Braak stages V–VI were incompatible with normal cognition. In 159 individuals with follow-up tau-PET, progression beyond stage III took place uniquely in the presence of amyloid-β positivity. Our findings support PET-based Braak staging as a framework to model the natural history of AD and monitor AD severity in living humans.