AbstractPatients with Alzheimer’s disease (AD) and clinically overlapping neurodegenerative diseases are classified molecularly using the A/T/N classification system. Apart from fluid biomarkers and structural MRI, the three-dimensional A/T/N system incorporates characteristic features from β-amyloid-PET (A), tau-PET (T), and FDG-PET (N). We evaluated if dynamic features of tau-PET with [18F]PI-2620 allow assessment of A/T/N in individual patients using a single imaging session. Cortical tissue clearance (K2a) of [18F]PI-2620 was validated as a surrogate of the β-amyloid status against β-amyloid-PET and cerebrospinal fluid (CSF) Aβ42/40ratio, demonstrating remarkable positive (91.5%) and negative (95.1%) predictive values at an AUC of 0.99 (P<0.0001). K2a outperformed cortical tau burden as a surrogate for β-amyloid status in 47 participants with a clinical diagnosis of probable AD (3/4-repeat(R)-tauopathy) and 82 β-amyloid-negative patients with primary 4R-tauopathies. Perfusion-like [18F]PI-2620 images (R1) were validated as a surrogate marker for neuronal injury, exhibiting strong quantitative and visual correlations with FDG-PET and early-phase β-amyloid-PET, as well as with volumetric MRI and CSF total tau levels. Composite quantitative A/T/N indices facilitated personalized staging along temporal disease trajectories. Our results suggest that [18F]PI-2620 imaging has the potential to facilitate the assessment of region and stage dependent PET-based A/T/N during a single dynamic PET session.Graphical Abstract

Purpose of the report Adults with Down Syndrome (DS) have a substantially increased risk for Alzheimer's disease (AD) due to the triplicated amyloid-precursor-protein gene on chromosome 21, resulting in amyloid and tau accumulation. However, tau PET assessments are not sufficiently implemented in DS-AD research or clinical work-up, and second-generation tau tracers such as [18F]PI-2620 have not been thoroughly characterized in adults with DS. We aim at illustrating feasibility and potential diagnostic value of tau PET imaging with [18F]PI-2620 for the diagnosis of DS-AD.Materials and methods Five adults with DS (40% female, aged 43-62) and cognitive decline underwent clinical assessments, neuropsychological testing, lumbar puncture and multimodal neuroimaging. All underwent [18F]PI-2620 tau PET. Visual read of tau PET scans was performed by three blinded raters, assessing increased tracer uptake in brain areas corresponding to the six Braak stage regions and basal ganglia.Results Visual read of tau burden revealed three tau-positive individuals which corresponded to their clinical decline while two cognitively stable individuals were rated as negative. Rating showed high inter-rater reliability for all Braak stages.Conclusion Tau PET imaging is a feasible and important biomarker assessment in the differential diagnosis of cognitive decline in adults with DS at risk of developing AD.

Abstract In Alzheimer’s disease (AD), Aβ triggers p-tau secretion, which drives tau aggregation. Therefore, it is critical to characterize modulators of Aβ-related p-tau increases which may alter AD trajectories. Here, we assessed whether factors known to alter tau levels in AD modulate the association between fibrillar Aβ and secreted p-tau181 determined in the cerebrospinal fluid (CSF). To assess potentially modulating effects of female sex, younger age, and ApoE4, we included 322 ADNI participants with cross-sectional/longitudinal p-tau181. To determine effects of microglial activation on p-tau181, we included 454 subjects with cross-sectional CSF sTREM2. Running ANCOVAs for nominal and linear regressions for metric variables, we found that women had higher Aβ-related p-tau181 levels. Higher sTREM2 was associated with elevated p-tau181, with stronger associations in women. Similarly, ApoE4 was related to higher p-tau181 levels and faster p-tau181 increases, with stronger effects in female ApoE4 carriers. Our results show that sex alone modulates the Aβ to p-tau axis, where women show higher Aβ-dependent p-tau secretion, potentially driven by elevated sTREM2-related microglial activation and stronger effects of ApoE4 carriership in women.

In Alzheimer’s disease (AD), younger symptom onset is associated with accelerated disease progression and tau spreading, yet the mechanisms underlying faster disease manifestation are unknown. To address this, we combined resting-state fMRI and longitudinal tau-PET in two independent samples of controls and biomarker-confirmed AD patients (ADNI/BioFINDER, n = 240/57). Consistent across both samples, we found that younger symptomatic AD patients showed stronger tau-PET in globally connected fronto-parietal hubs, i.e., regions that are critical for maintaining cognition in AD. Stronger tau-PET in hubs predicted faster subsequent tau accumulation, suggesting that tau in globally connected regions facilitates connectivity-mediated tau spreading. Further, stronger tau-PET in hubs mediated the association between younger age and faster tau accumulation in symptomatic AD patients, which predicted faster cognitive decline. These independently validated findings suggest that younger AD symptom onset is associated with stronger tau pathology in brain hubs, and accelerated tau spreading throughout connected brain regions and cognitive decline.

Tau pathology is the main driver of neuronal dysfunction in 4-repeat tauopathies, including cortico-basal degeneration and progressive supranuclear palsy. Tau is assumed to spread prion-like across connected neurons, but the mechanisms of tau propagation are largely elusive in 4-repeat tauopathies, characterized not only by neuronal but also by astroglial and oligodendroglial tau accumulation. Here, we assess whether connectivity is associated with 4R-tau deposition patterns by combining resting-state fMRI connectomics with both 2 nd generation 18 F-PI-2620 tau-PET in 46 patients with clinically diagnosed 4-repeat tauopathies and post-mortem cell-type-specific regional tau assessments from two independent progressive supranuclear palsy patient samples ( n = 97 and n = 96). We find that inter-regional connectivity is associated with higher inter-regional correlation of both tau-PET and post-mortem tau levels in 4-repeat tauopathies. In regional cell-type specific post-mortem tau assessments, this association is stronger for neuronal than for astroglial or oligodendroglial tau, suggesting that connectivity is primarily associated with neuronal tau accumulation. Using tau-PET we find further that patient-level tau patterns are associated with the connectivity of subcortical tau epicenters. Together, the current study provides combined in vivo tau-PET and histopathological evidence that brain connectivity is associated with tau deposition patterns in 4-repeat tauopathies.

Cognitive resilience is an important modulating factor of cognitive decline in Alzheimer's disease, but the functional brain mechanisms that support cognitive resilience remain elusive. Given previous findings in normal ageing, we tested the hypothesis that higher segregation of the brain's connectome into distinct functional networks represents a functional mechanism underlying cognitive resilience in Alzheimer's disease. Using resting-state functional MRI, we assessed both resting-state functional MRI global system segregation, i.e. the balance of between-network to within-network connectivity, and the alternate index of modularity Q as predictors of cognitive resilience. We performed all analyses in two independent samples for validation: (i) 108 individuals with autosomal dominantly inherited Alzheimer's disease and 71 non-carrier controls; and (ii) 156 amyloid-PET-positive subjects across the spectrum of sporadic Alzheimer's disease and 184 amyloid-negative controls. In the autosomal dominant Alzheimer's disease sample, disease severity was assessed by estimated years from symptom onset. In the sporadic Alzheimer's sample, disease stage was assessed by temporal lobe tau-PET (i.e. composite across Braak stage I and III regions). In both samples, we tested whether the effect of disease severity on cognition was attenuated at higher levels of functional network segregation. For autosomal dominant Alzheimer's disease, we found higher functional MRI-assessed system segregation to be associated with an attenuated effect of estimated years from symptom onset on global cognition (P = 0.007). Similarly, for patients with sporadic Alzheimer's disease, higher functional MRI-assessed system segregation was associated with less decrement in global cognition (P = 0.001) and episodic memory (P = 0.004) per unit increase of temporal lobe tau-PET. Confirmatory analyses using the alternate index of modularity Q revealed consistent results. In conclusion, higher segregation of functional connections into distinct large-scale networks supports cognitive resilience in Alzheimer's disease.

Alzheimer's disease (AD) is associated with reduced temporo-parietal cerebral blood flow (CBF). However, a substantial variability in CBF across the clinical spectrum of AD has been reported, possibly due to differences in primary AD pathologies. Here, we assessed CBF (ASL-MRI), tau (AV1451-PET) and amyloid (AV45/FBB-PET) in 156 subjects across the AD continuum. Using mixed-effect regression analyses, we assessed the local associations between amyloid-PET, tau-PET and CBF in a hypothesis-driven way focusing on each pathology's predilection areas. The contribution of Apolipoprotein E (APOE) genotype, and MRI markers of small vessel disease (SVD) to alterations in CBF were assessed as well. Tau-PET was associated with lower CBF in the entorhinal cortex, independent of Aβ. Amyloid-PET was associated with lower CBF in temporo-parietal regions. No associations between MRI markers of SVD and CBF were observed. These results provide evidence that in addition to Aβ, pathologic tau is a major correlate of CBF in early Braak stages, independent of Aβ, APOE genotype and SVD markers.

Tau pathology is the main driver of neuronal dysfunction in 4-repeat tauopathies (4RT), including cortico-basal degeneration and progressive supranuclear palsy (PSP). Tau is assumed to spread prion-like across connected neurons, but the mechanisms of tau propagation are largely elusive in 4RTs, characterized not only by neuronal but also by astroglial and oligodendroglial tau accumulation. Here, we assessed whether connectivity drives 4R-tau spreading patterns by combining resting-state fMRI connectomics with both 2nd generation 18F-PI-2620 tau-PET in 46 patients with clinically diagnosed 4RTs and post-mortem cell-type-specific regional tau assessments from two independent PSP samples (n=97/96). We found that inter-regional connectivity was associated with higher inter-regional correlation of both tau-PET and post-mortem tau levels in 4RTs. In regional cell-type specific post-mortem tau assessments, this association was stronger for neuronal than for astroglial or oligodendroglial tau, suggesting that connectivity is primarily associated with trans-neuronal tau spread. Using tau-PET we found that patient-level tau patterns can be predicted by the connectivity of subcortical tau epicenters. Together, the current study provides combined in vivo tau-PET and histopathological evidence for brain connectivity as a key mediator of trans-neuronal tau spreading in 4RTs.

AbstractBackgroundEpidemiological studies suggest that reserve capacity is associated with a significant delay of cognitive decline by up to 4 years in aging and dementia. Identifying brain substrates of reserve is a pivotal step to define potential intervention targets for brain stimulation in order to enhance reserve. We previously showed that higher global connectivity of specific richly connected hub regions contribute to reserve (Franzmeier et al. Brain 2018, Neitzel et al. Neurology 2019). However, apart from the role of local hubs, functional mechanisms at the level of major functional networks that support reserve are poorly understood. The segregation of the brain’s major functional network is a fundamental brain property that supports higher cognitive function (Chan et al. PNAS 2014, 2018). We hypothesized that higher system segregation is associated with attenuated cognitive decline in normal aging and Alzheimer’s disease (AD).MethodWe included 255 cognitively normal elderly subjects (age=52.48±16.12) from the RANN study, 108 individuals with autosomal‐dominant AD and their sibling non‐mutation carriers (n=71) from DIAN, and 152 amyloid‐positive subjects across the clinical AD‐spectrum from ADNI. Based on resting‐state fMRI‐assessed 400‐ROI functional connectivity matrix, we computed system segregation as the difference of within‐network and between‐network connectivity normalized to the within‐network connectivity. Higher segregation scores indicate higher segregation between the networks. In linear regression analyses, we tested whether higher system segregation was associated with 1) higher cognitive performance in elderly subjects, and 2) for AD, attenuated cognitive decline at a given level of disease severity (as measured by “estimated years from dementia symptom onset” (EYO) in autosomal‐dominant AD, and by 18F‐AV1451 tau‐PET in early‐Braak‐stage ROIs in sporadic AD).ResultIn cognitively normal subjects, higher system segregation was associated with higher composite scores of global cognition (p=0.001, Figure 1). For AD, higher system segregation was associated with an attenuated effect of disease severity on global cognition in autosomal‐dominant AD (interaction EYO by system segregation: p = 0.007, Figure 2), and an attenuated association between tau‐PET and ADAScog in sporadic AD (p=0.0009, Figure 3).ConclusionSystem segregation is associated with higher cognitive abilities in aging and enhances reserve capacity in Alzheimer’s disease.

AbstractBackgroundLoss of function of TREM2, a key receptor expressed on microglia, is associated with increased Alzheimer’s disease (AD) risk. In biomarker‐defined AD patients, we found previously that higher cerebrospinal‐fluid (CSF) levels of soluble TREM2 relative to the level of p‐tau (sTREM2/p‐tau ratio) are associated with attenuated clinical AD progression. This suggests that higher sTREM2/p‐tau, indicative of more activated microglia at a given level of pathology, may be beneficial in AD. Here, we asked the more general question whether higher sTREM2/p‐tau ratio levels attenuate the general risk to develop AD‐related cognitive decline and neurodegeneration in a large sample of cognitively normal to AD dementia subjects. To assess AD risk, we used a pre‐established polygenic hazard score (PHS) including 31 SNPs that are associated with age of AD onset (e.g. Tan et al., Brain, 2019). We determined whether higher sTREM2/p‐tau levels attenuate the effect of polygenic AD risk (i.e. PHS) on future cognitive decline and neurodegeneration.MethodsWe included 648 elderly cognitively normal to dementia subjects from ADNI with available CSF‐biomarker data (i.e. sTREM2, Aβ1‐42 and p‐tau), longitudinal cognitive assessments and structural MRI (∼4yrs follow‐up). The PHS was determined on GWAS data. Using linear regression, we tested the association between PHS, CSF‐assessed AD biomarkers or sTREM2, controlling for age, gender, education and diagnosis. Second, we determined whether higher sTREM2/p‐tau levels moderated the effect of PHS on annual change rates in global cognition (i.e. ADAS13), memory (i.e. ADNI‐MEM) and MRI‐assessed hippocampal volume, controlling for age, gender, education and diagnosis and baseline cognition.ResultsHigher polygenic AD risk, i.e. PHS, was associated with lower CSF Aβ1‐42 (β=‐0.354,p<0.001) and higher p‐tau levels (β=0.328,p<0.001), but not with sTREM2 (β=0.007,p=0.864; Figure 1). We found significant sTREM2/p‐tau x PHS interactions, such that individuals with higher sTREM2/p‐tau ratios had a lower effect of PHS on global cognitive (β=‐0.210,p=0.002) and memory decline (β =0.258,p=0.002) as well as hippocampal atrophy rates (β=0.262,p=0.002; Figure 2).ConclusionA higher sTREM2/p‐tau ratio is protective against the AD‐related polygenic risk for faster cognitive decline and hippocampus atrophy.

Global connectivity of the left frontal cortex (LFC), a hub of the cognitive control network, is associated with higher fluid intelligence and relatively preserved cognition despite age‐ and Alzheimer’s disease (AD)‐related brain changes, rendering LFC‐connectivity a candidate substrate of reserve (Franzmeier et al. Brain 2018). Yet, the mechanisms by which LFC‐connectivity supports cognition at the functional network level remain unclear. Functional network‐segregation within the brain guards against diffuse network organization and is a fundamental brain property central to efficient cognitive processes. Given that the control network, and in particular the LFC, is thought to orchestrate activity of other functional networks (Cole, Nat Neurosci, 2013), we hypothesized that the association between LFC‐connectivity and higher cognitive abilities such as executive function is mediated via enhanced network‐segregation.

In Alzheimer’s disease, PET-assessed tau pathology emerges locally and spreads throughout functionally connected regions.

Background The Apolipoprotein E ε4 allele (i.e. ApoE4) is the strongest genetic risk factor for sporadic Alzheimer’s disease (AD). TREM2 (i.e. Triggering receptor expressed on myeloid cells 2) is a microglial transmembrane protein brain that plays a central role in microglia activation in response to AD brain pathologies. Whether higher TREM2-related microglia activity modulates the risk to develop clinical AD is an open question. Thus, the aim of the current study was to assess whether higher sTREM2 attenuates the effects of ApoE4-effects on future cognitive decline and neurodegeneration. Methods We included 708 subjects ranging from cognitively normal (CN, n = 221) to mild cognitive impairment (MCI, n = 414) and AD dementia ( n = 73) from the Alzheimer’s disease Neuroimaging Initiative. We used linear regression to test the interaction between ApoE4-carriage by CSF-assessed sTREM2 levels as a predictor of longitudinally assessed cognitive decline and MRI-assessed changes in hippocampal volume changes (mean follow-up of 4 years, range of 1.7-7 years). Results Across the entire sample, we found that higher CSF sTREM2 at baseline was associated with attenuated effects of ApoE4-carriage (i.e. sTREM2 x ApoE4 interaction) on longitudinal global cognitive ( p = 0.001, Cohen’s f 2 = 0.137) and memory decline ( p = 0.006, Cohen’s f 2 = 0.104) as well as longitudinally assessed hippocampal atrophy ( p = 0.046, Cohen’s f 2 = 0.089), independent of CSF markers of primary AD pathology (i.e. Aβ 1–42 , p-tau 181 ). While overall effects of sTREM2 were small, exploratory subanalyses stratified by diagnostic groups showed that beneficial effects of sTREM2 were pronounced in the MCI group. Conclusion Our results suggest that a higher CSF sTREM2 levels are associated with attenuated ApoE4-related risk for future cognitive decline and AD-typical neurodegeneration. These findings provide further evidence that TREM2 may be protective against the development of AD.

AbstractBackgroundIn Alzheimer’s disease (AD), tau pathology spreads from the temporal lobe throughout the brain, ensuing cognitive decline. PET‐assessed tau‐spreading patterns are, however, heterogeneous across patients, posing challenges for assessing patient‐specific or group‐level longitudinal tau‐changes. Yet, this may become critical for disease management and evaluating tau‐targeting treatments. Using tau‐PET and resting‐state fMRI, we reported previously that tau spreads preferentially across functionally connected regions, supporting a trans‐neuronal tau‐spreading hypothesis (Franzmeier et al.,Brain,2019;NatComms, 2020). Here, we propose a novel connectivity‐based model to predict individual tau‐spreading patterns, which improves quantifying patient‐specific longitudinal tau‐changes over conventional staging approaches.MethodsWe included two samples with cross‐sectional AV1451‐tau‐PET of amyloid‐negative controls (Aβ‐;ADNI/BioFINDER, n=231/16) and AD spectrum patients (Aβ+;ADNI/BioFINDER, n=213/41), plus longitudinal tau‐PET in Aβ+ (ADNI/BioFINDER, n=83/41,∼1.3‐2yrs follow‐up). To determine tau‐abnormality, we transformed tau‐PET SUVRs of 200 regions of interest (ROIs, Fig.1A) to tau‐positivity probabilities using two‐component gaussian mixture models (Fig.1B&C). Multi‐leg connectivity‐based distance between 200‐ROIs was assessed on resting‐state fMRI of 1000 human connectome project participants (Fig.1D). In Aβ+, we rank‐ordered cross‐sectional tau‐abnormality probabilities across subjects and ROIs to determine hierarchical tau‐abnormality sequences (Fig.2A‐D). For “epicenters” with earliest tau‐abnormality (top 10% of rank‐ordered ROIs), connectivity‐based distance between epicenters and remaining ROIs (Fig.2E&F) was tested as a predictor of tau‐abnormality sequences. For subject‐level prediction of tau‐spreading, subject‐specific tau‐epicenters were defined as 10% ROIs with highest baseline tau‐abnormality and rates of longitudinal tau‐changes were determined in connectivity‐based distance to these epicenters.ResultsConnectivity‐based distance of tau epicenters predicted cross‐sectionally‐assessed tau‐positivity sequences in Aβ+ (ADNI: R2=0.52, p<0.0001; BioFINDER: R2=0.50, p<0.0001, Fig.2G&H). For subject‐specific tau‐spreading, we found strongest tau‐changes in those 25% ROIs (i.e. first Quartile, Q1‐ROI in Fig.3A) in closest connectivity‐based proximity to subject‐specific epicenters (Fig.3B&C). Tau‐changes in closest proximity to the epicenters were higher than in Braak‐stage‐specific or whole‐grey‐matter ROIs (Fig.3D&E). Sample size estimation for treatments targeting tau‐accumulation showed that using subject‐tailored ROIs in closest connectivity‐based proximity to tau epicenters for assessing tau‐changes decreases sample sizes by ∼40% when compared to using whole‐brain or Braak‐stage‐specific ROIs.ConclusionsConnectivity‐based distance of tau epicenters predicts subject‐level tau accumulation patterns, which improves detecting longitudinal tau‐changes.