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- Binette, Alexa Pichet, et al.
(author)
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Amyloid-associated increases in soluble tau is a key driver in accumulation of tau aggregates and cognitive decline in early Alzheimer
- 2022
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In: Alzheimer's and Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 18:S1
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Journal article (peer-reviewed)abstract
- Background: For optimal design of anti-amyloid-β (Aβ) and anti-tau clinical trials, it is important to understand how Aβ and soluble phosphorylated tau (p-tau) relate to the accumulation of tau aggregates assessed with positron emission tomography (PET) and subsequent cognitive decline across the Alzheimer's disease (AD) continuum. Method: We included 327 participants from the Swedish BioFINDER-2 cohort with cerebrospinal fluid (CSF) p-tau217, Aβ-PET, longitudinal tau-PET, and longitudinal cognition. The main groups of interest were Aβ-positive non-demented participants and AD dementia patients (Table 1 and Figure 1), and analyses were conducted separately in each group. First, we investigated how soluble p-tau217 and regional Aβ-PET were associated with tau-PET rate of change across the 200 brain parcels from the Schaefer atlas. We also tested the mediating effect of p-tau217 between Aβ-PET and tau-PET change. Second, we investigated how soluble p-tau217 and tau-PET change related to change in cognition, and mediation between these variables. Result: In early AD stages (non-demented participants), increased concentration of soluble p-tau217 was the main driver of accumulation of insoluble tau aggregates across the brain (measured as tau-PET rate of change), beyond the effect of regional Aβ-PET and baseline tau-PET (Figure 2A-C). Further, averaged across all regions, soluble p-tau217 mediated 54% of the association between Aβ and tau aggregation (Figure 2D). Higher soluble p-tau217 concentrations were also associated with cognitive decline, which was mediated by faster increase of tau aggregates (Figure 3). Repeating the same analyses in the AD dementia group, results were different. In late stage of AD, when Aβ fibrils and soluble p-tau levels have plateaued, soluble p-tau217 was not associated with accumulation of tau aggregates beyond baseline tau-PET (Figure 4A), and cognitive decline was driven by the accumulation rate of insoluble tau aggregates and not soluble p-tau217 (Figure 4B-C). Conclusion: Soluble p-tau is a main driver of tau aggregation and future cognitive decline in earlier stages of AD, whereas tau aggregation accumulation is more likely an important driver of disease in later stages. Overall, our data suggest that therapeutic approaches reducing soluble p-tau levels might be most favorable in early AD.
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| 2. |
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| 3. |
- Pichet Binette, Alexa, et al.
(author)
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Amyloid-associated increases in soluble tau relate to tau aggregation rates and cognitive decline in early Alzheimer's disease
- 2022
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In: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 13:1, s. 6635-6635
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Journal article (peer-reviewed)abstract
- For optimal design of anti-amyloid-β (Aβ) and anti-tau clinical trials, we need to better understand the pathophysiological cascade of Aβ- and tau-related processes. Therefore, we set out to investigate how Aβ and soluble phosphorylated tau (p-tau) relate to the accumulation of tau aggregates assessed with PET and subsequent cognitive decline across the Alzheimer's disease (AD) continuum. Using human cross-sectional and longitudinal neuroimaging and cognitive assessment data, we show that in early stages of AD, increased concentration of soluble CSF p-tau is strongly associated with accumulation of insoluble tau aggregates across the brain, and CSF p-tau levels mediate the effect of Aβ on tau aggregation. Further, higher soluble p-tau concentrations are mainly related to faster accumulation of tau aggregates in the regions with strong functional connectivity to individual tau epicenters. In this early stage, higher soluble p-tau concentrations is associated with cognitive decline, which is mediated by faster increase of tau aggregates. In contrast, in AD dementia, when Aβ fibrils and soluble p-tau levels have plateaued, cognitive decline is related to the accumulation rate of insoluble tau aggregates. Our data suggest that therapeutic approaches reducing soluble p-tau levels might be most favorable in early AD, before widespread insoluble tau aggregates.
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| 4. |
- Spotorno, Nicola, et al.
(author)
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Astrocytic function is associated with both amyloid-β and tau pathology in non-demented APOE 4 carriers
- 2022
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In: Brain Communications. - : Oxford University Press (OUP). - 2632-1297. ; 4:3
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Journal article (peer-reviewed)abstract
- A growing body of evidence suggests that astrocytes play a major role in the pathophysiology of Alzheimer's disease. Given that APOE is primarily expressed in astrocytes, these cells might be an important link between the APOE ϵ4 allele and the development of Alzheimer's disease pathology. Here, we investigate this hypothesis in vivo by measuring myo-inositol, a metabolite involved in astrocytic functions, with magnetic resonance spectroscopy. Currently, there is conflicting evidence regarding the relationship between APOE ϵ4 and myo-inositol concentration. Furthermore, data supporting a relationship between APOE ϵ4, myo-inositol and Alzheimer's disease pathology (amyloid-beta and tau proteins) in the preclinical stage of Alzheimer's disease are limited. A previous study revealed differences in myo-inositol levels between APOE ϵ4 carriers and non-carriers already in preclinical Alzheimer's disease participants. However, other reports showed no impact of APOE genotype on the association between myo-inositol and the rate of amyloid-beta accumulation. In the present study, we determined the effect of APOE genotype on the association between myo-inositol and both amyloid-β and tau deposition quantified by PET in 428 cognitively unimpaired elderly and patients with mild cognitive impairment from the Swedish BioFINDER-2 cohort. APOE genotype impacted the associations between myo-inositol and amyloid-β pathology as revealed by an interaction effect between APOE genotype and levels of myo-inositol (P < 0.001) such that higher myo-inositol concentration was related to more amyloid-beta pathology in APOE ϵ4 carriers only. A similar interaction effect was also found when investigating the effect of APOE on the association between myo-inositol and tau pathology (P < 0.01). Focusing on the APOE ϵ4 subsample, myo-inositol partially (17%) mediated the association between amyloid-beta and tau pathology (P < 0.05). Furthermore, in a subgroup of participants with available plasma levels of glial fibrillary acidic protein, a marker of astroglial activation and astrocytosis, we found that glial fibrillary acidic protein correlated with myo-inositol only in APOE e4 carriers (APOE ϵ4 carriers: P < 0.01; APOE ϵ4 non-carriers: P > 0.8), suggesting that myo-inositol might reflect an aspect of the astrocytic involvement in Alzheimer's pathology which is specific to the impact of APOE ϵ4. Therefore, we suggest that myo-inositol is a candidate in vivo marker to study the impact of APOE ϵ4 on the interplay between astrocytes and the pathophysiology of Alzheimer's disease.
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| 5. |
- Spotorno, Nicola, et al.
(author)
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The mean diffusion propagator model revealed cortical microstructural changes associated with both amyloid-β and tau pathology and astroglial activation
- 2022
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In: Alzheimer's and Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 18:S1
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Journal article (peer-reviewed)abstract
- Background: Markers of downstream events are a key component of clinical trials of disease-modifying therapies for Alzheimer’s disease (AD). Morphometric metrics like cortical thickness are established measures of atrophy but are not sensitive enough to detect Aβ-related changes that occur before overt atrophy become visible. We aimed to investigate to what extent diffusion MRI can provide sensitive markers of cortical microstructural changes that could complement morphometric macrostructural measures. Method: We applied the mean apparent diffusion propagator model (MAP-MRI) to diffusion MRI data from 492 cognitively unimpaired elderly and patients with mild cognitive impairment from the Swedish BioFINDER-2 cohort. MAP-MRI extends diffusion tensor imaging and provides metrics sensitive to subtle changes in the cortex. Participants were stratified in Aβ-negative/tau-negative, Aβ-positive/tau-negative, and Aβ-positive/tau-positive based on Aβ- and tau-PET uptake. Cortical regional values of both MAP-MRI metrics and CT were compared across groups. Associations between regional values of MAP-MRI metrics and both Aβ- and tau-PET uptake were also investigated as well as the association between MAP-MRI metrics and plasma level of GFAP, a marker of astroglial activation (available in 292 participants). Result: Mean square displacement (MSD) from MAP-MRI revealed widespread microstructural differences already between Aβ-negative/tau-negative and Aβ-positive/tau-negative participants with a spatial distribution that closely resembled the pattern of Aβ accumulation. In contrast, differences in cortical thickness appeared to be more limited (figure 1). MSD was also highly correlated with both Aβ- and tau-PET uptake even independently from one another (figure 2). Regional MSD values were associated with GFAP with a pattern that resemble Aβ accumulation, and GFAP partially mediated the association between Aβ and MSD. A sensitivity analysis controlling for cortical thickness revealed that the associations between MSD and Aβ-PET, tau-PET and GFAP were largely independent from macrostructural changes (figures 2-3). Conclusion: Metrics of cortical microstructural alteration derived from MAP-MRI are highly sensitive to multiple aspects of the AD pathological cascade. Of particular interest is the link between MSD, Aβ-PET and GFAP which suggests MSD might reflects microstructural changes related to the astrocytic response to Aβ aggregation. Therefore, MSD could help monitoring the response to anti-Aβ treatments in clinical trials.
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