Aims

Test whether astrocyte reactivity is associated with synaptic dysfunction independently of amyloid-β (Aβ) and tau pathologies.

Methods

Biomarkers were measured in the CSF of participants from the McGill TRIAD cohort. Individuals had available Aβ- and Tau-PET. We measured CSF Glial Fibrillary Acidic Protein (GFAP, a proxy of astrocyte reactivity), and synaptic markers (Growth Associated Protein 43 (GAP43), neurogranin (Ng), Synaptotagmin 1 (SYT1), presynaptic protein synaptosomal-associated protein 25 (SNAP-25)). Linear regressions adjusted for age, sex, clinical diagnosis, and Aβ/tau-PET were used to test the associations between astrocyte reactivity and synaptic markers.

Results

We studied 115 individuals [63 cognitively unimpaired (CU) and 52 cognitively impaired (CI)]. Remarkably, we found a significant association between CSF GFAP and GAP43 (β=0.1123, p<0.0001), Ng (β=0.0064, p=0.0098), SYT1 (β=0.0024, p<0.0001), SNAP-25 total (β=0.0018, p<0.0001), and SNAP-25 long (β=0.0009, p<0.0001) independent of both brain Aβ- and Tau-PET levels.

Conclusions

Our biomarker results support experimental literature suggesting that astrocyte reactivity plays a role in downstream synaptic dysfunction independent of the brain levels of Aβ and tau tangles pathologies. This supports in vitro literature suggesting that therapeutic interventions targeting astrocyte reactivity can contribute to halting AD progression.

Aims

Growing evidence suggests an increased age-independent prevalence of Alzheimer's disease (AD) in females compared to males. Elucidating how disease biomarkers correlate in females and males is critical to understanding the basis of sex differences in AD. Our aim was to evaluate sex-related differences in the association of plasma Glial fibrillary acidic protein (GFAP) levels, a biomarker of astrocyte reactivity, and Alzheimer's disease (AD) pathophysiology.

Methods

We cross-sectionally assessed participants from TRIAD cohorts. Unpaired t-test compare the difference in plasma GFAP levels between females and males. We performed linear regressions with an interaction term for sex to compare the associations of plasma GFAP with global Aβ PET load, cerebrovascular disease measured with white matter hyperintensity (WMH) , and neurodegeneration measured with hippocampal volume (HCV) between cognitively impaired females and males.

Results

We assessed 308 participants (MCI = 63 , AD =45 CN=200, mean age=69.8 (8) ). Females showed significantly higher GFAP levels than males (Fig 1). We found significant interaction terms and strong correlations between plasma GFAP levels and AD pathophysiology (Aβ PET) in females (R-squared=0.2; P=0.03) but not in males. Similarly, plasma GFAP was associated with vascular disease (WMH) (R-squared=0.3; P=0.005) and neurodegeneration (HCV atrophy) (R-squared= 0.13; P=0.003) only in females. No association was found between GFAP and AD biomarkers in females or males without cognitive impairment (Fig 2).

Conclusions

Our results suggest astrocyte reactivity is highly associated with AD pathophysiology in females than males. This may have important implications for elucidating the basis of the higher prevalence of AD in females.Yet, these results were generated with a limited number of subjects and using a cross-sectional design. Therefore, replication in larger, independent longitudinal datasets is needed to better understand the association of GFAP levels, sex, and AD.

Aims

Investigate the association between microglial activation (MA) and neuropsychiatric dysfunction in patients across the Alzheimer's disease (AD) continuum

Methods

Participants had Neuropsychiatry Inventory (NPI) and positron emission tomography (PET) for amyloid-β (Aβ) plaques ([18F]AZD4694), tau tangles ([18F]MK6240) and MA ([11C]PBR28) at the same time point. SUVRs were calculated, using the cerebellum gray matter as a reference, in the whole cortex, temporal meta-ROI, and posterior cingulate cortex (PCC) for [18F]AZD4694), [18F]MK6240, and [11C]PBR28, respectively. Linear regression tested the association of [11C]PBR28 levels with NPI scores accounting for covariates of interest. Analysis of covariance compared groups. Models were adjusted for age, sex, and clinical diagnosis.

Results

We studied 132 (86 CU, 28 MCI, and 18 AD dementia) participants from the Translational Biomarkers in Aging and Dementia (TRIAD) cohort. We found that [11C]PBR28 SUVR in the PCC was significantly associated with neuropsychiatric symptoms (Figures 1A and B). Interestingly, this association was independent of Aβ and tau levels (Table 1).

Figure 1. [11C]PBR28 SUVR levels are positively associated with NPI scores. A. Scatter plot showing the linear regression between [11C]PBR28 SUVR values and NPI scores. B. Bars show the mean and SD NPI scores in [11C]PBR28 negative and positive groups. [11C]PBR28 positivity was considered SUVR values 2.5 times the SD from the mean SUVR in PCC in CU young population (n = 17, aged 20 to 25 years).

Table 1. [11C]PBR28 SUVR values are associated with NPI score independently of AD hallmark proteins in individuals across AD continuum.

Conclusions

Our results suggest MA as a key element associated with neuropsychiatric dysfunction in AD independent of Aβ and tau pathologies. These findings provide additional rationale for the therapeutic effects of drugs targeting glial cell activation in AD patients.

Aims

CSF total tau(t-tau) is postulated as a marker of neuronal degeneration in the ATN criteria. Here, we examine the association between CSF t-tau and both neurodegeneration and synaptic loss.

Methods

We evaluated 128 older individuals (75 CU,33 MCI,20 AD) in the TRIAD cohort (McGill, Canada) with CSF t-tau, SNAP25long and Neurofilament Light (NfL), Amyloid-beta (Aβ) positron emission tomography and magnetic resonance imaging, and clinical assessments. We used increased SNAP25long as an index of synaptic dysfunction (S+) and reduced hippocampal volume as neurodegeneration (N+). S and N positivity were determined using a cutoff anchored in young CU individuals. Linear regression models were used to test the association between CSF t-tau, SNAP25long and NfL levels and hippocampal volume, adjusted for age, sex, and cognitive status. ANCOVA was employed to inspect CSF t-tau levels across the groups 1) S-N-; 2) S+N-; 3) S-N+; 4) S+N+, adjusted for age, sex, cognitive status, and Aβ burden.

Results

We found that a model with the addition of SNAP25long to the covariates explained 65% of the variance(p-value<0.0001) of CSF t-tau. Alternatively, hippocampal volume (R² =0.2187; p-value<0.0001) and NfL(R²=0.3671; p-value<0.0001) alone or in combination explained less than 40% of the variance of CSF t-tau (R² =0.3597; p-value<0.0001)(Figure 1). Interestingly, we observed an increase of CSF t-tau in the S+N- group but not in the S-N+, further supporting that CSF t-tau is abnormal in the presence of synaptic dysfunction rather than neurodegeneration.Additionally, Loess regression lines confirm a larger magnitude of change of synaptic dysfunction as a function of t-tau,compared with neurodegeneration(Figure 3).

Conclusions

Our results suggest that CSF t-tau may reflect synaptic loss rather than neuronal degeneration. This has implications for the interpretability of results obtained with CSF t-tau in biomarker studies.

Aims

Growing evidence suggests an increased age-independent prevalence of Alzheimer's disease (AD) in females compared to males. Elucidating how disease biomarkers correlate in females and males is critical to understanding the basis of sex differences in AD. Our aim was to evaluate sex-related differences in the association of plasma Glial fibrillary acidic protein (GFAP) levels, a biomarker of astrocyte reactivity, and Alzheimer's disease (AD) pathophysiology.

Methods

We cross-sectionally assessed participants from TRIAD cohorts. Unpaired t-test compare the difference in plasma GFAP levels between females and males. We performed linear regressions with an interaction term for sex to compare the associations of plasma GFAP with global Aβ PET load, cerebrovascular disease measured with white matter hyperintensity (WMH) , and neurodegeneration measured with hippocampal volume (HCV) between cognitively impaired females and males.

Results

We assessed 308 participants (MCI = 63 , AD =45 CN=200, mean age=69.8 (8) ). Females showed significantly higher GFAP levels than males (Fig 1). We found significant interaction terms and strong correlations between plasma GFAP levels and AD pathophysiology (Aβ PET) in females (R-squared=0.2; P=0.03) but not in males. Similarly, plasma GFAP was associated with vascular disease (WMH) (R-squared=0.3; P=0.005) and neurodegeneration (HCV atrophy) (R-squared= 0.13; P=0.003) only in females. No association was found between GFAP and AD biomarkers in females or males without cognitive impairment (Fig 2).

Conclusions

Our results suggest astrocyte reactivity is highly associated with AD pathophysiology in females than males. This may have important implications for elucidating the basis of the higher prevalence of AD in females.Yet, these results were generated with a limited number of subjects and using a cross-sectional design. Therefore, replication in larger, independent longitudinal datasets is needed to better understand the association of GFAP levels, sex, and AD.