Aims

Circulating neuronal extracellular vesicles (NEVs) of Alzheimer’s disease (AD) patients show high Tau and Amyloid-beta (Aβ) levels, whereas their astrocytic EVs (AEVs) contain high complement levels. We sought to examine the association between blood neural EV and brain tissue levels of AD pathogenic proteins in AD mouse models.

Methods

We immunocaptured NEVs and AEVs from plasma collected from fifteen wild type (WT), four 2xTg-AD, nine 5xFAD, and fifteen 3xTg-AD mice and assessed biomarker relationships with brain tissue levels.

Results

NEVs had higher total (tTau) and p181-Tau in 3xTg-AD compared to WT mice (tTau, P=0.001; p181-Tau, P=0.002). For all groups of mice (Fig. 1a-b), NEV levels of tTau correlated significantly with those in cerebral cortex (r=0.7, p<0.0001) and hippocampus (r=0.5, P=0.0005) and NEV levels of p181-Tau with those in cerebral cortex (r=0.6, P<0.0001) and hippocampus (r=0.7, P<0.0001). NEVs from 5xFAD compared to other mice had higher Abeta42 (P<0.005). NEV Abeta42 had strong correlations with Abeta42 in cortex (r=0.6, P=0.001) and hippocampus (r=0.7, P<0.0001; Fig. 1c). AEV C1q was elevated in 3xTg-AD compared to WT mice (P=0.005); AEV C1q had strong correlations with C1q in cortex (r=0.9, P<0.0001) and hippocampus (r=0.7, P<0.0001; Fig. 1d).

Conclusions

Biomarkers in blood NEVs and AEVs reflect their brain levels across multiple AD mouse models supporting their potential use as “liquid biopsy” for AD.

Aims

To investigate the efficacy of monoclonal antibodies against Amyloid-beta (Aβ) in Alzheimer’s disease (AD).

Methods

Pubmed, Web of Science and ClinicalTrials.gov were searched for phase III randomized controlled trials (RCTs) and random-effects meta-analyses were performed.

Results

Seventeen RCTs (12,585 patients) were included. Monoclonal antibodies improved the cognitive outcomes ADAS-Cog {SMD = -0.06 [95% CI (-0.10; -0.02), I²= 0%]} and MMSE {SMD = 0.05 [95% CI (0.01; 0.09), I²= 0%]}, but did not improve the cognitive/functional measure CDR-SOB.

Antibodies decreased PET amyloid {SMD = -1.02 [95% CI (-1.70; -0.34), I²= 95%]} and CSF p181-tau {SMD = -0.87 [95% CI (-1.32; -0.43), I² = 89%]}, but increased ARIA risk {RR = 4.30 [95% CI (2.39; 7.77), I²= 86%]}. Antibody effects on reducing PET amyloid SUVR were correlated with their effects on decreasing (improving) ADAS-Cog (r = 0.66, p = 0.02)

In subgroup analysis by drug, Aducanumab improved ADAS-Cog, CDR-SOB, ADCS-ADL, and decreased amyloid PET SUVR and CSF p181-tau. Solanezumab improved ADAS-Cog and MMSE, and increased (improved) CSF Aβ_1-40. Bapineuzumab, Gantenerumab and Crenezumab did not improve any clinical outcomes, but Bapineuzumab and Gantenerumab decreased CSF p181-tau. All drugs except Solanezumab increased ARIA risk.

Conclusions

The increased power of this meta-analysis allowed us to detect small clinical and large biomarker improvements induced by anti-Aβ monoclonal antibodies. These findings support the view that Aβ remains a rational target for AD drug development and provide moderate support for the continuous development of anti-Aβ monoclonal antibodies as a treatment for AD.