Pittsburgh Compound B

The factors that influence the progression of Alzheimer's disease (AD) after individuals become amyloid‐positive are poorly understood. This study examines how sex influences the longitudinal trajectories of plasma AD and neurodegenerative biomarkers in the years following a person's estimated onset of amyloid‐β.

Linear mixed‐effects modeling investigated overall and sex‐specific longitudinal trajectories of plasma biomarkers, brain volumes, and cognition relative to the estimated age of amyloid onset in a cohort of 78 amyloid‐positive Baltimore Longitudinal Study of Aging (BLSA) participants (n = 45 male; follow‐up time: 6.8 years [SD 3.31]). Amyloid status was ascertained with 11C‐Pittsburgh compound B (PiB) PET imaging.

After amyloid onset, men displayed steeper increases in pTau181, pTau231, and neurofilament light (NfL) compared to women. In this same period, men demonstrated steeper declines in brain volume and cognitive performance.

These findings suggest that sex influences the trajectory of AD pathology, neuronal injury, and symptom progression after individuals become amyloid‐positive.

Steeper rates of increase in pTau and GFAP among amyloid‐positive individuals.After amyloid onset, steeper increases in pTau and NfL concentrations in men than in women.Steeper declines in brain volume and cognition in men corroborate biomarker results.

A group of N‐phenylbenzofuran‐2‐carboxamide and N‐phenylbenzo[b]thiophene‐2‐carboxamide derivatives were designed and synthesized as a novel class of Aβ42 aggregation modulators. In the thioflavin‐T based fluorescence aggregation kinetics study, compounds 4 a, 4 b, 5 a and 5 b possessing a methoxyphenol pharmacophore were able to demonstrate concentration dependent inhibition of Aβ42 aggregation with maximum inhibition of 54 % observed for compound 4 b. In contrast, incorporation of a 4‐methoxyphenyl ring in compounds 4 d and 5 d led to a significant increase in Aβ42 fibrillogenesis demonstrating their ability to accelerate Aβ42 aggregation. Compound 4 d exhibited 2.7‐fold increase in Aβ42 fibrillogenesis when tested at the maximum concentration of 25 μM. These results were further confirmed by electron microscopy studies which demonstrates the ability of compounds 4 a, 4 b, 4 d, 5 a, 5 b and 5 d to modulate Aβ42 fibrillogenesis. Compounds 5 a and 5 b provided significant neuroprotection to mouse hippocampal neuronal HT22 cells against Aβ42‐induced cytotoxicity. Molecular docking studies suggest that the orientation of the bicyclic aromatic rings (either benzofuran or benzo[b]thiophene) plays a major role in moderating their ability to either inhibit or accelerate Aβ42 aggregation. Our findings support the application of these novel derivatives as pharmacological tools to study the mechanisms of Aβ42 aggregation.