For therapies aimed at Alzheimer's disease, it seems obvious that an effective drug must act on the brain. But according to the results presented at the 12th conference of clinical trials on Alzheimer's disease, which was held from December 4 to 7 in San Diego, California, a therapy could also influence the brain without ever penetrating the blood-brain barrier.
Apabetalone is a small, orally administered molecule that was created by Resverlogix Corp. Researchers reported at the 12th Alzheimer's Clinical Trials Conference that apabetalone appears to slow cognitive decline, but only in those most affected and after one year of administration.
Apabetalone essentially blocks the association between BET and acetylated lysines, crushing the transcription of hundreds of genes. Previously, researchers had reported that BET proteins stimulate the expression of a myriad of genes involved in inflammation, lipid metabolism and vascular function, making apabetalone a candidate treatment for cardiovascular and other chronic diseases of aging.
Many genes targeted by apabetalone are found downstream of the tumor necrosis factor α (TNFα), a master regulator of inflammation. The results presented at the conference by Ewelina Kulikowski of Resverlogix, suggest that apabetalone could attenuate the inflammatory responses provoked by TNFα, soothe vascular inflammation - and perhaps even limit the chronic activation of glial cells on the other side of the blood-brain barrier.
The BETonMACE multicentre phase III trial was designed to determine whether apabetalone in combination with statins could decrease heart events compared to treatment with statins alone.
Participants in the trial had type 2 diabetes, acute coronary syndrome and low levels of high density lipoprotein (HDL). The trial continued for up to 250 cardiovascular events. Although the drug tended to reduce cardiovascular events, the effect did not reach statistical significance.
Of the 2,425 people enrolled in the trial, 469 people over the age of 70 participated in a cognitive sub-study, the Montreal Cognitive Assessment (MoCA). While the MoCA scores decreased slightly or remained stable in the treatment and placebo groups among participants in the two high MoCA groups, those with the lowest MoCA scores appeared to benefit from treatment.
Among the 97 participants in this subgroup, those taking apabetalone improved on average by three points on the test between the baseline and 27 months, while those on placebo, curiously, improved by 1 point . Researchers believe the drug alleviates cognitive impairment by targeting inflammation in the vascular system.
The idea that an inflamed vascular endothelium - particularly in the vessels that make up the blood-brain barrier, could damage brain health and decrease cognitive ability, confirms the results of previous studies.