Atabecestat has been related to dose-related cognitive deterioration in preclinical AD

Treatment with atabecestat, a non-selective oral β-secretase inhibitor, was associated with dose-related cognitive deterioration in patients with preclinical Alzheimer’s disease (AD), and these effects were observed as early as 3 months after starting therapy, according to study results published in JAMA Neurology .

In this double-blind phase 2b / 3 study, conducted at 143 centers in 14 countries, 557 patients who were amyloid-positive but cognitively normal (mean age 70.4 years) were randomly given 5 mg atabecestat (n = 189) treated. 25 mg (n = 183) or placebo (n = 185). The originally planned 1650 participants were not included in the study because it was terminated prematurely due to hepatic adverse events (AEs).

The primary outcome was the change in preclinical Alzheimer’s Cognitive Composite score from baseline. Additional secondary outcomes included changes in cognitive function index and repeatable battery to assess the total scale score of neuropsychological status from baseline. Study investigators also monitored safety throughout the study.

Treatment with 25 mg atabecestat was associated with significant cognitive deterioration after 6 months compared to placebo for the preclinical Alzheimer’s Cognitive Composite (smallest square mean difference -1.09; 95% CI -1.66 to -0.53; P. <0.001) and 12 months (mean of the least squares: -1.62; 95% CI: -2.49 to -0.76; P <0.001). The 25 mg atabecestate therapy was also associated with a deterioration in the repeatable battery for assessing the neuropsychological status after 3 months (mean of the least squares: -3.70; 95% CI: -5.76 to -1.63; P <0.001).

There were no deaths during the study, but the study researchers noted a high incidence of serious treatment-related side effects with atabecestat compared to placebo. Treatment with atabecestat was also associated with higher rates of neuropsychiatric side effects, including depression-related, cognitive-related, sleep / dream-related, and anxiety-related side effects.

Treatment with the 25 mg dose of atabecestat was associated with greater mean weight loss at 12 months compared to the 5 mg and placebo groups (-1.68 kg versus 0.41 kg versus 0.21 kg). The results showed that newly occurring transaminase elevations more than three times the upper limit of normal occurred in 7 participants from 20 to 110 days after discontinuation of the atabecestat dose. The transaminase levels eventually returned to normal.

The study’s investigators added that recovery was evident up to 6 months after treatment was discontinued. In an exploratory analysis, total brain volume in the 25 mg atabecestate group decreased after 6 months and 12 months compared to the placebo arm.

One limitation of this study was the shortening, mainly due to the premature discontinuation of the atabecestat dose.

The study’s researchers concluded that the study’s results may help better understand the mechanisms underlying transient cognitive deterioration and to investigate whether there is a pathway for low-dose BACE inhibition in the Future.”

Disclosure: This clinical study was supported by Janssen. Several authors on the study stated links to the pharmaceutical industry. For a full list of the authors’ information, see the original reference.


Sperling R., Henley D., Aisen PS, et al. Efficacy, Safety, and Biomarker Results of Atabecestat in Preclinical Alzheimer’s Disease: An Abbreviated Phase 2b / 3 Randomized Clinical Trial. Published online January 19, 2021. JAMA Neurol. doi: 10.1001 / jamaneurol.2020.4857

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