Randomized Trial of Verubecestat for Prodromal Alzheimer’s Disease

Abstract

both in Spain (M.B.).

AAV mediated delivery of a novel anti-BACE1 VHH reduces Abeta in an Alzheimer’s disease mouse model

“…At present, the levels of Ab decrease necessary to produce an effect in AD are undetermined (Kennedy et al, 2016;Timmers et al, 2018;Egan et al, 2019) . However, there are reasons to believe that a sustained steady state reduction, similar to that which we report, may be worthwhile pursuing.…”

“…Second, a mutation in human APP, which reduces cleavage by BACE1 (Jonsson et al, 2012), leads to a reduction in cerebral Ab of approximately 20%, with carriers showing lifelong protection against AD and cognitive decline (although issues with the mutation affecting aggregation of Ab peptides cannot be fully excluded) (Maloney et al, 2014;Benilova et al, 2014). Sustained protection through low to moderate levels of CNS-localized BACE1-specific inhibition may well have the additional benefit of reducing, or avoiding, toxicity related to complete loss of BACE1 function, such as hypomyelination (Willem et al, 2006), aberrant synaptic homeostasis and plasticity (Filser et al, 2015), axon guidance abnormalities (Rajapaksha et al, 2011;Cao et al, 2012;Ou-Yang et al, 2018), impairments in spatial and working memory (Henley et al, 2019;Knopman, 2019;Egan et al, 2019) and retinal pathology (Cai et al, 2012). In this respect, it is important to note that the levels of BACE1 inhibition achieved with AAV-mediated delivery of VHH-B9 did not substantially affect cleavage of the alternative BACE1 substrate seizure protein 6 (SEZ6), which is important for maintenance of dendritic spines and synaptic plasticity (Gunnersen et al, 2007;Pigoni et al, 2016;Zhu et al, 2018).…”

Informed consent, therapeutic misconception, and clinical trials for Alzheimer's disease

“…35 For example, solanezumab, an anti-amyloid therapy, did not significantly affect cognitive decline in participants with mild dementia due to Alzheimer's disease, 36 and verubecestat, an anti-amyloid therapy, did not significantly improve clinical dementia ratings in participants with prodromal Alzheimer's disease and may have worsened cognitive and daily function for some participants. 37 Aducanumab, an anti-amyloid therapy, did not appear to significantly affect cognitive decline in participants with mild dementia due to Alzheimer's disease, although more recent data may suggest a reduction in clinical decline for people with Alzheimer's disease. 38,39 The point here is not to offer further explanation as to the reasons for the failure of these trials (see reference 38 for an example of such a discussion) but to highlight the complex decisional framework underlying enrollment in a clinical trials for Alzheimer's disease where desperation and misconception may inadvertently increase the exposure to risk for this vulnerable population.…”

A unified model of dementias and age‐related neurodegeneration

“…These include the scope of possible downstream outcomes of cell senescence, such as the effects on Aβ, tau proteins, mitochondrial dysfunction, and inflammation. This model predicts that any intervention (eg, monoclonal antibodies [MAB] or beta‐site APP‐cleaving protein [BACE]) aimed solely at amyloid faces two obstacles: (1) amyloid is only one among many cascades of downstream pathology resulting from cell senescence and (2) amyloid turnover is a dynamic process, and although MAB interventions may transiently improve extant plaques, they will not affect the recurrence and turnover of such plaques. The cell senescence model therefore predicts that any intervention aimed at a single portion of the cascade of pathology (ie, Aβ plaques) will show a small and transient delay in the disease course, but not affect the subsequent vector of the disease.…”

“…93,94 Absent such intervention, telomerase expression in human neural stem cells falls with recurrent cell division. 174 175,176 ) aimed solely at amyloid faces two obstacles: (1) Aging is an underlying risk factor, because older individuals have glial cells that are, on the average, more senescent (ie, have shorter telomeres 184 ) than those of younger individuals.…”