Aims

Basal forebrain cholinergic neurons (BFCNs) degenerate during normal aging and early stages of Alzheimer’s disease (AD). The p75 neurotrophin receptor (p75NTR) is expressed by BFCNs and modulates pro- and anti-apoptotic pathways as well as neurite and neuritic spine integrity. Pharmacological modulation of this receptor with LM11A-31 reverses basal forebrain axonal pathology in mouse models of AD.

Older, late-onset AD subjects tend to have greater proportions of mixed etiology dementia while younger AD subjects are considered to have a greater proportion of pure AD pathology. This prompted the examination of age-dependent effects of LM11A-31 in human AD with longitudinal structural magnetic resonance imaging (sMRI) and cerebrospinal fluid (CSF) biomarkers.

Methods

Participants with mild to moderate AD (MMSE score=18-26; age 55-85) were enrolled in a six-month placebo-controlled phase 2a safety and exploratory endpoint trial of LM11A-31. For placebo and drug, age groups were defined using a median-split: younger (<72 years) and older (>=72 years).

Results

Older subjects exhibited smaller BF volumes at baseline than younger subjects in both placebo and drug groups, and exhibited no differences in AD stage according to MMSE score or CSF p-tau/Aβ42 ratio at baseline. Results outlining age-group specific effects of LM11A-31 on longitudinal CSF and neuroimaging biomarkers will be presented.

Conclusions

This investigation points to the possibility that certain biomarkers can demonstrate age-dependency in response to therapeutic interventions in the context of mild-moderate AD. Our results may inform biomarker selection and design of future studies of LM11A-31 in human AD.