Mixed dementia is a complex form of dementia in which heterogeneous disease states co-exist, the most
common being pathologic characteristics of vascular dementia (VaD), such as chronic stroke infarcts, alongside
pathologic characteristics of Alzheimer’s disease (AD). It is unknown precisely how many patients presently
diagnosed with a particular type of dementia actually have mixed dementia, however post-mortem analyses
suggest that the condition may be present in nearly 50% of patients clinically diagnosed with AD. Yet despite the
frequent co-existence of VaD and AD, little is known about how these diseases influence each other, in part due
to the lack of adequate animal models of mixed dementia, and there are no proven disease modifying therapies.
To address this need, the goal of this proposal is to test if a first-in-class small molecule, orally bioavailable p75
neurotrophin receptor (p75NTR) ligand, LM11A-31, currently in Phase IIa clinical trials for the treatment of AD,
also has efficacy in two different mouse models of post-stroke mixed dementia. The first, is an innovative model
of post-stroke mixed dementia in which in the weeks following stroke, aged wildtype (wt) mice exhibit cholinergic
neurodegeneration along with the appearance of neuritic plaques resembling those found in AD (Aim 1). The
second, is a transgenic mouse model of mixed dementia in which aged AßPPL/S mice that have undergone a
stroke develop more severe AD pathology than their age-matched counterparts (Aim 2). In both of these models,
mice also develop delayed cognitive impairments in the weeks after stroke. Positive results obtained here would
be the first validation that p75NTR is an effective therapeutic target in two post-stroke mixed dementia models,
and could fast-track LM11A-31 into post-stroke mixed dementia clinical testing.