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Parkinson's disease (PD) and Alzheimer's disease (AD) are recognized to coexist on a spectrum of neurodegeneration, and it has been proposed that molecular interactions among pathogenic proteins are a basis for the overlap between these two diseases. We instead hypothesize that degeneration of the nigro-striatal dopaminergic system enhances the clinical penetrance of early stage AD. To determine the effect of striatal dopamine on the pathological effects in an experimental model of AD, APPSWE/PS1ΔE9 mice received striatal injections of the neurotoxin 6-hydroxydopamine (6OHDA). Animals were tested in a Barnes maze protocol and a water T-maze protocol at different ages to determine the onset of cognitive impairment. APPSWE/PS1ΔE9 mice that received 6OHDA injections showed significant impairment in Barnes maze performance at an earlier age than controls. Additionally, at 12 months of age APPswe/PS1ΔE9+6OHDA mice demonstrated worse behavioral flexibility in a task-switch phase of the water T-maze than other groups. To determine the neuroprotective effects of dopaminergic neurotransmission against Aβ42 toxicity, neuronal branch order and dendrite length was quantified in primary medium spiny neuron (MSN) cultures pretreated with increasing doses of the D1 and D2 receptor agonists before being exposed to oligomerized Aβ42. While there was no difference in Aβ peptide levels or plaque burden between groups, in murine MSN culture dopaminergic agonists prevented a toxic response to Aβ42. Depletion of dopamine in the striatum exacerbated the cognitive impairment seen in a mouse model of early stage AD, which may be due to a protective effect of dopaminergic innervation against Aβ striatal neurotoxicity.