Project 455739

Apathy is a common, early, and disabling symptom in dementias such as Alzheimer's disease (AD) and is characterized by reduced self-initiated behavior. Attempts to treat apathy include methylphenidate, a dopamine releasing agent, and repetitive transcranial magnetic stimulation (rTMS), a non-invasive brain stimulation method. Both treatments were only modestly effective in reducing apathy in patients with AD and its precursor state, mild cognitive impairment. Emerging evidence suggests that rTMS may also partly act by releasing dopamine, indicating that both treatments share a common mechanism of action. Here, we hypothesize that providing methylphenidate prior to rTMS (or "priming") will be an effective treatment for apathy. By increasing dopamine availability, priming is expected to improve the ability of rTMS to stimulate apathy-specific circuits while minimizing possible adverse effects of higher doses of each treatment. Sixty dementia patients with apathy will receive either methylphenidate (20 mg/day for 2 weeks) and active rTMS (10 sessions over two weeks), methylphenidate and sham rTMS, placebo and rTMS, or placebo and sham rTMS. Our primary aim is to determine if apathy is reduced to a greater degree in patients receiving methylphenidate-primed rTMS compared to those receiving other treatment combinations. Stability of treatment benefits will be determined after 12 weeks. We will also explore blood-based biomarkers of treatment response that will enable novel hypothesis-generating analyses.