Effects of Atomoxetine in Mild Cognitive Impairment

The Alzheimer's Disease (AD) epidemic is a looming crisis, with an urgent need for new
therapies to delay or prevent symptom onset and progression. Advances in AD biomarker
research have demonstrated changes in amyloid, brain metabolism, and other pathophysiologies
prior to the onset of memory loss, with some markers possibly changing one or two decades
earlier. Since MCI coincides with the onset of brain atrophy, this early stage of AD
pathogenesis may offer a critical window of time to initiate novel therapies aimed at the
secondary wave of events that lead to progressive neurodegeneration.

From recently emerged basic research in animal models of AD: loss of norepinephrine (NE)
incites a pro-inflammatory condition that is neurotoxic and reduces Aß clearance, and
remarkably, rescue of norepinephrine reverses these effects and slows neurodegeneration. This
study seeks to extend this proof-of-concept to humans for the first time. The study proposes
that atomoxetine, a selective norepinephrine transport inhibitor, is an ideal drug to
translate these findings to humans because it is already FDA-approved and safe in the elderly

Subjects with mild cognitive impairment (amnestic or multi-domain subtypes) will be randomly
assigned to treatment with placebo or flexible doses of the Norepinephrine Transporter (NET)
inhibitor atomoxetine, starting with 10 mg po daily and increasing weekly by increments to a
maximum of 100 mg po daily or the maximum tolerated dose. Participants will be treated for
upto 29 weeks, and will undergo venous blood draws and lumbar puncture for biomarker analyses
at baseline and up to weeks 29. At a maximum of 29 weeks time point, subjects assigned to
active treatment will crossover to placebo and those subjects who were initially randomized
to placebo will initiate active treatment.

Participants who complete study are eligible to receive open-label Atomoxetine at the
maximum-tolerated dose received during the double-blind phase of the trial. Subjects in the
open label are seen every at week 29 upto maximum of 2 years.

Inclusion

- Subjects must have a subjective memory concern as reported by subject, study partner
or clinician.

- Meets Alzheimer's Disease Neuroimaging Initiative (ADNI) criteria for diagnosis of
MCI. Subjects with amnestic (single or multi-domain) will be eligible, as both
subtypes of MCI are at high risk for progression to AD.

- Abnormal memory function documented by assessment using the Logical Memory subscale
(Delayed Paragraph Recall, Paragraph A only) from the Wechsler Memory Scale-Revised
(the maximum score is 25):

- <11 for 16 or more years of education

- <9 for 8-15 years of education

- <6 for <7 years of education

- Mini-Mental State Exam score between 24 and 30 (inclusive). Exceptions may be made for
subjects with less than 8 years of education at the discretion of the PI.

- Clinical Dementia Rating = 0.5. Memory Box score must be at least 0.5.

- General cognition and functional performance sufficiently preserved such that a
diagnosis of AD cannot be made by the physician at the time of the screening visit.

- Cholinesterase inhibitors and memantine are allowable if stable for 12 weeks prior to
screen.

- Stability of Permitted Medications for 4 weeks. In particular, subjects may washout
from excluded medication for at least 4 weeks prior to screening.

- Geriatric Depression Scale (GDS) ≤ than 6.

- Male or female outpatients aged 50-90 (inclusive).

- Study partner has regular contact with the subject adequate to provide a reliable
assessment of the subject's level of function, and can be available for all clinic
visits, either in person or by telephone, for the duration of the study.

- Visual and auditory acuity adequate for neuropsychological testing.

- Good general health with no diseases expected to interfere with the study.

- For women of child-bearing potential (i.e., one who is biologically capable of
becoming pregnant), must be willing to use a medically acceptable form or birth
control or practice abstinence for the duration of her participation in the trial.
Acceptable methods of birth control include: oral or patch contraception, or
medroxyprogesterone (Depo-Provera®) or other intramuscular contraceptive injection, or
implantation of levonorgestrel (Norplant®) system, an Intrauterine Device (IUD), a
reliably-employed barrier method (e.g. diaphragm, cervical cap or condom), or a male
partner who is surgically sterilized.

- Modified Rosen Hachinski ≤ 4.

- Completed six grades of education or has a good work history (sufficient to exclude
mental retardation).

- Able to communicate in English with study personnel.

- Able to understand the nature of the study and must provide written informed consent
prior to conduct of any study procedures.

- Willing to undergo repeated MRIs (3Tesla) and at least three Positron-Emission
Tomography (PET) scans. No medical contraindications to MRI.

- Agrees to blood collection for Apolipoprotein (APOE) epsilon, CYP2D6 and biomarker
testing.

- Agrees to lumbar puncture over the course of the study for the collection of CSF. CSF
levels of Ab42, total Tau, and Tau phosphorylated at threonine 181 consistent with
underlying AD pathology according to established threshold values at Emory and the
ADNI Biomarker Core

Exclusion

- Any significant neurologic disease other than MCI and suspected incipient AD, such as
Parkinson's disease, multi-infarct dementia, Huntington's disease, normal pressure
hydrocephalus, brain tumor, progressive supranuclear palsy, poorly controlled seizure
disorder, subdural hematoma, multiple sclerosis, or history of significant head trauma
followed by persistent neurologic deficits or known structural brain abnormalities.

- Screening/baseline MRI scan with evidence of infection, large vessel infarction or
other focal structural lesions that could account for the memory deficits. Subjects
with multiple lacunes or lacunes in a critical memory structure are excluded.

- Contraindication to MRI due to presence of pacemakers, aneurysm clips, artificial
heart valves, ear implants, metal fragments or foreign objects in the eyes, skin or
body, or excessive weight.

- Presence of clinically significant suicide risk, based on the Investigator's judgment
informed by a structured clinician interview. Any suicide attempt within the past 1
year of the screening visit is exclusionary.

- Major depression, bipolar disorder as described in DSM-IV within the past 1 year, or
history of schizophrenia (DSM-IV). Psychotic features, agitation or behavioral
problems within the last 3 months which could lead to difficulty complying with the
protocol.

- History of alcohol or substance abuse or dependence within the past 2 years (DSM-IV
criteria).

- Allergic to any component of atomoxetine (Strattera).

- Any uncontrolled medical condition that is expected to preclude completion of the
study, or any medical condition which would represent a contraindication to
atomoxetine pharmacotherapy (e.g. hepatic insufficiency, untreated hypertension,
untreated cardiovascular or cerebrovascular disease).

- Known serious structural cardiac abnormalities, cardiomyopathy, serious heart rhythm
abnormalities, or other serious cardiac problems.

- History of narrow angle glaucoma.

- History of pheochromocytoma.

- Clinically significant abnormal findings on screening laboratory tests or physical
exam. Abnormalities in Vitamin B12 level, Thyroid Function Tests (TFTs) or Liver
Function Tests (LFTs) that might interfere with the study. A low Vitamin B12 level is
exclusionary, unless follow-up labs (homocysteine and methylmalonic acid indicate that
it is not physiologically significant.

- Slow metabolizer of atomoxetine (i.e., CYP2D6 polymorphism).

- Women who are pregnant or lactating, or who plan to become pregnant during the study.

- Current use of warfarin (exclusionary for lumbar puncture).

- Inability to obtain initial CSF sample.

- Use within 60 days of a monoamine oxidase inhibitor or a potent CYP2D6 inhibitor.

- Current use of anti-psychotic medication.

- Current use of the following anti-depressant medications that act on NET: duloxetine,
venlafaxine, desvenlafaxine, imipramine, or amitryptiline.

- Current participation in another clinical trial. Participation in clinical studies
involving neuropsychological measures being collected more than one time per year.

- CSF profile is not consistent with underlying Alzheimer's Disease pathology.

- Reasonable likelihood for non-compliance with the protocol or any other reason, in the
opinion of the investigator, prohibits enrollment of subject into the study.

- Exceptions to these guidelines may be considered on a case-by-case basis at the
discretion of the protocol director.