Inclusion criteria:
In order to be eligible for participation in this trial, the subject must:
1. Be = 50 and = 85 years of age at the Screening Visit.
Meet the following criteria (2-5) for a diagnosis of prodromal AD
2. Each subject must report a history of subjective memory decline with gradual onset and slow progression for at least one year before Screening, that is either corroborated by an informant who knows the subject well or is documented in medical records.
3. Each subject must have objective impairment in episodic memory at Screening that is = 1.0 SD below the appropriate population mean as measured by the RBANS (Repeatable Battery for the Assessment of Neuropsychological Status). To meet this criterion, an RBANS delayed memory index score of =85 is required for entry. (Note: the proportion of subjects with RBANS delayed memory index scores ranging from 79 to 85 (approximately 1.5 to 1.0 SD below the appropriate population mean), inclusive, will not exceed 10-30% of the total number randomized).
4. Each subject must have general cognitive function and activities of daily living sufficiently intact, based on clinical assessment, so as not to meet criteria for mild AD dementia (based on DSM-IV-TR and NINCDS-ADRDA criteria).
5. Each subject must have a positive amyloid imaging PET scan using [18F]flutemetamol at Screening* or positive CSF tau:Aß42 ratio at Screening (see Trial Manuals for details). PET is the primary inclusion tool for the trial. Subjects who fail to meet inclusion criteria based on PET but qualify based on CSF will be enrolled in a separate CSF subgroup of the trial. (Refer to Protocol Section 7.1.3.4 for direction regarding initiation of CSF collection in the trial.)
*Subjects with a prior positive amyloid imaging PET scan or a Screening PET scan with florbetaben or florbetapir may be enrolled without a Screening flutemetamol scan with Sponsor approval (see Section 7.1.2.5.7).
6. Have an MMSE score = 24 at Screening.
7. Be able to read at a 6th grade level or equivalent, as determined by the investigator, and must have a history of academic achievement and/or employment sufficient to exclude mental retardation.
8. If receiving an acetylcholinesterase inhibitor, memantine, medical food/supplement (e.g., vitamin E), and/or herbal medications for AD, be on a stable dose for at least the three months before Screening, and the subject must be willing to remain on the same dose for the duration of the trial. The treatment and dose that the subject is receiving at Screening must not be changed during the trial unless medically necessary to ensure subject safety. Additional treatments [including herbal medications] for AD that are not specified in the protocol must not be initiated during the trial. The subject and trial partner must agree that they do not plan to discontinue treatment or initiate additional AD treatments during the trial unless medically necessary. (See Section 5.5.2 for additional details regarding use of other AD therapy.)
9. Have a reliable and competent trial partner/informant who must have a close relationship with the subject, have face to face contact at least three days a week for a minimum of six waking hours a week (or more in accordance with local requirements), be willing to accompany the subject to all req
Exclusion criteria:
1. Has a Rosen-modified Hachinski Ischemia Score > 4 at Screening (i.e., evidence of vascular dementia).
2. Has a known history of stroke or evidence from screening imaging scan (e.g., MRI or CT) that is clinically important in the investigator's opinion.
3. Meets the criteria for a diagnosis of AD dementia, including probable or possible AD, based on DSM-IV-TR or NINCDS-ADRDA [21] criteria at Screening or Baseline.
4. Has evidence of a clinically relevant neurological disorder other than the disease being studied (i.e., prodromal AD) at Screening, including but not limited to: vascular dementia, parkinsonism, frontotemporal dementia, Huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis, progressive supranuclear palsy, neurosyphilis, dementia with Lewy bodies, other types of dementia, mental retardation, hypoxic cerebral damage, cognitive impairment due to other disorders, or head trauma with loss of consciousness that led to persistent cognitive deficits.
5. Has a history of seizures or epilepsy within the last five years before Screening.
6. Has evidence of a clinically relevant or unstable psychiatric disorder, based on DSM-IV-TR criteria, including schizophrenia or other psychotic disorder, bipolar disorder, major depression, or delirium. Major depression in remiss ion is not exclusionary.
7. Has evidence of a current episode of major depression based on investigator's judgment. A score on the 15-item Geriatric Depression Scale (GDS) of 5 or more requires an assessment by an appropriate health care professional to evaluate for the presence of major depression. Subjects with a score of 5 or more who are not diagnosed with major depression following such an assessment may be included in the trial.
8. Is at imminent risk of self-harm, based on clinical interview and responses on the Columbia Suicide Severity Rating Scale (C-SSRS), or of harm to others in the opinion of the investigator. Subjects must be excluded if they report suicidal ideation with intent, with or without a plan or method (e.g., positive response to items 4 or 5 in assessment of suicidal ideation on the C-SSRS) in the past two months or suicidal behavior in the past six months.
9. Has a history of alcoholism or drug dependency/abuse within the last five years before Screening.
10. Does not have an MRI scan obtained within 12 months before Screening available for central review and is unwilling or not eligible to undergo an MRI scan (e.g., metal implants, obesity) at the Screening Visit (see MRI Procedure Manual and Imaging Charter for details). Exception: A head CT scan obtained at Screening or within 12 months before Screening may be accepted for evaluation of the eligibility criteria on a case-by-case basis, as approved by the Sponsor (e.g., when MRI is contraindicated for the subject). The head CT must be suitable for central review.
Note: Once 20% of subjects have been randomized based on historical MRI or CT scans, no further historical MRIs or CT scans will be accepted.
11. Has an MRI scan obtained at Screening that shows evidence of a neurological disorder other than prodromal AD or:
- evidence of a prior macrohemorrhage,
- symptomatic vasogenic edema in the investigator´s judgment,
- > 3 lac
