The purpose of this study is to develop small molecule radio-labeled probes of beta-amyloid, to be used with positron emission tomography (PET) for early detection and treatment monitoring of Alzheimer disease (AD). The study hypothesis is that PET imaging of small molecule probes, in the form of novel fluorescent dyes with radioactive labels, will demonstrate cerebral patterns in patients with AD that are distinct from those of age-matched persons who are cognitively intact.

This is a naturalistic study in which clinical evaluations and brain scans will be performed on 72 people with Down syndrome (DS), 36 non-demented and 36 with dementia, as well as 36 age-matched healthy controls. Participants will receive comprehensive clinical and neuropsychological assessments. PET and MRI scans will be performed at baseline and after two years of follow up. All participants will have blood drawn for APOE genotyping during their baseline evaluations. The intellectual range of participants with DS will be restricted to IQ scores of 45 to 60 (moderate range) to reduce variability, particularly due to extreme low levels of intellectual ability.

Inclusion Criteria:

• Age 45 years or older
• No significant cerebrovascular disease - modified Ischemic Score of < 4
• Adequate visual and auditory acuity to allow neuropsychological testing
• Screening laboratory tests and ECG without significant abnormalities that might interfere with the study

Additional Inclusion Criteria for Controls

• MMSE score between 24 and 30 (unless < 8 years of educational achievement)
• The following medications are allowed if stable for > 1 month: antidepressants (without anticholinergic effects) if not currently depressed and no history of major depression for 2 years; estrogen replacement therapy; thyroid replacement therapy as long as individual is euthyroid; antihypertensives that do not influence cognitive function

Additional Inclusion Criteria for Individuals with Down syndrome

• Family member or caregiver available; caregiver relationship 2 years or longer
• Karyotype DX of trisomy or translocation DS Mosaic form of Down syndrome
• English-speaking

Exclusion Criteria:

• Evidence of neurological or other physical illness that could produce cognitive deterioration; volunteers with a history of TIAs, carotid bruits, or lacunes on MRI scan will be excluded
• Parkinson's Disease
• History of myocardial infarction within the previous year or unstable cardiac disease
• Uncontrolled hypertension (systolic BP > 170 or diastolic BP > 100), history of significant liver disease, clinically significant pulmonary disease, diabetes, or cancer
• Major psychiatric disorders, such as bipolar disorder or schizophrenia
• Medicines that could influence psychometric test results
• Use of any of the following drugs: centrally active beta-blockers, narcotics, clonidine, anti-Parkinsonian medications, benzodiazepines, systemic corticosteroids, medications with significant cholinergic or anticholinergic effects, anti-convulsants, or warfarin
• Current diagnosis or history of alcoholism or drug dependence
• Evidence of untreated depression or untreated anxiety
• Use of any investigational drugs within the previous month or longer, depending on drug half-life
• Contraindication for MRI scan (e.g., metal in body, claustrophobia)
• Diagnosis of possible or probable AD or any other dementia (e.g., vascular, Lewy body, frontotemporal) or MCI

Additional Exclusion Criteria for Individuals with Down syndrome

• Mosaic form of Down syndrome
• History of clinically significant neurological disorder or disease and Psychiatric diagnosis or treatment within 3 months prior to screening

Individuals will be identified and recruited using IRB approved flyers distributed to treating clinicians, caregivers from Board and Care homes, sheltered workshop administrators (where potential participants are employed), and representatives of County Regional Centers (primary evaluation and treatment centers for developmentally delayed individuals).