The purpose of this study is to determine whether asymptomatic older individuals with high amyloid burden will subsequently manifest cognitive impairment and eventually progress to clinical Alzheimer's Disease (AD).

There is compelling evidence supporting amyloid as one of the key pathologic agents in AD. Autopsy studies suggest the amount and location of fibrillar amyloid deposition does not relate strongly to the degree and type of clinical impairment, compared to tau pathology and neuronal loss. A substantial percentage of individuals known to be cognitively intact prior to death demonstrate significant amyloid pathology at autopsy. PIB-PET studies of older normal individuals have also demonstrated significant amyloid deposition in substantial percentages.

This study will test the hypothesis that amyloid is associated with synaptic dysfunction and neuronal damage. While some individuals are able to compensate for amyloid-related toxicity for an extended time period, sensitive imaging and neuropsychological markers will reveal that normal subjects with evidence of high amyloid burden do demonstrate evidence of abnormality consistent with prodromal AD.

The study will use a combination of functional, structural, and cognitive measures to detect early effects of amyloid deposition, and will utilize PIB retention in order to characterize the relationship of amyloid to neuropsychological and imaging markers of prodromal AD. The relationship of PIB retention to genetic, plasma and cerebrospinal fluid (CSF) biomarkers will be explored. These preliminary data will be used to determine whether asymptomatic older individuals with high amyloid burden will subsequently manifest cognitive impairment and eventually progress to clinical AD. When completed, this project will either provide evidence that the presence of amyloid deposition is a useful biomarker for incipient AD or raise the possibility that amyloid deposition examined in isolation is insufficient to predict early symptoms and progression of AD.

Inclusion Criteria:

• Age range from 60 to 90 years
• Clinical Dementia Rating (CDR) Score of 0
• Mini Mental State Exam of 27-30
• A study partner who can answer questions pertaining to daily functioning
• Perform within 1.5 standard deviation of age and education matched norms on screening tests of attention and executive function, language, visuospatial perception and episodic memory
• Stable medications for at least 30 days
• Fluent in English
• Modified Hachinski Score of <4
• Geriatric Depression Scale Score <10

Exclusion Criteria:

• Diagnosis of MCI or dementia
• Individuals with contraindications to MRI (i.e., implanted metal including pacemakers, cerebral spinal fluid shunts, aneurysm clips, artificial heart valves, ear implants or metal/foreign objects in the eyes and those with a history of claustrophobia)
• Unstable medications or on medications with CNS effects including cholinesterase inhibitors, memantine, and antidepressants
• Major psychiatric disorders such as schizophrenia, schizoaffective disorder, major affective disorder, or treatment with ECT (mild depression that is well treated with stable dose of SSRI antidepressants will be allowed)
• Multiple sclerosis or other autoimmune disorders
• Huntington's disease
• Head injury, post-traumatic dementia or seizures
• Metabolic encephalopathy, CNS infection, hydrocephalus
• Cardiovascular disease, stroke, congestive heart failure
• Substance abuse within the past 2 years
• Active cancer
• Active hematological, renal, pulmonary, endocrine or hepatic disorders

Longitudinal cohort of the Massachusetts Alzheimer's Disease Research Center and community volunteers