Implications of Amyloid Pathology

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