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Gary W. Small, MD; Prabha Siddarth, PhD; Alison C. Burggren, PhD; Vladimir Kepe, PhD; Linda M. Ercoli, PhD; Karen J. Miller, PhD; Helen Lavretsky, MD; Paul M. Thompson, PhD; Greg M. Cole, PhD; S. C. Huang, PhD; Michael E. Phelps, PhD; Susan Y. Bookheimer, PhD; Jorge R. Barrio, PhD

Arch Gen Psychiatry. 2009;66(1):81-87.

Context  Amyloid senile plaques and tau neurofibrillary tangles are neuropathological hallmarks of Alzheimer disease that accumulate in the brains of people without dementia years before they develop dementia. Positron emission tomography (PET) scans after intravenous injections of 2-(1-{6-[(2-[F-18]fluoroethyl)(methyl)amino]-2-naphthyl}ethylidene)malononitrile (FDDNP), which binds to plaques and tangles in vitro, demonstrate increased cerebral binding in patients with Alzheimer disease compared with cognitively intact controls. Here we investigated whether known risk factors for Alzheimer disease and dementia are associated with FDDNP-PET binding.

Objective  To determine if impaired cognitive status, older age, apolipoprotein E-4 (APOE-4) genetic risk for Alzheimer disease, family history of dementia, and less education are associated with increased regional cerebral FDDNP-PET binding.

Design  Cross-sectional clinical study.

Setting  A university research institute.

Participants  Volunteer sample of 76 middle-aged and older persons without dementia (mean age, 67 years) including 36 with mild cognitive impairment. Of the 72 subjects with genetic data, 34 were APOE-4 carriers.

Main Outcome Measures  The FDDNP-PET signal in brain regions of interest, including medial and lateral temporal, posterior cingulate, parietal, and frontal.

Results  For all regions studied, cognitive status was associated with increased FDDNP binding (P < .02 to .005). Older age was associated with increased lateral temporal FDDNP binding. Carriers of APOE-4 demonstrated higher frontal FDDNP binding than noncarriers. In the mild cognitive impairment group, age was associated with increased medial and lateral temporal FDDNP binding, and APOE-4 carriers had higher medial temporal binding than noncarriers.

Conclusions  Impaired cognitive status, older age, and APOE-4 carrier status are associated with increased brain FDDNP-PET binding in persons without dementia, consistent with previous clinical and postmortem studies associating these risk factors with amyloid plaque and tau tangle accumulation. Stratifying subject groups according to APOE-4 carrier status, age, and cognitive status may therefore be an informative strategy in future clinical trials using FDDNP-PET.

Author Affiliations: Department of Psychiatry and Biobehavioral Sciences and Semel Institute for Neuroscience and Human Behavior (Drs Small, Siddarth, Burggren, Ercoli, Miller, Lavretsky, and Bookheimer), Departments of Molecular and Medical Pharmacology (Drs Kepe, Huang, Phelps, and Barrio) and Neurology (Drs Thompson and Cole), Alzheimer's Disease Center (Drs Small and Cole) and Center on Aging (Dr Small), David Geffen School of Medicine, University of California, Los Angeles.

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