The overall goal of the proposed research is to investigate whether clinically normal older individuals with evidence of fibrillar amyloid deposition are in the prodromal phases of Alzheimer's disease. We will study 100 clinically normal individuals (CDR 0;MMSE 27-30;performance within <1.5 SD on age and education matched neuropsychological test norms) with PIB PET amyloid imaging to accomplish three specific aims: 1) To investigate the factors associated with high amyloid deposition in normals, including age, cognitive reserve, family history and genetic risk-factors for AD;2) To investigate whether normals with high amyloid burden demonstrate abnormalities on functional and structural imaging measures, consistent with the alterations seen in prodromal AD;and 3) To determine if normals with high amyloid deposition are more likely to demonstrate clinical decline on sensitive measures of episodic memory and progress to a stage of mild cognitive impairment (MCI). Our preliminary data, as well as reports from other groups, suggest that a substantial proportion of clinically normal individuals have evidence of amyloid deposition on PIB PET imaging, in a pattern similar to that observed in clinical AD. Our preliminary data suggest that these normals with high amyloid deposition demonstrate functional and structural alterations in a specific set of brain regions, similar to the pattern of image abnormality commonly reported in MCI and AD. We hypothesize that higher levels of PIB retention will correlate with greater functional abnormality on functional MRI and FDG- PET imaging, as well as greater atrophy in medial temporal lobe and parietal cortices on volumetric MRI. Furthermore, we hypothesize that normals with high amyloid burden will manifest impairment on challenging episodic memory tests, and will demonstrate a higher likelihood of clinical decline towards MCI and ultimately clinical AD. This project will draw heavily on the resources of the MADRC, in particular, the Longitudinal Cohort of the Clinical Core, the Neuroimaging SubCore, and the Data/Statistics Core, as well as interface closely with the investigation of amyloid deposition in Projects 2 and 3.

Public Health Relevance

The long presymptomatic phase of AD provides a critical opportunity for potential intervention with effective therapies. It is essential, however, to develop biological and imaging markers that will track disease progression in the presymptomatic phases and predict onset of clinical symptoms. This project will provide fundamental information on the relationship of amyloid deposition to brain dysfunction and clinical decline.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Specialized Center (P50)
Project #
Application #
Study Section
Special Emphasis Panel (ZAG1-ZIJ-4)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Massachusetts General Hospital
United States
Zip Code
Makaretz, Sara J; Quimby, Megan; Collins, Jessica et al. (2018) Flortaucipir tau PET imaging in semantic variant primary progressive aphasia. J Neurol Neurosurg Psychiatry 89:1024-1031
Gallagher, Damien; Kiss, Alex; Lanctot, Krista et al. (2018) Depression and Risk of Alzheimer Dementia: A Longitudinal Analysis to Determine Predictors of Increased Risk among Older Adults with Depression. Am J Geriatr Psychiatry 26:819-827
Davis, Jeremy J (2018) Performance validity in older adults: Observed versus predicted false positive rates in relation to number of tests administered. J Clin Exp Neuropsychol 40:1013-1021
Haaksma, Miriam L; Calderón-Larrañaga, Amaia; Olde Rikkert, Marcel G M et al. (2018) Cognitive and functional progression in Alzheimer disease: A prediction model of latent classes. Int J Geriatr Psychiatry 33:1057-1064
Wimalaratne, Sarala M; Juty, Nick; Kunze, John et al. (2018) Uniform resolution of compact identifiers for biomedical data. Sci Data 5:180029
Lin, Ming; Gong, Pinghua; Yang, Tao et al. (2018) Big Data Analytical Approaches to the NACC Dataset: Aiding Preclinical Trial Enrichment. Alzheimer Dis Assoc Disord 32:18-27
Ramsey, Christine M; Gnjidic, Danijela; Agogo, George O et al. (2018) Longitudinal patterns of potentially inappropriate medication use following incident dementia diagnosis. Alzheimers Dement (N Y) 4:1-10
Woerman, Amanda L; Kazmi, Sabeen A; Patel, Smita et al. (2018) Familial Parkinson's point mutation abolishes multiple system atrophy prion replication. Proc Natl Acad Sci U S A 115:409-414
Woerman, Amanda L; Kazmi, Sabeen A; Patel, Smita et al. (2018) MSA prions exhibit remarkable stability and resistance to inactivation. Acta Neuropathol 135:49-63
Kirson, Noam Y; Scott Andrews, J; Desai, Urvi et al. (2018) Patient Characteristics and Outcomes Associated with Receiving an Earlier Versus Later Diagnosis of Probable Alzheimer's Disease. J Alzheimers Dis 61:295-307

Showing the most recent 10 out of 966 publications