Abstract
Alzheimer’s disease (AD) progresses insidiously over decades. Therefore, study of preclinical AD is critical to identify early pathophysiological changes as potential targets for prevention or treatment. The brain processes at the preclinical stage remain minimally understood. Aside from age, the E4 allele of APOE flags a group at particularly high risk of late-onset AD (LOAD). Studies of these individuals could provide insights about the ontogenesis of AD offering clues for novel treatment strategies. To this end, cognitively normal, APOE*E4 homozygotes from the Alzheimer’s Diseases Neuroimaging Research Initiative database (ADNI-LONI) provided fluorodeoxyglucose and amyloid (florbetapir) PET scans (n = 8 and 7, respectively; mean age 76 years). Their scans were compared to those of matched cognitively normal elders who were not E4 carriers. There was dissociation in the distribution between glucose uptake and amyloid deposition in the homozygotes. Peak hypometabolism localized bilaterally along the medial temporal cortex. In contrast, peak amyloid deposition localized principally to the putamen, a finding also seen in preclinical carriers of autosomal dominant AD mutations and preclinical AD associated with Down syndrome. Additional regions of amyloid deposition in homozygotes were medial prefrontal cortices including the anterior cingulate, middle and inferior frontal cortices, and middle and inferior occipital cortices. These findings contrast with those reported for LOAD. These data begin to characterize elders with normal cognition despite high AD risk in comparison to the known phenotypes of patients with LOAD.
- Aging
- Alzheimer’s Disease Neuroimaging Initiative
- amyloid
- APOE*E4
- brain metabolism
- positron emission tomography
Footnotes
The authors declare no competing financial interests.
↵* Data collection and sharing for this project was funded by the Alzheimer’s Disease Neuroimaging Initiative (ADNI; National Institutes of Health Grant U01 AG024904) and DOD ADNI (Department of Defense award number W81XWH-12-2-0012). ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: AbbVie, Alzheimer’s Association; Alzheimer’s Drug Discovery Foundation; Araclon Biotech; BioClinica, Inc.; Biogen; Bristol-Myers Squibb Company; CereSpir, Inc.; Cogstate; Eisai Inc.; Elan Pharmaceuticals, Inc.; Eli Lilly and Company; EuroImmun; F. Hoffmann-La Roche Ltd and its affiliated company Genentech, Inc.; Fujirebio; GE Healthcare; IXICO Ltd.; Janssen Alzheimer Immunotherapy Research & Development, LLC.; Johnson & Johnson Pharmaceutical Research & Development LLC.; Lumosity; Lundbeck; Merck & Co., Inc.; Meso Scale Diagnostics, LLC.; NeuroRx Research; Neurotrack Technologies; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Piramal Imaging; Servier; Takeda Pharmaceutical Company; and Transition Therapeutics. The Canadian Institutes of Health Research is providing funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health (www.fnih.org). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer’s Therapeutic Research Institute at the University of Southern California. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of Southern California.This work was funded by VA 5I01CX000501 (JVP). This material is the result of work supported with resources and the use of facilities at the Minneapolis Veterans Health Care System, Minneapolis, MN. The contents do not represent the views of the U.S. Department of Veterans Affairs or the United States Government.
Data used in preparation of this article were obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database (adni.loni.usc.edu). As such, the investigators within the ADNI contributed to the design and implementation of ADNI and/or provided data but did not participate in analysis or writing of this report. A complete listing of ADNI investigators can be found at http://adni.loni.usc.edu/wp-content/uploads/how_to_apply/ADNI_Acknowledgement_List.pdf.
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