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. 2014 Oct 28;83(18):1613-9.
doi: 10.1212/WNL.0000000000000939. Epub 2014 Sep 26.

Unrecognized preclinical Alzheimer disease confounds rs-fcMRI studies of normal aging

Matthew R Brier  1 , Jewell B Thomas  2 , Abraham Z Snyder  2 , Liang Wang  2 , Anne M Fagan  2 , Tammie Benzinger  2 , John C Morris  2 , Beau M Ances  2
Affiliations

Unrecognized preclinical Alzheimer disease confounds rs-fcMRI studies of normal aging

Matthew R Brier et al. Neurology. .

Abstract

Objective: To determine whether, and to what degree, preclinical Alzheimer disease (AD) confounds studies of healthy aging where "healthy" is based on cognitive normality alone.

Methods: We examined the effects of preclinical AD in cognitively normal older individuals using resting-state functional connectivity MRI. We investigated 2 groups of cognitively normal participants: one group with evidence of preclinical AD as assessed by CSF markers of AD and the other group with normal CSF biomarkers.

Results: There were significant interactions between age and biomarker status in the default-mode, dorsal attention, and salience resting-state networks. In the group with evidence of preclinical AD, there were dramatic changes in functional connectivity with age. In the group without evidence of preclinical AD, those changes were greatly attenuated. In most regions with significant interactions of age and biomarker status, the age-related change in functional connectivity in the normal biomarker group was indistinguishable from zero.

Conclusions: These results suggest that preclinical AD accounts for a substantial portion of the reported effects of aging in the extant functional connectivity literature.

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Conflict of interest statement

M. Brier, J. Thomas, A. Snyder, and L. Wang report no disclosures relevant to the manuscript. A. Fagan consults for Roche and Lilly USA. T. Benzinger has a research grant from Avid Radiopharmaceuticals (a wholly owned subsidiary of Eli Lilly), and has received other support from the National Multiple Sclerosis Society (travel for grant review). J. Morris has participated in drug trials with Janssen Immunotherapy, Pfizer, and Eli Lilly, and has received honoraria from the Charles A. Dana Foundation, Eli Lilly, and Eisai. B. Ances reports no disclosures relevant to the manuscript. Go to Neurology.org for full disclosures.

Figures

Figure 1
Figure 1. Preclinical AD accounts for a large fraction of observed effects of age
Maps of βage in the DMN (PCC seed) and SAL (dACC seed). βage for each group (CDR0− and CDR0+) extracted from equation 1. Only voxels belonging to clusters exhibiting a significant interaction of age and presence of pathology are shown. For each cluster, the CDR0− group shows βage values near 0 (green) indicating change with age and the CDR0+ group shows large magnitude changes with age (dark blue and dark red). (A) Changes associated with a PCC seed. (B) Changes associated with a dACC seed. AD = Alzheimer disease; CDR = Clinical Dementia Rating; dACC = dorsal anterior cingulate cortex; DMN = default mode network; PCC = posterior cingulate cortex; SAL = salience network.
Figure 2
Figure 2. The slope of the aging effect is reduced in the CDR0− group
Scatterplots for each participant separated according to group (CDR0− vs CDR0+). (A) Values averaged across voxels in significant clusters scattered against age of each participant. For each ROI pair (PCC as seed), the slope in the CDR0+ (red) group is significantly steeper than the slope in the CDR0− (black) group as determined by a significant interaction of age × biomarker status (table 2). (B) Similar to panel A, but showing effects between the dACC and the significant clusters identified therein. As with the PCC, in each ROI pair, the slope of the CDR0+ regression is steeper than the CDR0− regression (table 2). CDR = Clinical Dementia Rating; Crblm = cerebellum; dACC = dorsal anterior cingulate cortex; iOcc = inferior occipital; lFr = left frontal; lTmp = left temporal; mPFC = medial prefrontal cortex; PCC = posterior cingulate cortex; rHC = right hippocampus; rLP = right lateral parietal; ROI = region of interest; rTmp = right temporal; sPar = superior parietal; Thal = thalamus.
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