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Brain Imaging and Behavior

, Volume 11, Issue 2, pp 401–409 | Cite as

Genetic resilience to amyloid related cognitive decline

  • Timothy J. Hohman
  • Logan Dumitrescu
  • Nancy J. Cox
  • Angela L. Jefferson
  • for the Alzheimer’s Neuroimaging Initiative
SI: Resilience/Reserve in AD

Abstract

Preclinical Alzheimer’s disease (AD) is characterized by amyloid deposition in the absence of overt clinical impairment. There is substantial heterogeneity in the long-term clinical outcomes among amyloid positive individuals, yet limited work has focused on identifying molecular factors driving resilience from amyloid-related cognitive impairment. We apply a recently developed predicted gene expression analysis (PrediXcan) to identify genes that modify the association between baseline amyloid deposition and longitudinal cognitive changes. Participants free of clinical AD (n = 631) were selected from the AD Neuroimaging Initiative (ADNI) who had a baseline positron emission tomography measure of amyloid deposition (quantified as a standard uptake value ratio), longitudinal neuropsychological data, and genetic data. PrediXcan was used to impute gene expression levels across 15 heart and brain tissues. Mixed effect regression models assessed the interaction between predicted gene expression levels and amyloid deposition on longitudinal cognitive outcomes. The predicted gene expression levels for two genes in the coronary artery (CNTLN, PROK1) and two genes in the atrial appendage (PRSS50, PROK1) interacted with amyloid deposition on episodic memory performance. The predicted gene expression levels for two additional genes (TMC4 in the basal ganglia and HMBS in the aorta) interacted with amyloid deposition on executive function performance. Post-hoc analyses provide additional validation of the HMBS and PROK1 effects across two independent subsets of ADNI using two additional metrics of amyloid deposition. These results highlight a subset of unique candidate genes of resilience and provide evidence that cell-cycle regulation, angiogenesis, and heme biosynthesis likely play a role in AD progression.

Keywords

Amyloid Resilience Genetics PrediXcan Cognition PET 

Notes

Compliance with ethical standards

This research was supported in part by the Building Interdisciplinary Research Careers in Women’s Health program (K12-HD043483, TJH), K01-AG049164 (TJH), R01-HL111516 (ALJ), R01-AG034962 (ALJ), K24-AG046373 (ALJ), and the Vanderbilt Memory & Alzheimer’s Center.

Conflict of interest

The authors report no conflicts of interest.

Informed consent

Informed consent was obtained from all participants included in the study.

Supplementary material

11682_2016_9615_MOESM1_ESM.docx (34 kb)
ESM 1 (DOCX 34 kb)
11682_2016_9615_MOESM2_ESM.xlsx (2.1 mb)
ESM 2 (XLSX 2194 kb)

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Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • Timothy J. Hohman
    • 1
  • Logan Dumitrescu
    • 1
  • Nancy J. Cox
    • 2
  • Angela L. Jefferson
    • 1
  • for the Alzheimer’s Neuroimaging Initiative
  1. 1.Vanderbilt Memory & Alzheimer’s CenterVanderbilt University Medical CenterNashvilleUSA
  2. 2.Vanderbilt Genetics Institute, Division of Genetic MedicineVanderbilt University Medical CenterNashvilleUSA

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