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Alzheimers Dement. 2017 Dec;13(12):1380-1388. doi: 10.1016/j.jalz.2017.05.002. Epub 2017 Jun 15.

Neuropathologic features of TOMM40 '523 variant on late-life cognitive decline.

Author information

1
Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA; Department of Neurological Sciences, Rush University Medical Center, Chicago, IL, USA. Electronic address: lei_yu@rush.edu.
2
Department of Neurology, Duke University School of Medicine, Durham, NC, USA.
3
Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA; Discipline of Geriatrics, Faculty of Medicine of the University of Sao Paulo, Brazil.
4
Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA; Department of Neurological Sciences, Rush University Medical Center, Chicago, IL, USA; Department of Behavioral Sciences, Rush University Medical Center, Chicago, IL, USA.
5
Zinfandel Pharmaceuticals, Inc., Research Triangle Park, NC, USA.
6
Center for Translational and Computational Neuroimmunology, Department of Neurology, Columbia University Medical Center, New York, NY, USA; Program in Medical and Population Genetics, Broad Institute, Cambridge, MA, USA.
7
Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA; Department of Neurological Sciences, Rush University Medical Center, Chicago, IL, USA.

Abstract

INTRODUCTION:

The study investigated the role of neuropathologies in the relationship between TOMM40 '523 genotype and late-life cognitive decline.

METHODS:

Participants were community-dwelling older persons who had annual cognitive assessments and brain autopsies after death. Genotyping used DNA from peripheral blood or postmortem brain tissue. Linear mixed models assessed the extent to which the association of '523 genotype with cognitive decline is attributable to neuropathologies.

RESULTS:

Relative to ε3/ε3 homozygotes with '523-S/VL or '523-VL/VL genotype, both '523-L carriers and ε3/ε3 homozygotes with '523-S/S genotype had faster cognitive decline. The association of '523-L with cognitive decline was attenuated and no longer significant after controlling for Alzheimer's and other neuropathologies. By contrast, the association of '523-S/S was unchanged.

DISCUSSION:

There are two distinct TOMM40 '523 signals in relation to late-life cognitive decline. One signal primarily acts through AD and other common neuropathologies, whereas the other operates through a different mechanism.

KEYWORDS:

APOE; Alzheimer's disease; Late-life cognitive decline; Neuropathologies; TOMM40 '523

PMID:
28624335
PMCID:
PMC5723540
DOI:
10.1016/j.jalz.2017.05.002
[Indexed for MEDLINE]
Free PMC Article

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