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Front Aging Neurosci. 2017 Apr 10;9:87. doi: 10.3389/fnagi.2017.00087. eCollection 2017.

Genetics of Aggression in Alzheimer's Disease (AD).

Lukiw WJ1,2,3,4, Rogaev EI5,6,7,8.

Author information

1
Louisiana State University (LSU) Neuroscience Center, Louisiana State University Health Science CenterNew Orleans, LA, USA.
2
Department of Ophthalmology, Louisiana State University Health Science CenterNew Orleans, LA, USA.
3
Department of Neurology, Louisiana State University Health Science CenterNew Orleans, LA, USA.
4
Bollinger Professor of Alzheimer's disease (AD), Louisiana State University Health Sciences CenterNew Orleans, LA, USA.
5
Vavilov Institute of General Genetics, Russian Academy of SciencesMoscow, Russia.
6
Center for Brain Neurobiology and Neurogenetics, Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of SciencesNovosibirsk, Russia.
7
Department of Psychiatry, Brudnick Neuropsychiatric Research Institute, University of Massachusetts Medical SchoolWorcester, MA, USA.
8
School of Bioengineering and Bioinformatics, Lomonosov Moscow State UniversityMoscow, Russia.

Abstract

Alzheimer's disease (AD) is a terminal, age-related neurological syndrome exhibiting progressive cognitive and memory decline, however AD patients in addition exhibit ancillary neuropsychiatric symptoms (NPSs) and these include aggression. In this communication we provide recent evidence for the mis-regulation of a small family of genes expressed in the human hippocampus that appear to be significantly involved in expression patterns common to both AD and aggression. DNA array- and mRNA transcriptome-based gene expression analysis and candidate gene association and/or genome-wide association studies (CGAS, GWAS) of aggressive attributes in humans have revealed a surprisingly small subset of six brain genes that are also strongly associated with altered gene expression patterns in AD. These genes encoded on five different chromosomes (chr) include the androgen receptor (AR; chrXq12), brain-derived neurotrophic factor (BDNF; chr11p14.1), catechol-O-methyl transferase (COMT; chr22q11.21), neuronal specific nitric oxide synthase (NOS1; chr12q24.22), dopamine beta-hydroxylase (DBH chr9q34.2) and tryptophan hydroxylase (TPH1, chr11p15.1 and TPH2, chr12q21.1). Interestingly, (i) the expression of three of these six genes (COMT, DBH, NOS1) are highly variable; (ii) three of these six genes (COMT, DBH, TPH1) are involved in DA or serotonin metabolism, biosynthesis and/or neurotransmission; and (iii) five of these six genes (AR, BDNF, COMT, DBH, NOS1) have been implicated in the development, onset and/or propagation of schizophrenia. The magnitude of the expression of genes implicated in aggressive behavior appears to be more pronounced in the later stages of AD when compared to MCI. These recent genetic data further indicate that the extent of cognitive impairment may have some bearing on the degree of aggression which accompanies the AD phenotype.

KEYWORDS:

aggression-Alzheimer’s disease (AD); androgen receptor (AR); brain derived neurotrophic factor (BDNF); catechol-O-methyl transferase (COMT); dopamine beta-hydroxylase (DBH); neuronal specific nitric oxide synthase (NOS1); retrogenesis and schizophrenia; tryptophan hydroxylase (TPH)

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