A Pilot Study of Gene/Gene and Gene/Environment Interactions in Alzheimer Disease

Abstract

Al zheimer Disease (AD [MIM 104300]) is a common,complex genetic disorder with a prevalence rate of 5% to 10% and an incidence that increases exponentially after the age of 65 years. A majority of AD cases manifest as sporadic late onset form (LOAD [MIM 606626]), typically with onset above the age of 65 years.Clinical manifestations of the disease are associated with alterations in some or all of the following neurotransmitter networks: the forebrain cholinergic system, noradrenergic system, and telencephalon somatostatinergic system. 1 In addition, the interaction of cholesterol metabolism, inflammatory processes, and APOE has been implicated in contributing to the pathogenesis and/or progression of the disease.Because evidence of genomic variation in association with LOAD is increasingly emerging in both mutational and Background: Although some genes associated with increased risk of Alzheimer Disease (AD) have been identified, few data exist related to gene/gene and gene/environment risk of AD. The purpose of this pilot study was to explore gene/gene and gene/environment associations in AD and to obtain data for sample size estimates for larger, more definitive studies of AD. Methods:The effect of gene/gene and gene/environment interaction related to late onset Alzheimer Disease (LOAD) was investigated in 153 subjects with LOAD and 302 gender matched controls enrolled in the Personalized Medicine Research Project, a population-based bio-repository. Genetic risk factors examined included APOE, ACE, OLR1, and CYP46 genes, and environmental factors included smoking, total cholesterol, LDL, HDL, triglycerides, C-reactive protein, blood pressure, statin use, and body mass index. Results:The mean age of the cases was 78.2 years and the mean age of the controls was 87.2 years. APOE4 was significantly associated with LOAD (OR=3.55, 95%CL=1.70, 7.45). Cases were significantly more likely to have ever smoked cigarettes during their life (49.3% versus 38.4%, p=0.03). The highest recorded blood pressure and pulse pressure measurements were significantly higher in the controls than the cases (all P<0.005). Although not statistically significant in this pilot study, the relationship of the following factors was associated in opposite directions with LOAD based on the presence of an APOE4 allele: obesity at the age of 50, ACE, OLR1, and CYP46. Conclusions:These pilot data suggest that gene/gene and gene/environment interactions may be important in LOAD, with APOE, a known risk factor for LOAD, affecting the relationship of ACE and OLR1 to LOAD. Replication with a larger sample size and in other racial/ethnic groups is warranted and the allele and risk factor frequencies will assist in choosing an appropriate sample size for a definitive study.

Obesity and sex interact in the regulation of Alzheimer's disease

“…For example, mid-life obesity (Ghebranious et al, 2011) and high fat and calorie intake (Luchsinger et al, 2002), are associated with greater risk for AD only in apoE4 subjects. Men with both type 2 diabetes and the apoE4 allele have a 5.5 times greater risk of AD, as well as greater AD neuropathology than men with neither risk factor (Peila et al, 2002).…”

HDL-cholesterol and apolipoproteins in relation to dementia

“…The full texts of the remaining 40 publications were assessed for eligibility. A total of 28 studies were included in the qualitative synthesis of which 12 had a prospective study design [14, 16, 18, 19**, 20, 21, 22, 23, 24, 25**, 26, 27] and 16 had a cross-sectional design [28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43]. By hand search of reference lists and recent updates of included studies one additional publication was identified [44].…”

“…Six cross-sectional studies were identified that addressed the association of HDL-C in relation to dementia [28, 29, 30, 32, 33, 39], providing conflicting results (Table 2). Comparing 150 participants with AD to 197 control individuals from the Texas Alzheimer’s Disease Research and Care Consortium, Warren et al found lower HDL-C levels in participants with AD [39].…”

“…Another study of relatively small sample size including 29 participants with AD and 19 control subjects found no difference in HDL-C levels [28]. Similarly, investigations in subsamples of the Personalized Medicine Research Project sample including 455 participants [32] and the Australian Imaging, Biomarkers and Lifestyle (AIBL) study including 564 participants [33] revealed no difference in HDL-C concentrations comparing participants with AD to controls [32, 33]. …”

Characterizing Gene and Protein Crosstalks in Subjects at Risk of Developing Alzheimer’s Disease: A New Computational Approach

“…Similarly, the enrichment of metabolic pathways, organismal systems including nervous and immune system pathways, and common signaling pathways of the environmental information processing category is also expected and well-supported in the literature [54][55][56][57][58][59][60][61][62][63][64][65][66][67][68]. Interestingly, several genetic information processing pathways, including cell cycle regulation and DNA replication and repair, were found to be enriched.…”