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Aging and disease    2019, Vol. 10 Issue (3) : 510-519     DOI: 10.14336/AD.2018.0606
Orginal Article |
Genetic Interaction of APOE and FGF1 is Associated with Memory Impairment and Hippocampal Atrophy in Alzheimer’s Disease
Ya-Ting Chang1, Hiroaki Kazui2, Manabu Ikeda2, Chi-Wei Huang1, Shu-Hua Huang3, Shih-Wei Hsu4, Wen-Neng Chang1, Chiung-Chih Chang1,*
1Department of Neurology, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan
2Department of Psychiatry, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan
3Department of Nuclear Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan
4Department of Radiology, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan
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Abstract  

The APOE and fibroblast growth factor 1 (FGF1) have both been associated with amyloid β accumulation and neurodegeneration. Investigation the effect of APOE-FGF1 interactions on episodic memory (EM) deficits and hippocampus atrophy (HA) might elucidate the complex clinical-pathological relationship in Alzheimer’s disease (AD). EM performance and hippocampal volume (HV) were characterized in patients with mild AD based on APOE-ε4 carrier status (APOE-ε4 carriers versus non-carriers) and FGF1 single nucleotide polymorphism (FGF1-rs34011-GG versus FGF1-rs34011-A-allele carriers). The clinical-pathological relationships within each genotypic group (ε4+/GG-carrier, ε4+/A-allele-carrier, ε4-/GG-carrier and ε4-/A-allele-carrier) were analyzed. There were no significant differences between the FGF1-rs34011-GG and FGF1-rs34011-A-allele carriers for the level of EM performance or HV (p> 0.05). The bilateral HV was significantly smaller and EM impairment was significantly worse in ε4+/GG-carrier than in ε4-/A-allele-carrier, and an interaction effect of APOE (APOE-ε4 carriers versus non-carriers) with FGF1 (FGF1-rs34011-GG versus FGF1-rs34011-A-allele carriers) predicted EM impairment (F4,92= 3.516, p= 0.018) and structural changes in voxel-based morphometry. Our data shows that concurrent consideration of APOE and FGF1 polymorphisms might be required to understand the clinical-pathological relationship in AD.

Keywords APOE      episodic memory      FGF1      genetic interaction      hippocampus     
Corresponding Authors: Chang Chiung-Chih   
Issue Date: 02 May 2018
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Ya-Ting Chang
Hiroaki Kazui
Manabu Ikeda
Chi-Wei Huang
Shu-Hua Huang
Shih-Wei Hsu
Wen-Neng Chang
Chiung-Chih Chang
Cite this article:   
Ya-Ting Chang,Hiroaki Kazui,Manabu Ikeda, et al. Genetic Interaction of APOE and FGF1 is Associated with Memory Impairment and Hippocampal Atrophy in Alzheimer’s Disease[J]. Aging and disease, 2019, 10(3): 510-519.
URL:  
http://www.aginganddisease.org/EN/10.14336/AD.2018.0606     OR     http://www.aginganddisease.org/EN/Y2019/V10/I3/510
APOE-ε4 carriersAPOE-ε4 non-carriersP valueGG-carriersA-allele-
carriers
P value
Sample size (n)38594849

Age (years)71.2±7.371.7±8.10.76571.1±8.571.9±7.00.597

Sex (% male)47.4%59.3%0.24858.3%51.0%0.469

Education (years)8.0±2.38.7±4.90.5028.6±4.98.2±5.30.701

MMSE21.2±5.722.1±6.10.44921.0±6.622.5±5.10.204

CDR0.6±0.30.5±0.20.2820.58±0.280.53±0.240.319

Episodic memory scores

 CVVLT-30 s4.2±2.85.1±2.60.1334.6±2.74.9±2.70.497
 CVVLT-10 min2.7±3.34.2±3.10.0343.5±3.33.8±3.20.567
 CVVLT-cued3.6±3.24.9±2.60.0334.3±3.04.6±2.90.637

TIV (liter)1.4±0.11.4±0.20.8221.3±0.21.4±0.10.551

TIV adjusted volume *10-3

 Left hippocampus1.0±0.21.2±0.20.0011.1±0.21.2±0.20.356
 Right hippocampus1.1±0.31.3±0.20.0081.2±0.31.3±0.20.106
Table 1  Demographic and clinical data of patients with Alzheimer’s disease grouped based on APOE-ε4 carriers versus non-carriers or FGF1-rs34011-GG (GG-carriers) versus FGF1-rs34011-A-allele carriers (A-allele-carriers).
xyzF-scoreVoxels
Right hippocampus21-18-13.59.71641410
Left hippocampus-31.5-15-1210.16481522
Right inferior temporal gyrus42-1.5-31.59.8974167
Right middle temporal gyrus48-48-1.511.4739203
Table 2  Two-way analysis of variance voxel-based morphometry showing effect of APOE-FGF1 interactions on structural atrophy in grey matter.
All patients with ADε4+/GG-
carriers
ε4+/A-allele-
carriers
ε4-/GG- carriersε4-/A-allele-carriers
TIV adjusted left hippocampal volume
CVVLT-30 s scores0.525*
(<0.001)
0.769*
(0.002)
0.454*
(0.023)
0.598*
(<0.001)
0.230
(0.279)
CVVLT-10 min scores0.595*
(<0.001)
0.812*
(0.001)
0.676*
(<0.001)
0.533*
(0.001)
0.263
(0.215)
CVVLT-cued scores0.526*
(<0.001)
0.518
(0.070)
0.574*
0.003
0.505*
(0.002)
0.143
(0.506)
TIV adjusted right hippocampal volume
CVVLT-30 s scores0.554*
(<0.001)
0.837*
(<0.001)
0.606*
(0.001)
0.493*
(0.003)
0.278
(0.189)
CVVLT-10 min scores0.611*
(<0.001)
0.745*
(0.003)
0.757*
(<0.001)
0.524*
(0.001)
0.229
(0.282)
CVVLT-cued scores0.564*
(<0.001)
0.631*
(0.021)
0.665*
(<0.001)
0.467*
(0.005)
0.202
(0.506)
Table 3  Correlations between memory performance scores and hippocampal volume.
Figure 1.  Episodic memory and hippocampal volume among genotypic groups

Plot displaying (A) scores in episodic memory performance and (B) hippocampal volume in each genotypic group. *P< 0.05 as compared with the ε4+/GG group. CVVLT, Chinese version of the Verbal Learning Test (CVVLT-30 s: words recalled after 30 seconds; CVVLT-10 min: words recalled after 10 minutes; CVVLT-cued: words recalled with cued procedures); ε4+/GG: APOE-ε4 carriers with FGF1-rs34011-GG genotype; ε4+/A-allele: APOE-ε4 carriers with FGF1-rs34011-A-allele genotype; ε4-/GG: APOE-ε4 non-carriers with FGF1-rs34011-GG genotype; ε4-/A-allele: APOE-ε4 non-carriers with FGF1-rs34011-A-allele genotype; TIV, total intracranial volume.

Figure 2.  Genetic interaction effects on episodic memory and regional volume

(A) Effect of APOE-FGF1 (rs34011) interaction on scores in episodic memory performance; (B) Statistical maps of APOE-FGF1 (rs34011) interaction effect on regional atrophy on Montreal Neurological Institute template brain. A-allele-carriers: FGF1-rs34011-A-allele carriers; CVVLT, Chinese version of the Verbal Learning Test (CVVLT-30 s: words recalled after 30 seconds; CVVLT-10 min: words recalled after 10 minutes; CVVLT-cued: words recalled with cued procedures); GG-carriers: FGF1-rs34011-GG carriers.

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