Hypometabolism detected by fluorodeoxyglucose F18 positron emission tomography ([18F] FDG PET) is an early neuropathologic changes in Alzheimer’s disease (AD) and provides important pathologic staging information.
Objective:
This study aimed to discover genetic interactions that regulate longitudinal glucose metabolic decline in AD-related brain regions.
Methods:
A total of 586 non-Hispanic white individuals from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) 1/GO/2 cohorts that met all quality control criteria were included in this study. Genome-wide association study of glucose metabolic decline in regions of interest (ROIs) was performed with linear regression under the additive genetic model.
Results:
We identified two novel variants that had a strong association with longitudinal metabolic decline in different ROI. Rs4819351-A in gene 1-acylglycerol-3-phosphate O-acyltransferase 3 (AGPAT3) demonstrated reduced metabolic decline in right temporal gyrus (p = 3.97×10–8, β= –0.016), while rs13387360-T in gene LOC101928196 demonstrated reduced metabolic decline in left angular gyrus (p = 1.69×10–8, β= –0.027).
Conclusion:
Our results suggest two genome-wide significant SNPs (rs4819351, rs13387360) in AGPAT3 and LOC101928196 as protective loci that modulate glucose metabolic decline. These two genes should be further investigated as potential therapeutic target for neurodegeneration diseases.
JagustW, ReedB, MungasD, EllisW, DecarliC (2007) What does fluorodeoxyglucose PET imaging add to a clinical diagnosis of dementia?Neurology69, 871–877.
2.
GallivanoneF, Della RosaPA, CastiglioniI (2016) Statistical voxel-based methods and [18F]FDG PET brain imaging: Frontiers for the diagnosis of AD. Curr Alzheimer Res13, 682–694.
3.
de LeonMJ, ConvitA, WolfOT, TarshishCY, DeSantiS, RusinekH, TsuiW, KandilE, SchererAJ, RocheA, ImossiA, ThornE, BobinskiM, CaraosC, LesbreP, SchlyerD, PoirierJ, ReisbergB, FowlerJ (2001) Prediction of cognitive decline in normal elderly subjects with 2-[(18)F]fluoro-2-deoxy-D-glucose/poitron-emission tomography (FDG/PET). Proc Natl Acad Sci U S A98, 10966–10971.
4.
HerholzK, WestwoodS, HaenseC, DunnG (2011) Evaluation of a calibrated (18)F-FDG PET score as a biomarker for progression in Alzheimer disease and mild cognitive impairment. J Nucl Med52, 1218–1226.
5.
SmailagicN, LafortuneL, KellyS, HydeC, BrayneC (2018) 18F-FDG PET for prediction of conversion to Alzheimer’s disease dementia in people with mild cognitive impairment: An updated systematic review of test accuracy. J Alzheimers Dis64, 1175–1194.
6.
NiccoliT, CabecinhaM, TillmannA, KerrF, WongCT, CardenesD, VincentAJ, BettediL, LiL, GronkeS, DolsJ, PartridgeL (2016) Increased glucose transport into neurons rescues Abeta toxicity in Drosophila. Curr Biol26, 2550.
7.
PotkinSG, GuffantiG, LakatosA, TurnerJA, KruggelF, FallonJH, SaykinAJ, OrroA, LupoliS, SalviE, WeinerM, MacciardiF, Alzheimer’s Disease Neuroimaging Initiative (2009) Hippocampal atrophy as a quantitative trait in a genome-wide association study identifying novel susceptibility genes for Alzheimer’s disease. PLoS One4, e6501.
8.
RamananVK, RisacherSL, NhoK, KimS, ShenL, McDonaldBC, YoderKK, HutchinsGD, WestJD, TallmanEF, GaoS, ForoudTM, FarlowMR, De JagerPL, BennettDA, AisenPS, PetersenRC, JackCRJr., TogaAW, GreenRC, JagustWJ, WeinerMW, SaykinAJ, Alzheimer’s Disease Neuroimaging Initiative (2015) GWAS of longitudinal amyloid accumulation on 18F-florbetapir PET in Alzheimer’s disease implicates microglial activation gene IL1RAP. Brain138, 3076–3088.
FranssonP, MarrelecG (2008) The precuneus/posterior cingulate cortex plays a pivotal role in the default mode network: Evidence from a partial correlation network analysis. Neuroimage42, 1178–1184.
11.
LeechR, SharpDJ (2014) The role of the posterior cingulate cortex in cognition and disease. Brain137, 12–32.
12.
ChristopherL, NapolioniV, KhanRR, HanSS, GreiciusMD, Alzheimer’s Disease Neuroimaging Initiative (2017) A variant in PPP4R3A protects against alzheimer-related metabolic decline. Ann Neurol82, 900–911.
13.
MosconiL, TsuiWH, HerholzK, PupiA, DrzezgaA, LucignaniG, ReimanEM, HolthoffV, KalbeE, SorbiS, Diehl-SchmidJ, PerneczkyR, ClericiF, CaselliR, Beuthien-BaumannB, KurzA, MinoshimaS, de LeonMJ (2008) Multicenter standardized 18F-FDG PET diagnosis of mild cognitive impairment, Alzheimer’s disease, and other dementias. J Nucl Med49, 390–398.
14.
RodriguesF, SilveiraM (2014) Longitudinal FDG-PET features for the classification of Alzheimer’s disease. Conf Proc IEEE Eng Med Biol Soc2014, 1941–1944.
LandauSM, HarveyD, MadisonCM, KoeppeRA, ReimanEM, FosterNL, WeinerMW, JagustWJ, Alzheimer’s Disease Neuroimaging Initiative (2011) Associations between cognitive, functional, and FDG-PET measures of decline in AD and MCI. Neurobiol Aging32, 1207–1218.
18.
RischN, MerikangasK (1996) The future of genetic studies of complex human diseases. Science273, 1516–1517.
19.
BittnerT, ZetterbergH, TeunissenCE, OstlundREJr., MilitelloM, AndreassonU, HubeekI, GibsonD, ChuDC, EichenlaubU, HeissP, KoboldU, LeinenbachA, MadinK, ManuilovaE, RabeC, BlennowK (2016) Technical performance of a novel, fully automated electrochemiluminescence immunoassay for the quantitation of beta-amyloid (1-42) in human cerebrospinal fluid. Alzheimers Dement12, 517–526.
20.
JackCRJr., KnopmanDS, JagustWJ, PetersenRC, WeinerMW, AisenPS, ShawLM, VemuriP, WisteHJ, WeigandSD, LesnickTG, PankratzVS, DonohueMC, TrojanowskiJQ (2013) Tracking pathophysiological processes in Alzheimer’s disease: An updated hypothetical model of dynamic biomarkers. Lancet Neurol12, 207–216.
21.
HsiehTC, LinWY, DingHJ, SunSS, WuYC, YenKY, KaoCH (2012) Sex- and age-related differences in brain FDG metabolism of healthy adults: An SPM analysis. J Neuroimaging22, 21–27.
22.
SacherJ, Okon-SingerH, VillringerA (2013) Evidence from neuroimaging for the role of the menstrual cycle in the interplay of emotion and cognition. Front Hum Neurosci7, 374.
23.
ColemanRA, LeeDP (2004) Enzymes of triacylglycerol synthesis and their regulation. Prog Lipid Res43, 134–176.
24.
VanceJE (2015) Phospholipid synthesis and transport in mammalian cells. Traffic16, 1–18.
25.
SalvadorGA, Ilincheta de BoscheroMG, PasquareSJ, GiustoNM (2005) Phosphatidic acid and diacylglycerol generation is regulated by insulin in cerebral cortex synaptosomes from adult and aged rats. J Neurosci Res81, 244–252.
26.
ZhangC, HwarngG, CooperDE, GrevengoedTJ, EatonJM, NatarajanV, HarrisTE, ColemanRA (2015) Inhibited insulin signaling in mouse hepatocytes is associated with increased phosphatidic acid but not diacylglycerol. J Biol Chem290, 3519–3528.
27.
BoscoD, FavaA, PlastinoM, MontalciniT, PujiaA (2011) Possible implications of insulin resistance and glucose metabolism in Alzheimer’s disease pathogenesis. J Cell Mol Med15, 1807–1821.
28.
de la MonteSM (2012) Brain insulin resistance and deficiency as therapeutic targets in Alzheimer’s disease. Curr Alzheimer Res9, 35–66.
LuB, JiangYJ, ZhouY, XuFY, HatchGM, ChoyPC (2005) Cloning and characterization of murine 1-acyl-sn-glycerol 3-phosphate acyltransferases and their regulation by PPARalpha in murine heart. Biochem J385, 469–477.
