Whether brain-derived neurotrophic factor (BDNF) Met carriage impacts the risk or progression of Alzheimer’s disease (AD) is unknown.
Objective:
To evaluate the interaction of BDNF Met and APOE4 carriage on cerebral metabolic rate for glucose (CMRgl), amyloid burden, hippocampus volume, and cognitive decline among cognitively unimpaired (CU) adults enrolled in the Arizona APOE cohort study.
Methods:
114 CU adults (mean age 56.85 years, 38% male) with longitudinal FDG PET, magnetic resonance imaging, and cognitive measures were BDNF and APOE genotyped. A subgroup of 58 individuals also had Pittsburgh B (PiB) PET imaging. We examined baseline CMRgl, PiB PET amyloid burden, CMRgl, and hippocampus volume change over time, and rate of change in cognition over an average of 15 years.
Results:
Among APOE4 carriers, BDNF Met carriers had significantly increased amyloid deposition and accelerated CMRgl decline in regions typically affected by AD, but without accompanying acceleration of cognitive decline or hippocampal volume changes and with higher baseline frontal CMRgl and slower frontal decline relative to the Val/Val group. The BDNF effects were not found among APOE4 non-carriers.
Conclusion:
Our preliminary studies suggest that there is a weak interaction between BDNF Met and APOE4 on amyloid-β plaque burden and longitudinal PET measurements of AD-related CMRgl decline in cognitively unimpaired late-middle-aged and older adults, but with no apparent effect upon rate of cognitive decline. We suggest that cognitive effects of BDNF variants may be mitigated by compensatory increases in frontal brain activity—findings that would need to be confirmed in larger studies.
MorrisJC, RoeCM, XiongC, FaganAM, GoateAM, HoltzmanDM, MintunMA (2010) APOE predicts amyloid-beta but not tau Alzheimer pathology in cognitively normal aging. Ann Neurol67, 122–131.
2.
ReimanEM, ChenK, LiuX, BandyD, YuM, LeeW, AyutyanontN, KepplerJ, ReederSA, LangbaumJB, AlexanderGE, KlunkWE, MathisCA, PriceJC, AizensteinHJ, DeKoskyST, CaselliRJ (2009) Fibrillar amyloid-beta burden in cognitively normal people at 3 levels of genetic risk for Alzheimer’s disease. Proc Natl Acad Sci U S A106, 6820–6825.
3.
KokE, HaikonenS, LuotoT, HuhtalaH, GoebelerS, HaapasaloH, KarhunenPJ (2009) Apolipoprotein E-dependent accumulation of Alzheimer disease-related lesions begins in middle age. Ann Neurol65, 650–657.
4.
CaselliRJ, DueckAC, OsborneD, SabbaghMN, ConnorDJ, AhernGL, BaxterLC, RapcsakSZ, ShiJ, WoodruffBK, LockeDE, SnyderCH, AlexanderGE, RademakersR, ReimanEM (2009) Longitudinal modeling of age-related memory decline and the APOE epsilon4 effect. N Engl J Med361, 255–263.
5.
MorminoEC, BetenskyRA, HeddenT, SchultzAP, WardA, HuijbersW, RentzDM, JohnsonKA, SperlingRA, Alzheimer’s Disease Neuroimaging Initiative; Australian Imaging Biomarkers and Lifestyle Flagship Study of Ageing; Harvard Aging Brain Study (2014) Amyloid and APOE epsilon4 interact to influence short-term decline in preclinical Alzheimer disease. Neurology82, 1760–1767.
6.
NielsenHM, ChenK, LeeW, ChenY, BauerRJ3rd, ReimanE, CaselliR, BuG (2017) Peripheral apoE isoform levels in cognitively normal APOE epsilon3/epsilon4 individuals are associated with regional gray matter volume and cerebral glucose metabolism. Res Ther9, 5.
7.
ReimanEM, CaselliRJ, ChenK, AlexanderGE, BandyD, FrostJ (2001) Declining brain activity in cognitively normal apolipoprotein E epsilon 4 heterozygotes: A foundation for using positron emission tomography to efficiently test treatments to prevent Alzheimer’s disease. Proc Natl Acad Sci U S A98, 3334–3339.
8.
ReimanEM, CaselliRJ, YunLS, ChenK, BandyD, MinoshimaS, ThibodeauSN, OsborneD (1996) Preclinical evidence of Alzheimer’s disease in persons homozygous for the epsilon 4 allele for apolipoprotein E. N Engl J Med334, 752–758.
9.
ReimanEM, ChenK, AlexanderGE, CaselliRJ, BandyD, OsborneD, SaundersAM, HardyJ (2005) Correlations between apolipoprotein E epsilon4 gene dose and brain-imaging measurements of regional hypometabolism. Proc Natl Acad Sci U S A102, 8299–8302.
10.
SmallGW, ErcoliLM, SilvermanDH, HuangSC, KomoS, BookheimerSY, LavretskyH, MillerK, SiddarthP, RasgonNL, MazziottaJC, SaxenaS, WuHM, MegaMS, CummingsJL, SaundersAM, Pericak-VanceMA, RosesAD, BarrioJR, PhelpsME (2000) Cerebral metabolic and cognitive decline in persons at genetic risk for Alzheimer’s disease. Proc Natl Acad Sci U S A97, 6037–6042.
11.
SmallGW, MazziottaJC, CollinsMT, BaxterLR, PhelpsME, MandelkernMA, KaplanA, La RueA, AdamsonCF, ChangL, et al. (1995) Apolipoprotein E type 4 allele and cerebral glucose metabolism in relatives at risk for familial Alzheimer disease. JAMA273, 942–947.
12.
ThambisettyM, Beason-HeldL, AnY, KrautMA, ResnickSM (2010) APOE epsilon4 genotype and longitudinal changes in cerebral blood flow in normal aging. Arch Neurol67, 93–98.
13.
ReimanEM, UeckerA, CaselliRJ, LewisS, BandyD, de LeonMJ, De SantiS, ConvitA, OsborneD, WeaverA, ThibodeauSN (1998) Hippocampal volumes in cognitively normal persons at genetic risk for Alzheimer’s disease. Ann Neurol44, 288–291.
14.
ChenZY, PatelPD, SantG, MengCX, TengKK, HempsteadBL, LeeFS (2004) Variant brain-derived neurotrophic factor (BDNF) (Met66) alters the intracellular trafficking and activity-dependent secretion of wild-type BDNF in neurosecretory cells and cortical neurons. J Neurosci24, 4401–4411.
15.
EganMF, KojimaM, CallicottJH, GoldbergTE, KolachanaBS, BertolinoA, ZaitsevE, GoldB, GoldmanD, DeanM, LuB, WeinbergerDR (2003) The BDNF val66met polymorphism affects activity-dependent secretion of BDNF and human memory and hippocampal function. Cell112, 257–269.
16.
FrielingsdorfH, BathKG, SolimanF, DifedeJ, CaseyBJ, LeeFS (2010) Variant brain-derived neurotrophic factor Val66Met endophenotypes: Implications for posttraumatic stress disorder. Ann N Y Acad Sci1208, 150–157.
17.
BesteC, BauneBT, DomschkeK, FalkensteinM, KonradC (2010) Paradoxical association of the brain-derived-neurotrophic-factor val66met genotype with response inhibition. Neuroscience166, 178–184.
18.
ZivadinovR, Weinstock-GuttmanB, BenedictR, Tamano-BlancoM, HusseinS, AbdelrahmanN, DurfeeJ, RamanathanM (2007) Preservation of gray matter volume in multiple sclerosis patients with the Met allele of the rs6265 (Val66Met) SNP of brain-derived neurotrophic factor. Hum Mol Genet16, 2659–2668.
19.
OrosziG, LaptevaL, DavisE, YarboroCH, WeickertT, Roebuck-SpencerT, BleibergJ, RosensteinD, PaoM, LipskyPE, GoldmanD, LipskyRH, IlleiGG (2006) The Met66 allele of the functional Val66Met polymorphism in the brain-derived neurotrophic factor gene confers protection against neurocognitive dysfunction in systemic lupus erythematosus. Ann Rheum Dis65, 1330–1335.
20.
BarbeyAK, ColomR, PaulE, ForbesC, KruegerF, GoldmanD, GrafmanJ (2014) Preservation of general intelligence following traumatic brain injury: Contributions of the Met66 brain-derived neurotrophic factor. One9, e88733.
21.
NacmiasB, PicciniC, BagnoliS, TeddeA, CelliniE, BraccoL, SorbiS (2004) Brain-derived neurotrophic factor, apolipoprotein E genetic variants and cognitive performance in Alzheimer’s disease. Lett367, 379–383.
22.
Richter-SchmidingerT, AlexopoulosP, HornM, MausS, ReichelM, RheinC, LewczukP, SidiropoulosC, KneibT, PerneczkyR, DoerflerA, KornhuberJ (2011) Influence of brain-derived neurotrophic-factor and apolipoprotein E genetic variants on hippocampal volume and memory performance in healthy young adults. J Neural Transm (Vienna)118, 249–257.
AdamczukK, De WeerAS, NelissenN, ChenK, SleegersK, BettensK, Van BroeckhovenC, VandenbulckeM, ThiyyaguraP, DupontP, Van LaereK, ReimanEM, VandenbergheR (2013) Polymorphism of brain derived neurotrophic factor influences beta amyloid load in cognitively intact apolipoprotein E epsilon4 carriers. Clin2, 512–520.
28.
CaselliRJ, DueckAC, LockeDE, Hoffman-SnyderCR, WoodruffBK, RapcsakSZ, ReimanEM (2011) Longitudinal modeling of frontal cognition in APOE epsilon4 homozygotes, heterozygotes, and noncarriers. Neurology76, 1383–1388.
29.
CaselliRJ, ReimanEM, LockeDE, HuttonML, HentzJG, Hoffman-SnyderC, WoodruffBK, AlexanderGE, OsborneD (2007) Cognitive domain decline in healthy apolipoprotein E epsilon4 homozygotes before the diagnosis of mild cognitive impairment. Arch Neurol64, 1306–1311.
30.
CaselliRJ, ReimanEM, OsborneD, HentzJG, BaxterLC, HernandezJL, AlexanderGG (2004) Longitudinal changes in cognition and behavior in asymptomatic carriers of the APOE e4 allele. Neurology62, 1990–1995.
31.
LiangWS, ChenK, LeeW, SidharK, CorneveauxJJ, AllenAN, MyersA, VillaS, MeechoovetB, PruzinJ, BandyD, FleisherAS, LangbaumJB, HuentelmanMJ, JensenK, DunckleyT, CaselliRJ, KaibS, ReimanEM (2011) Association between GAB2 haplotype and higher glucose metabolism in Alzheimer’s disease-affected brain regions in cognitively normal APOEepsilon4 carriers. Neuroimage54, 1896–1902.
32.
SternRA, AdlerCH, ChenK, NavitskyM, LuoJ, DodickDW, AloscoML, TripodisY, GoradiaDD, MartinB, MastroeniD, FrittsNG, JarnaginJ, DevousMDSr., MintunMA, PontecorvoMJ, ShentonME, ReimanEM (2019) Tau positron-emission tomography in former National Football League players. N Engl J Med380, 1716–1725.
33.
LangbaumJB, ChenK, LeeW, ReschkeC, BandyD, FleisherAS, AlexanderGE, FosterNL, WeinerMW, KoeppeRA, JagustWJ, ReimanEM, Alzheimer’s Disease Neuroimaging Initiative (2009) Categorical and correlational analyses of baseline fluorodeoxyglucose positron emission tomography images from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Neuroimage45, 1107–1116.
34.
FischlB, SalatDH, BusaE, AlbertM, DieterichM, HaselgroveC, van der KouweA, KillianyR, KennedyD, KlavenessS, MontilloA, MakrisN, RosenB, DaleAM (2002) Whole brain segmentation: Automated labeling of neuroanatomical structures in the human brain. Neuron33, 341–355.
35.
FischlB, SalatDH, van der KouweAJ, MakrisN, SegonneF, QuinnBT, DaleAM (2004) Sequence-independent segmentation of magnetic resonance images. Neuroimage23 Suppl 1, S69–84.
36.
LoweVJ, WeigandSD, SenjemML, VemuriP, JordanL, KantarciK, BoeveB, JackCRJr., KnopmanD, PetersenRC (2014) Association of hypometabolism and amyloid levels in aging, normal subjects. Neurology82, 1959–1967.
37.
KnopmanDS, JackCRJr., LundtES, WeigandSD, VemuriP, LoweVJ, KantarciK, GunterJL, SenjemML, MielkeMM, MachuldaMM, RobertsRO, BoeveBF, JonesDT, PetersenRC (2016) Evolution of neurodegeneration-imaging biomarkers from clinically normal to dementia in the Alzheimer disease spectrum. Aging46, 32–42.
38.
XiaH, WangM, LiJQ, TanCC, CaoXP, TanL, YuJT, Alzheimer’s Disease Neuroimaging Initiative (2019) The influence of BDNF Val66Met polymorphism on cognition, cerebrospinal fluid, and neuroimaging markers in non-demented elderly. J Alzheimers Dis68, 405–414.
39.
CechovaK, AndelR, AngelucciF, ChmatalovaZ, MarkovaH, LaczoJ, VyhnalekM, MatoskaV, KaplanV, NedelskaZ, WardD, HortJ (2020) Impact of APOE and BDNF Val66Met gene polymorphisms on cognitive functions in patients with amnestic mild cognitive impairment. J Alzheimers Dis73, 247–257.
40.
XuC, WangZ, FanM, LiuB, SongM, ZhenX, JiangT, Alzheimer’s Disease Neuroimaging Initiative (2010) Effects of BDNF Val66Met polymorphism on brain metabolism in Alzheimer’s disease. Neuroreport21, 802–807.
41.
CerasaA, TongiorgiE, FeraF, GioiaMC, ValentinoP, LiguoriM, MannaI, ZitoG, PassamontiL, NisticoR, QuattroneA (2010) The effects of BDNF Val66Met polymorphism on brain function in controls and patients with multiple sclerosis: An imaging genetic study. Brain Res207, 377–386.
42.
LambYN, ThompsonCS, McKayNS, WaldieKE, KirkIJ (2015) The brain-derived neurotrophic factor (BDNF) val66met polymorphism differentially affects performance on subscales of the Wechsler Memory Scale - Third Edition (WMS-III). Front Psychol6, 1212.
