Insulin Resistance is Associated with Increased Levels of Cerebrospinal Fluid Biomarkers of Alzheimer’s Disease and Reduced Memory Function in At-Risk Healthy Middle-Aged Adults
Restricted accessResearch articleFirst published online June 7, 2016
Insulin Resistance is Associated with Increased Levels of Cerebrospinal Fluid Biomarkers of Alzheimer’s Disease and Reduced Memory Function in At-Risk Healthy Middle-Aged Adults
Background: Type 2 diabetes is associated with an increased risk for Alzheimer’s disease (AD). Regulation of normal insulin function may be important in reducing the prevalence of dementia due to AD, particularly in individuals who harbor genetic risk for or have a parental family history of AD. The relationship between insulin resistance (IR) and AD pathology remains poorly understood, particularly in midlife prior to the onset of clinical metabolic disease or cognitive decline.
Objective: We examined associations between IR as indexed by HOMA-IR, cerebrospinal fluid (CSF) biomarkers of AD pathology, and memory in middle-aged adults enriched for AD. We postulated that higher HOMA-IR and APOEɛ4 carriage would be associated with greater CSF AD pathology and poor memory performance.
Methods: Cognitively asymptomatic middle-aged adults (N = 70, mean age = 57.7 years) from the Wisconsin Alzheimer’s Disease Research Center with a parental family history of dementia due to AD underwent lumbar puncture, blood draw, and neuropsychological testing. CSF AD biomarkers including soluble amyloid-β protein precursor β (sAβPPβ), amyloid-β42 (Aβ42), and phosphorylated tau (P-tau181) were examined with respect to HOMA-IR and APOEɛ4 status. Delayed memory performance was examined with respect to HOMA-IR, CSF AD biomarkers, and APOEɛ4 status.
Results: Higher HOMA-IR was associated with higher sAβPPβ and Aβ42 . APOEɛ4 carriers had significantly higher levels of sAβPPα, sAβPPβ, and P-tau181/Aβ42 compared to noncarriers. The concurrent presence of higher HOMA-IR and CSF AD pathology predicted worse delayed memory performance.
Conclusion: Overall, the findings suggest that IR and APOEɛ4 are contributing factors to the development of AD pathology in midlife, and provide support for targeting insulin function as a potentially modifiable risk factor for AD.
ArvanitakisZ, WilsonRS, BieniasJL, EvansDA, BennettDA (2004) Diabetes mellitus and risk of Alzheimer disease and decline in cognitive function. Arch Neurol61, 661–666.
2.
ChengG, HuangC, DengH, WangH (2012) Diabetes as a risk factor for dementia and mild cognitive impairment: A meta-analysis of longitudinal studies. Intern Med J42, 484–491.
3.
LiX, SongD, LengSX (2015) Link between type 2 diabetes and Alzheimer’s disease: From epidemiology to mechanism and treatment. Clin Interv Aging10, 549–560.
4.
OttA, StolkRP, van HarskampF, PolsHA, HofmanA, BretelerMM (1999) Diabetes mellitus and the risk of dementia: The Rotterdam Study. Neurology53, 1937–1942.
5.
PeilaR, RodriguezBL, LaunerLJ (2002) Type 2 diabetes, APOE gene, and the risk for dementia and related pathologies. Diabetes51, 1256–1262.
6.
SchrijversEMC, WittemanJCM, SijbrandsEJG, HofmanA, KoudstaalPJ, BretelerMMB (2010) Insulin metabolism and the risk of Alzheimer disease The Rotterdam Study. Neurology75, 1982–1987.
7.
International Diabetes, Federation (2014) IDF Diabetes Atlas, 6th edition, International Diabetes Federation, Brussels.
8.
de la MonteSM, WandsJ (2005) Review of insulin and insulin-like growth factor expression, signaling, and malfunction in the central nervous system: Relevance to Alzheimer’s disease. J Alzheimers Dis7, 45–61.
9.
KnowlerWC, Barrett-ConnerE, FowlerSE, HammanRF, LachinJM, WalkerEA, NathanDM, GroupDPPR (2002) Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med346, 393–403.
HeniM, KullmannS, PreisslH, FritscheA, HaringHU (2015) Impaired insulin action in the human brain: Causes and metabolic consequences. Nat Rev Endocrinol11, 701–711.
12.
CraftS, WatsonGS (2004) Insulin and neurodegenerative disease: Shared and specific mechanisms. Lancet Neurol3, 169–178.
13.
HennebergN, HoyerS (1995) Desensitization of the neuronal insulin receptor: A new approach in the etiopathogenesis of late-onset sporadic dementia of the Alzheimer type (SDAT)?Arch Gerontol Geriatr21, 63–74.
14.
ZhaoWQ, ChenH, QuonMJ, AlkonDL (2004) Insulin and the insulin receptor in experimental models of learning and memory. Eur J Pharmacol490, 71–81.
15.
BakerLD, CrossDJ, MinoshimaS, BelongiaD, WatsonGS, CraftS (2011) Insulin resistance and Alzheimer-like reductions in regional cerebral glucose metabolism for cognitively normal adults with prediabetes or early type 2 diabetes. Arch Neurol68, 51–57.
16.
TschritterO, PreisslH, HennigeAM, StumvollM, PorubskaK, FrostR, MarxH, KloselB, LutzenbergerW, BirbaumerN, HaringHU, FritscheA (2006) The cerebrocortical response to hyperinsulinemia is reduced in overweight humans: A magnetoencephalographic study. Proc Natl Acad Sci U S A103, 12103–12108.
17.
ConvitA, WolfOT, TarshishC, de LeonMJ (2003) Reduced glucose tolerance is associated with poor memory performance and hippocampal atrophy among normal elderly. Proc Natl Acad Sci U S A100, 2019–2022.
18.
WilletteAA, XuG, JohnsonSC, BirdsillAC, JonaitisEM, SagerMA, HermannBP, La LeonRueA, AsthanaS, BendlinBB (2013) Insulin resistance, brain atrophy, and cognitive performance in late middle-aged adults. Diabetes Care36, 443–449.
19.
WilletteAA, BendlinBB, StarksEJ, BirdsillAC, JohnsonSC, ChristianBT, OkonkwoOC, La RueA, HermannBP, KoscikRL, JonaitisEM, SagerMA, AsthanaS (2015) Association of insulin resistance with cerebral glucose uptake in late middle-aged adults at risk for Alzheimer disease. JAMA Neurol72, 1013–1020.
20.
MatsuzakiT, SasakiK, TanizakiY, HataJ, FujimiK, MatsuiY, SekitaA, SuzukiSO, KanbaS, KiyoharaY, IwakiT (2010) Insulin resistance is associated with the pathology of Alzheimer disease: The Hisayama Study. Neurology75, 764–770.
21.
MoranC, BeareR, PhanTG, BruceDG, CallisayaML, SrikanthV, Alzheimer’s Disease Neuroimaging Initiative (ADNI) (2015) Type 2 diabetes mellitus and biomarkers of neurodegeneration. Neurology85, 1123–1130.
22.
ArvanitakisZ, SchneiderJA, WilsonRS, LiY, ArnoldSE, WangZ, BennettDA (2006) Diabetes is related to cerebral infarction but not to AD pathology in older persons. Neurology67, 1960–1965.
23.
BeeriMS, SilvermanJM, DavisKL, MarinD, GrossmanHZ, SchmeidlerJ, PurohitDP, PerlDP, DavidsonM, MohsRC, HaroutunianV (2005) Type 2 diabetes is negatively associated with Alzheimer’s disease neuropathology. J Gerontol A Biol Sci Med Sci60, 471–475.
24.
RobertsRO, KnopmanDS, ChaRH, MielkeMM, PankratzVS, BoeveBF, KantarciK, GedaYE, JackCRJr, PetersenRC, LoweVJ (2014) Diabetes and elevated hemoglobin A1c levels are associated with brain hypometabolism but not amyloid accumulation. J Nucl Med55, 759–764.
25.
ThambisettyM, Jeffrey MetterE, YangA, DolanH, MaranoC, ZondermanAB, TroncosoJC, ZhouY, WongDF, FerrucciL, EganJ, ResnickSM, O’BrienRJ (2013) Glucose intolerance, insulin resistance, and pathological features of Alzheimer disease in the Baltimore Longitudinal Study of Aging. JAMA Neurol70, 1167–1172.
26.
WilletteAA, JohnsonSC, BirdsillAC, SagerMA, ChristianB, BakerLD, CraftS, OhJ, StatzE, HermannBP, JonaitisEM, KoscikRL, La RueA, AsthanaS, BendlinBB (2015) Insulin resistance predicts brain amyloid deposition in late middle-aged adults. Alzheimers Dement11, 504–510e501.
27.
NunanJ, SmallDH (2000) Regulation of APP cleavage by alpha-, beta- and gamma-secretases. FEBS Lett483, 6–10.
28.
NalivaevaNN, TurnerAJ (2013) The amyloid precursor protein: A biochemical enigma in brain develoment, function and disease. FEBS Lett587, 2046–2054.
29.
van der KantR, GoldsteinLS (2015) Cellular functions of the amyloid precursor protein from development to dementia. Dev Cell32, 502–515.
LacorPN, BunielMC, FurlowPW, ClementeAS, VelascoPT, WoodM, ViolaKL, KleinWL (2007) Abeta oligomer-induced aberrations in synapse composition, shape, and density provide a molecular basis for loss of connectivity in Alzheimer’s disease. J Neurosci27, 796–807.
32.
LambertMP, BarlowAK, ChromyBA, EdwardsC, FreedR, LiosatosM, MorganTE, RozovskyI, TrommerB, ViolaKL, WalsP, ZhangC, FinchCE, KrafftGA, KleinWL (1998) Diffusible, nonfibrillar ligands derived from Aβ1-42 are potent central nervous system neurotoxins. Proc Natl Acad Sci U S A96, 6448–6453.
33.
RowanMJ, KlyubinI, CullenWK, AnwylR (2003) Synaptic plasticity in animal models of early Alzheimer’s disease. Philos Trans R Soc Lond B Biol Sci358, 821–828.
FarrisW, MansourianS, ChangY, LindsleyL, EckmanEA, FroschMP, EckmanCB, TanziRE, SelkoeDJ, GuenetteS (2003) Insulin-degrading enzyme regulates the levels of insulin, amyloid beta-protein, and the beta-amyloid precursor protein intracellular domain in vivo. Proc Natl Acad Sci U S A100, 4162–4167.
36.
GaspariniL, GourasGK, WangR, GrossRS, BealMF, GreengardP, XuH (2001) Stimulation of beta-amyloid precursor protein trafficking by insulin reduces intraneuronal beta-amyloid and requires mitogen-activated protein kinase signaling. J Neurosci21, 2561–2570.
37.
HoL, QinW, PomplPN, XiangZ, WangJ, ZhaoZ, PengY, CambareriG, RocherA, MobbsCV, HofPR, PasinettiGM (2004) Diet-induced insulin resistance promotes amyloidosis in a transgenic mouse model of Alzheimer’s disease. FASEB J18, 902–904.
38.
ReimanEM, ChenK, AlexanderGE, CaselliRJ, BandyD, OsborneD, SaundersAM, HardyJ (2004) Functional brain abnormalities in young adults at genetic risk for late-onset Alzheimer’s dementia. Proc Natl Acad Sci U S A101, 284–289.
39.
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.
40.
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.
41.
CorderE, SaundersA, StrittmatterW, SchmechelD, GaskellP, SmallG, RosesA, HainesJ, Pericak-VanceM (1993) Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science261, 921–923.
42.
LemaitreH, CrivelloF, DufouilC, GrassiotB, TzourioC, AlperovitchA, MazoyerB (2005) No epsilon4 gene dose effect on hippocampal atrophy in a large MRI database of healthy elderly subjects. Neuroimage24, 1205–1213.
43.
Salomon-ZimriS, Boehm-CaganA, LirazO, MichaelsonDM (2014) Hippocampus-related cognitive impairments in young apoE4 targeted replacement mice. Neurodegener Dis13, 86–92.
44.
MahleyRW, WeisgraberKH, HuangY (2006) Apolipoprotein E4: A causative factor and therapeutic target in neuropathology, including Alzheimer’s disease. Proc Natl Acad Sci U S A103, 5644–5651.
45.
ChenY, DurakoglugilMS, XianX, HerzJ (2010) ApoE4 reduces glutamate receptor function and synaptic plasticity by selectively impairing ApoE receptor recycling. Proc Natl Acad Sci U S A107, 12011–12016.
46.
AdluruN, DesticheDJ, LuSY, DoranST, BirdsillAC, MelahKE, OkonkwoOC, AlexanderAL, DowlingNM, JohnsonSC, SagerMA, BendlinBB (2014) White matter microstructure in late middle-age: Effects of apolipoprotein E4 and parental family history of Alzheimer’s disease. Neuroimage Clin4, 730–742.
47.
HoneaRA, SwerdlowRH, VidoniED, GoodwinJ, BurnsJM (2010) Reduced gray matter volume in normal adults with a maternal family history of Alzheimer disease. Neurology74, 113–120.
48.
HoneaRA, SwerdlowRH, VidoniED, BurnsJM (2011) Progressive regional atrophy in normal adults with a maternal history of Alzheimer disease. Neurology76, 822–829.
49.
JohnsonSC, SchmitzTW, TrivediMA, RiesML, TorgersonBM, CarlssonCM, AsthanaS, HermannBP, SagerMA (2006) The influence of Alzheimer disease family history and apolipoprotein E epsilon4 on mesial temporal lobe activation. J Neurosci26, 6069–6076.
50.
JohnsonSC, ChristianBT, OkonkwoOC, OhJM, HardingS, XuG, HillmerAT, WootenDW, MuraliD, BarnhartTE, HallLT, RacineAM, KlunkWE, MathisCA, BendlinBB, GallagherCL, CarlssonCM, RowleyHA, HermannBP, DowlingNM, AsthanaS, SagerMA (2014) Amyloid burden and neural function in people at risk for Alzheimer’s disease. Neurobiol Aging35, 576–584.
51.
MosconiL, RinneJO, TsuiWH, BertiV, LiY, WangH, MurrayJ, ScheininN, NagrenK, WilliamsS, GlodzikL, De SantiS, VallabhajosulaS, de LeonMJ (2010) Increased fibrillar amyloid-beta burden in normal individuals with a family history of late-onset Alzheimer’s. Proc Natl Acad Sci U S A107, 5949–5954.
52.
OkonkwoOC, XuG, DowlingNM, BendlinBB, LaRueA, HermannBP, KoscikR, JonaitisE, RowleyHA, CarlssonCM, AsthanaS, SagerMA, JohnsonSC (2012) Family history of Alizheimer disease predicts hippocampal atrophy in healthy middle-aged adults. Neurology78, 1769–1776.
53.
CupplesLA, FarrerLA, SadovnickAD, RelkinN, WhitehouseP, GreenRC (2004) Estimating risk curves for first-degree relatives of patients with Alzheimer’s disease: The REVEAL study. Genet Med6, 192–196.
54.
HendersonVW (2014) Three midlife strategies to prevent cognitive impairment due to Alzheimer’s disease. Climacteric17, 38–46.
55.
McKhannGM, DrachmanD, FolsteinM, KatzmanR, PriceD, StadlanEM (1984) Clinical diagnosis of Alzheimer’s disease: Report of the NINCDS-ADRDA Work Group1 under the auspices of Department of Health and Human Services Task Force on Alzheimer’s Disease. Neurology34, 939–944.
56.
McKhannGM, KnopmanDS, ChertkowH, HymanBT, JackCRJr, KawasCH, KlunkWE, KoroshetzWJ, ManlyJJ, MayeuxR, MohsRC, MorrisJC, RossorMN, ScheltensP, CarrilloMC, ThiesB, WeintraubS, PhelpsCH (2011) The diagnosis of dementia due to Alzheimer’s disease: Recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement7, 263–269.
57.
KawasCH, SegalJ, StewartWF, CorradaM, ThalLJ (1994) A validation study of the Dementia Questionnaire. Arch Neurol51, 901–906.
58.
MatthewsDR, HoskerJP, RudenskiAS, NaylorBA, TreacherDF, TurnerRC (1985) Homeostasis model assessment: Insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia28, 412–419.
59.
PalmqvistS, ZetterbergH, BlennowK, VestbergS, AndreassonU, BrooksDJ, OweniusR, HagerstromD, WollmerP, MinthonL, HanssonO (2014) Accuracy of brain amyloid detection in clinical practice using cerebrospinal fluid beta-amyloid 42: A cross-validation study against amyloid positron emission tomography. JAMA Neurol71, 1282–1289.
60.
StraussE, ShermanE, SpreenO (2006) Rey Auditory Verbal Learning Test. In Compendium of Neuropsychological Tests, 3rd ed. Oxford University Press, pp. 776–807.
61.
Estevez-GonzalezA, KulisevskyJ, BoltesA, OterminP, Garcia-SanchezC (2003) Rey verbal learning test is a useful tool for differential diagnosis in the preclinical phase of Alzheimer’s disease: Comparison with mild cognitive impairment and normal aging. Int J Geriatr Psychiatry18, 1021–1028.
62.
EwersM, WalshC, TrojanowskiJQ, ShawLM, PetersenRC, JackCRJr, FeldmanHH, BokdeAL, AlexanderGE, ScheltensP, VellasB, DuboisB, WeinerM, HampelH, North American Alzheimer’s Disease Neuroimaging Initiative (2012) Prediction of conversion from mild cognitive impairment to Alzheimer’s disease dementia based upon biomarkers and neuropsychological test performance. Neurobiol Aging33, 1203–1214.
63.
DeviL, AlldredMJ, GinsbergSD, OhnoM (2012) Mechanisms underlying insulin deficiency-induced acceleration of beta-amyloidosis in a mouse model of Alzheimer’s disease. PLoS One7, e32792.
64.
HoL, QinW, PomplPN, XiangZ, WangJ, ZhaoZ, PengY, CambareriG, RocherA, MobbsCV, HofPR, PasinettiGM (2004) Diet-induced insulin resistance promotes amyloidosis in a transgenic mouse model of Alzheimer’s disease. FASEB J18, 902–904.
KounnasMZ, MoirRD, RebeckGW, BushAL, ArgravesWS, TanziRE, HymanBT, StricklandDK (1995) LDL receptor-related protein, a multifunctional ApoE receptor, binds secreted beta-amyloid precursor protein and mediates its degradation. Cell82, 331–340.
67.
CraftS, AsthanaS, SchellenbergG, BakerL, CherrierM, BoytAA, MartinsRN, RaskindM, PerkindE, PlymateS (2000) Insulin effects on glucose metabolism, memory, and plasma amyloid precursor protein in Alzheimer’s disease differ according to apolipoprotein-E genotype. Ann N Y Acad Sci903, 222–228.
QiuWQ, FolsteinMF (2006) Insulin, insulin-degrading enzyme and amyloid-beta peptide in Alzheimer’s disease: Review and hypothesis. Neurobiol Aging27, 190–198.
70.
SchmechelDE, SaundersAM, StrittmatterWJ, CrainBJ, HuletteCM, JooSH, Pericak-VanceMA, GoldgaberD, RosesAD (1993) Increased amyloid beta-peptide deposition in cerebral cortex as a consequence of apolipoprotein E genotype in late-onset Alzheimer disease. Proc Natl Acad Sci U S A90, 9649–9653.
71.
BenedictC, BrooksSJ, KullbergJ, BurgosJ, KemptonMJ, NordenskjoldR, NylanderR, KilanderL, CraftS, LarssonEM, JohanssonL, AhlstromH, LindL, SchiothHB (2012) Impaired insulin sensitivity as indexed by the HOMA score is associated with deficits in verbal fluency and temporal lobe gray matter volume in the elderly. Diabetes Care35, 488–494.
72.
RasgonNL, KennaHA, WroolieTE, KelleyR, SilvermanD, BrooksJ, WilliamsKE, PowersBN, HallmayerJ, ReissA (2011) Insulin resistance and hippocampal volume in women at risk for Alzheimer’s disease. Neurobiol Aging32, 1942–1948.
ConvitA, de AsisJ, de LeonMJ, TarshishCY, De SantiS, RusinekH (2000) Atrophy of the medial occipitotemporal, inferior, and middle temporal gyri in non-demented elderly predict decline to Alzheimer’s disease. Neurobiol Aging21, 19–26.
75.
DuAT, SchuffN, AmendD, LaaksoMP, HsuYY, JagustWJ, YaffeK, KramerJH, ReedB, NormanD, ChuiHC, WeinerMW (2001) Magnetic resonance imaging of the entorhinal cortex and hippocampus in mild cognitive impairment and Alzheimer’s disease. J Neurol Neurosurg Psychiatry71, 441–447.
76.
PennanenC, KivipeltoM, TuomainenS, HartikainenP, HänninenT, LaaksoMP, HallikainenM, VanhanenM, NissinenA, HelkalaE, VainioP, VanninenR, PartanenK, SoininenH (2004) Hippocampus and entorhinal cortex in mild cognitive impairment and early AD. Neurobiol Aging25, 303–310.
77.
WangL, ZangY, HeY, LiangM, ZhangX, TianL, WuT, JiangT, LiK (2006) Changes in hippocampal connectivity in the early stages of Alzheimer’s disease: Evidence from resting state fMRI. Neuroimage31, 496–504.
78.
CardosoS, CorreiaS, SantosRX, CarvalhoC, SantosMS, OliveiraCR, PerryG, SmithMA, ZhuX, MoreiraPI (2009) Insulin is a two-edged knife on the brain. J Alzheimers Dis18, 483–507.
79.
ZhaoWQ, AlkonDL (2001) Role of insulin and insulin receptor in learning and memory. Mol Cell Endocrinol177, 125–134.
80.
KorolDL, GoldPE (1998) Glucose, memory, and aging. Am J Clin Nutr67, 764S–771S.
