Plasma phosphorylated-tau181 (p-tau181) is a promising biomarker for Alzheimer’s disease (AD) and may offer utility for predicting preclinical disease.
Objective:
To evaluate the prospective association between plasma p-tau181 and amyloid-β (Aβ) and tau-PET deposition in cognitively unimpaired individuals.
Methods:
Plasma p-tau181 levels were measured at baseline in 52 [48% women, mean 64.4 (SD 5.5) years] cognitively unimpaired Framingham Offspring cohort participants using samples stored between 2011–2014 who subsequently underwent 11C-Pittsburgh Compound-B (PiB)-PET and/or 18F-Flortaucipir (FTP)-PET scans (n = 18 with tau-PET) a mean of 6.8 (SD 0.6) years later. Our primary outcomes included Aβ-precuneus, Aβ-FLR (frontal, lateral, and retrosplenial cortices) and tau-global composite region PET deposition. Secondary outcomes included individual regional Aβ and tau PET-deposition. P-tau181 was compared with plasma neurofilament light chain (NFL) and glial fibrillary acidic protein (GFAP) in predicting PET outcomes.
Results:
P-tau181 was associated with increased Aβ deposition in the FLR (β±SE, 1.25±0.30, p < 0.0001), precuneus (1.35±0.29, p < 0.001), and other cortical regions. Plasma NFL (1.30±0.49, p = 0.01) and GFAP (1.46±0.39, p < 0.001) were also associated with FLR Aβ deposition. In models including all three biomarkers adjusted for age, sex, APOE E4 allele, AD polygenic risk score and cortical atrophy score, p-tau181 (0.93±0.31, p < 0.01, R2 = 0.18) and GFAP (0.93±0.41, p = 0.03, R2 = 0.11), but not NFL (0.25±0.51, p = 0.62, R2 = 0.01), were associated with FLR-Aβ deposition. Plasma p-tau181 was not associated with tau-PET burden.
Conclusion:
In cognitively unimpaired adults, elevated plasma p-tau181 is associated with future increased Aβ deposition across multiple brain regions. Our results highlight the potential utility of p-tau181 as a blood-biomarker to screen for brain-amyloid deposition in cognitively healthy individuals in a community-setting.
KarikariTK, PascoalTA, AshtonNJ, JanelidzeS, BenedetAL, RodriguezJL, ChamounM, SavardM, KangMS, TherriaultJ, SchöllM, MassarwehG, SoucyJP, HöglundK, BrinkmalmG, MattssonN, PalmqvistS, GauthierS, StomrudE, ZetterbergH, HanssonO, Rosa-NetoP, BlennowK (2020) Blood phosphorylated tau 181 as a biomarker for Alzheimer’s disease: A diagnostic performance and prediction modelling study using data from four prospective cohorts. Lancet Neurol19, 422–433.
2.
KarikariTK, BenedetAL, AshtonNJ, Lantero RodriguezJ, SnellmanA, Suárez-CalvetM, Saha-ChaudhuriP, LussierF, KvartsbergH, RialAM, PascoalTA, AndreassonU, SchöllM, WeinerMW, Rosa-NetoP, TrojanowskiJQ, ShawLM, BlennowK, ZetterbergH (2021) Diagnostic performance and prediction of clinical progression of plasma phospho-tau181 in the Alzheimer’s Disease Neuroimaging Initiative. Mol Psychiatry26, 429–442.
3.
MielkeMM, HagenCE, XuJ, ChaiX, VemuriP, LoweVJ, AireyDC, KnopmanDS, RobertsRO, MachuldaMM, JackCRJr., PetersenRC, DageJL (2018) Plasma phospho-tau181 increases with Alzheimer’s disease clinical severity and is associated with tau- and amyloid-positron emission tomography. Alzheimers Dement14, 989–997.
4.
JanelidzeS, MattssonN, PalmqvistS, SmithR, BeachTG, SerranoGE, ChaiX, ProctorNK, EichenlaubU, ZetterbergH, BlennowK, ReimanEM, StomrudE, DageJL, HanssonO (2020) Plasma P-tau181 in Alzheimer’s disease: Relationship to other biomarkers, differential diagnosis, neuropathology and longitudinal progression to Alzheimer’s dementia. Nat Med26, 379–386.
5.
ThijssenEH, La JoieR, WolfA, StromA, WangP, IaccarinoL, BourakovaV, CobigoY, HeuerH, SpinaS, VandeVredeL, ChaiX, ProctorNK, AireyDC, ShcherbininS, Duggan EvansC, SimsJR, ZetterbergH, BlennowK, KarydasAM, TeunissenCE, KramerJH, GrinbergLT, SeeleyWW, RosenH, BoeveBF, MillerBL, RabinoviciGD, DageJL, RojasJC, BoxerAL (2020) Diagnostic value of plasma phosphorylated tau181 in Alzheimer’s disease and frontotemporal lobar degeneration. Nat Med26, 387–397.
6.
MoscosoA, GrotheMJ, AshtonNJ, KarikariTK, RodriguezJL, SnellmanA, Suárez-CalvetM, ZetterbergH, BlennowK, SchöllM (2021) Time course of phosphorylated-tau181 in blood across the Alzheimer’s disease spectrum. Brain144, 325–339.
CullenNC, LeuzyA, PalmqvistS, JanelidzeS, StomrudE, PesiniP, SarasaL, AlluéJA, ProctorNK, ZetterbergH, DageJL, BlennowK, Mattsson-CarlgrenN, HanssonO (2021) Individualized prognosis of cognitive decline and dementia in mild cognitive impairment based on plasma biomarker combinations. Nat Aging1, 114–123.
9.
TherriaultJ, BenedetAL, PascoalTA, LussierFZ, TissotC, KarikariTK, AshtonNJ, ChamounM, BezginG, MathotaarachchiS, GauthierS, Saha-ChaudhuriP, ZetterbergH, BlennowK, Rosa-NetoP (2021) Association of plasma P-tau181 with memory decline in non-demented adults. Brain Commun3, fcab136.
10.
RauchmannBS, Schneider-AxmannT, PerneczkyR (2021) Associations of longitudinal plasma p-tau181 and NfL with tau-PET, Aβ-PET and cognition. J Neurol Neurosurg Psychiatry92, 1289–1295.
11.
SchöllM, MaassA, MattssonN, AshtonNJ, BlennowK, ZetterbergH, JagustW (2019) Biomarkers for tau pathology. Mol Cell Neurosci97, 18–33.
12.
FeinleibM, KannelWB, GarrisonRJ, McNamaraPM, CastelliWP (1975) The Framingham Offspring Study. Design and preliminary data. Prev Med4, 518–525.
13.
SatizabalC, BeiserAS, SeshadriS (2016) Incidence of dementia over three decades in the Framingham Heart Study. N Engl J Med375, 93–94.
14.
BeckerJA, HeddenT, CarmasinJ, MayeJ, RentzDM, PutchaD, FischlB, GreveDN, MarshallGA, SallowayS, MarksD, BucknerRL, SperlingRA, JohnsonKA (2011) Amyloid-β associated cortical thinning in clinically normal elderly. Ann Neurol69, 1032–1042.
15.
GatchelJR, DonovanNJ, LocascioJJ, SchultzAP, BeckerJA, ChhatwalJ, PappKV, AmariglioRE, RentzDM, BlackerD, SperlingRA, JohnsonKA, MarshallGA (2017) Depressive symptoms and tau accumulation in the inferior temporal lobe and entorhinal cortex in cognitively normal older adults: A pilot study. J Alzheimers Dis59, 975–985.
16.
IkonomovicMD, KlunkWE, AbrahamsonEE, MathisCA, PriceJC, TsopelasND, LoprestiBJ, ZiolkoS, BiW, PaljugWR, DebnathML, HopeCE, IsanskiBA, HamiltonRL, DeKoskyST (2008) Post-mortem correlates of in vivo PiB-PET amyloid imaging in a typical case of Alzheimer’s disease. Brain131, 1630–1645.
17.
DesikanRS, SégonneF, FischlB, QuinnBT, DickersonBC, BlackerD, BucknerRL, DaleAM, MaguireRP, HymanBT, AlbertMS, KillianyRJ (2006) An automated labeling system for subdividing the human cerebral cortex on MRI scans into gyral based regions of interest. Neuroimage31, 968–980.
18.
LoganJ, AlexoffD, FowlerJS (2011) The use of alternative forms of graphical analysis to balance bias and precision in PET images. J Cereb Blood Flow Metab31, 535–546.
19.
PriceJC, KlunkWE, LoprestiBJ, LuX, HogeJA, ZiolkoSK, HoltDP, MeltzerCC, DeKoskyST, MathisCA (2005) Kinetic modeling of amyloid binding in humans using PET imaging and Pittsburgh Compound-B. J Cereb Blood Flow Metab25, 1528–1547.
20.
HanseeuwBJ, BetenskyRA, MorminoEC, SchultzAP, SepulcreJ, BeckerJA, JacobsHIL, BuckleyRF, LaPointMR, VanniniP, DonovanNJ, ChhatwalJP, MarshallGA, PappKV, AmariglioRE, RentzDM, SperlingRA, JohnsonKA (2018) PET staging of amyloidosis using striatum. Alzheimers Dement14, 1281–1292.
21.
RajiCA, BeckerJT, TsopelasND, PriceJC, MathisCA, SaxtonJA, LoprestiBJ, HogeJA, ZiolkoSK, DeKoskyST, KlunkWE (2008) Characterizing regional correlation, laterality and symmetry of amyloid deposition in mild cognitive impairment and Alzheimer’s disease with Pittsburgh Compound B. J Neurosci Methods172, 277–282.
22.
JohnsonKA, GregasM, BeckerJA, KinnecomC, SalatDH, MoranEK, SmithEE, RosandJ, RentzDM, KlunkWE, MathisCA, PriceJC, DekoskyST, FischmanAJ, GreenbergSM (2007) Imaging of amyloid burden and distribution in cerebral amyloid angiopathy. Ann Neurol62, 229–234.
23.
GonzalesMM, SamraJ, O’DonnellA, MackinRS, SalinasJ, JacobME, SatizabalCL, AparicioHJ, ThibaultEG, SanchezJS, FinneyR, RubinsteinZB, MayblyumDV, KillianyRJ, DecarliCS, JohnsonKA, BeiserAS, SeshadriS (2021) Association of midlife depressive symptoms with regional amyloid-β and tau in the Framingham Heart Study. J Alzheimers Dis82, 249–260.
24.
VlassenkoAG, BenzingerTL, MorrisJC (2012) PET amyloid-beta imaging in preclinical Alzheimer’s disease. Biochim Biophys Acta1822, 370–379.
25.
JohnsonKA, SchultzA, BetenskyRA, BeckerJA, SepulcreJ, RentzD, MorminoE, ChhatwalJ, AmariglioR, PappK, MarshallG, AlbersM, MauroS, PepinL, AlverioJ, JudgeK, PhiliossaintM, ShoupT, YokellD, DickersonB, Gomez-IslaT, HymanB, VasdevN, SperlingR (2016) Tau positron emission tomographic imaging in aging and early Alzheimer disease. Ann Neurol79, 110–119.
26.
HanseeuwBJ, BetenskyRA, JacobsHIL, SchultzAP, SepulcreJ, BeckerJA, CosioDMO, FarrellM, QuirozYT, MorminoEC, BuckleyRF, PappKV, AmariglioRA, DewachterI, IvanoiuA, HuijbersW, HeddenT, MarshallGA, ChhatwalJP, RentzDM, SperlingRA, JohnsonK (2019) Association of amyloid and tau with cognition in preclinical Alzheimer disease: A longitudinal study. JAMA Neurol76, 915–924.
27.
SanchezJS, BeckerJA, JacobsHIL, HanseeuwBJ, JiangS, SchultzAP, ProperziMJ, KatzSR, BeiserA, SatizabalCL, O’DonnellA, DeCarliC, KillianyR, FakhriGE, NormandinMD, Gómez-IslaT, QuirozYT, RentzDM, SperlingRA, SeshadriS, AugustinackJ, PriceJC, JohnsonKA (2021) The cortical origin and initial spread of medial temporal tauopathy in Alzheimer’s disease assessed with positron emission tomography. Sci Transl Med13, eabc0655.
28.
KunkleBW, Grenier-BoleyB, SimsR, BisJC, DamotteV, NajAC, BolandA, VronskayaM, van der LeeSJ, Amlie-WolfA, et al. (2019) Genetic meta-analysis of diagnosed Alzheimer’s disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing. Nat Genet51, 414–430.
29.
HardyJ, SelkoeDJ (2002) The amyloid hypothesis of Alzheimer’s disease: Progress and problems on the road to therapeutics. Science297, 353–356.
30.
SatoC, BarthélemyNR, MawuenyegaKG, PattersonBW, GordonBA, Jockel-BalsarottiJ, SullivanM, CrispMJ, KastenT, KirmessKM, KanaanNM, YarasheskiKE, Baker-NighA, BenzingerTLS, MillerTM, KarchCM, BatemanRJ (2018) Tau kinetics in neurons and the human central nervous system. Neuron97, 1284–1298.e1287.
31.
Mattsson-CarlgrenN, AnderssonE, JanelidzeS, OssenkoppeleR, InselP, StrandbergO, ZetterbergH, RosenHJ, RabinoviciG, ChaiX, BlennowK, DageJL, StomrudE, SmithR, PalmqvistS, HanssonO (2020) Aβ deposition is associated with increases in soluble and phosphorylated tau that precede a positive Tau PET in Alzheimer’s disease. Sci Adv6, eaaz2387.
