Studies suggest that plasma Alzheimer's disease (AD) biomarkers may aid in the overall diagnosis of AD, but their utility among patients with atypical clinical presentations of AD are unknown.
Objective
The main objective of this study was to determine the relationship between amyloid-β (Aβ) and tau plasma biomarkers and PET measures of both Aβ and tau in atypical AD. The secondary objective was to determine if plasma biomarkers could differentiate patients with different atypical AD phenotypes and whether they were related to measures of disease severity.
Methods
We assessed whether plasma p-tau 181 and Aβ42/40 were associated with Aβ and tau PET uptake, clinical phenotype and severity in 77 patients with PET biomarker-confirmed atypical AD.
Results
Plasma Aβ42/40 ratio showed positive associations with tau PET uptake, with higher (more normal) Aβ42/40 ratio associated with higher tau uptake; the ratio was not associated with Aβ PET. No associations were noted with plasma p-tau 181. Plasma Aβ42/40 ratio and p-tau 181 concentrations were not associated with AD phenotype or cognitive severity.
Conclusion
Plasma Aβ42/40 ratio and p-tau 181 concentrations are not associated with amyloid or tau PET or with clinical severity among individuals presenting with atypical AD.
FrisoniGBAltomareDThalDR, et al.The probabilistic model of Alzheimer disease: the amyloid hypothesis revised. Nat Rev Neurosci2022; 23: 53–66.
2.
GaltonCJPattersonKXuerebJH, et al.Atypical and typical presentations of Alzheimer's disease: a clinical, neuropsychological, neuroimaging and pathological study of 13 cases. Brain2000; 123(Pt 3): 484–498.
3.
Graff-RadfordJYongKXXApostolovaLG, et al.New insights into atypical Alzheimer's disease in the era of biomarkers. Lancet Neurol2021; 20: 222–234.
4.
DuboisBFeldmanHHJacovaC, et al.Advancing research diagnostic criteria for Alzheimer's disease: the IWG-2 criteria. Lancet Neurol2014; 13: 614–629.
5.
CrutchSJLehmannMSchottJM, et al.Posterior cortical atrophy. Lancet Neurol2012; 11: 170–178.
6.
Gorno-TempiniMLBrambatiSMGinexV, et al.The logopenic/phonological variant of primary progressive aphasia. Neurology2008; 71: 1227–1234.
7.
OssenkoppeleRPijnenburgYAPerryDC, et al.The behavioural/dysexecutive variant of Alzheimer's disease: clinical, neuroimaging and pathological features. Brain2015; 138: 2732–2749.
8.
TownleyRAGraff-RadfordJMantyhWG, et al.Progressive dysexecutive syndrome due to Alzheimer's disease: a description of 55 cases and comparison to other phenotypes. Brain Commun2020; 2: fcaa068.
9.
ShirDPhamNTTBothaH, et al.Clinicoradiologic and neuropathologic evaluation of corticobasal syndrome. Neurology2023; 101: e289–e299.
10.
SchollMMaassAMattssonN, et al.Biomarkers for tau pathology. Mol Cell Neurosci2019; 97: 18–33.
11.
AshtonNJSchollMHeurlingK, et al.Update on biomarkers for amyloid pathology in Alzheimer's disease. Biomark Med2018; 12: 799–812.
12.
Perez-GrijalbaVRomeroJPesiniP, et al.Plasma Abeta42/40 ratio detects early stages of Alzheimer's disease and correlates with CSF and neuroimaging biomarkers in the AB255 study. J Prev Alzheimers Dis2019; 6: 34–41.
13.
DoeckeJDPerez-GrijalbaVFandosN, et al.Total abeta(42)/abeta(40) ratio in plasma predicts amyloid-PET status, independent of clinical AD diagnosis. Neurology2020; 94: e1580–e1591.
14.
FandosNPerez-GrijalbaVPesiniP, et al.Plasma amyloid beta 42/40 ratios as biomarkers for amyloid beta cerebral deposition in cognitively normal individuals. Alzheimers Dement (Amst)2017; 8: 179–187.
15.
JanelidzeSBarthelemyNRSalvadoG, et al.Plasma phosphorylated tau 217 and Abeta42/40 to predict early brain Abeta accumulation in people without cognitive impairment. JAMA Neurol2024; 81: 947–957.
16.
CoomansEMVerberkIMWOssenkoppeleR, et al.A head-to-head comparison between plasma pTau181 and Tau PET along the Alzheimer's disease Continuum. J Nucl Med2023; 64: 437–443.
17.
TissotCTherriaultJKunachP, et al.Comparing tau status determined via plasma pTau181, pTau231 and [(18)F]MK6240 tau-PET. EBioMedicine2022; 76: 103837.
18.
ShenXNHuangYYChenSD, et al.Plasma phosphorylated-tau181 as a predictive biomarker for Alzheimer's amyloid, tau and FDG PET status. Transl Psychiatry2021; 11: 585.
19.
RisacherSLFandosNRomeroJ, et al.Plasma amyloid beta levels are associated with cerebral amyloid and tau deposition. Alzheimers Dement (Amst)2019; 11: 510–519.
20.
ChatterjeePPedriniSDoeckeJD, et al.Plasma Abeta42/40 ratio, p-tau181, GFAP, and NfL across the Alzheimer's disease continuum: a cross-sectional and longitudinal study in the AIBL cohort. Alzheimers Dement2023; 19: 1117–1134.
21.
OssenkoppeleRReimandJSmithR, et al.Tau PET correlates with different Alzheimer's disease-related features compared to CSF and plasma p-tau biomarkers. EMBO Mol Med2021; 13: e14398.
22.
BarthelemyNRLiYJoseph-MathurinN, et al.A soluble phosphorylated tau signature links tau, amyloid and the evolution of stages of dominantly inherited Alzheimer's disease. Nat Med2020; 26: 398–407.
23.
KarikariTKPascoalTAAshtonNJ, et al.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 Neurol2020; 19: 422–433.
24.
PereiraJBJanelidzeSStomrudE, et al.Plasma markers predict changes in amyloid, tau, atrophy and cognition in non-demented subjects. Brain2021; 144: 2826–2836.
25.
CrookRHardyJDuffK. Single-day apolipoprotein E genotyping. J Neurosci Methods1994; 53: 125–127.
26.
NasreddineZSPhillipsNABedirianV, et al.The Montreal cognitive assessment, MoCA: a brief screening tool for mild cognitive impairment. J Am Geriatr Soc2005; 53: 695–699.
27.
HughesCPBergLDanzigerWL, et al.A new clinical scale for the staging of dementia. Br J Psychiatry1982; 140: 566–572.
28.
PacheMSmeetsCHGasioPF, et al.Colour vision deficiencies in Alzheimer's disease. Age Ageing2003; 32: 422–426.
29.
BrazisPWGraff-RadfordNRNewmanNJ, et al.Ishihara color plates as a test for simultanagnosia. Am J Ophthalmol1998; 126: 850–851.
30.
LansingAEIvnikRJCullumCM, et al.An empirically derived short form of the Boston naming test. Arch Clin Neuropsychol1999; 14: 481–487.
31.
GoodglassHBarresiB. Boston diagnostic Aphasia examination: short form record booklet 2000. New York, NY: Lippincott Williams & Wilkins, 2000.
32.
WarringtonEJamesM. The visual object and space perception battery 1991. Bury St Edmunds, Suffolk, UK: Thames Valley Test Company, 1991.
33.
MarksJDSyrjanenJAGraff-RadfordJ, et al.Comparison of plasma neurofilament light and total tau as neurodegeneration markers: associations with cognitive and neuroimaging outcomes. Alzheimers Res Ther2021; 13: 199.
34.
SyrjanenJACampbellMRAlgeciras-SchimnichA, et al.Associations of amyloid and neurodegeneration plasma biomarkers with comorbidities. Alzheimers Dement2022; 18: 1128–1140.
35.
WhitwellJLMartinPGraff-RadfordJ, et al.The role of age on tau PET uptake and gray matter atrophy in atypical Alzheimer's disease. Alzheimers Dement2019; 15: 675–685.
36.
JosephsKADuffyJRStrandEA, et al.Characterizing a neurodegenerative syndrome: primary progressive apraxia of speech. Brain2012; 135: 1522–1536.
37.
AvantsBBEpsteinCLGrossmanM, et al.Symmetric diffeomorphic image registration with cross-correlation: evaluating automated labeling of elderly and neurodegenerative brain. Med Image Anal2008; 12: 26–41.
SchwarzCGGunterJLWardCP, et al.The Mayo clinic adult life span template: better quantification across the life span. Alzheimers Dement2017; 13: P792.
40.
JackCRJrWisteHJTherneauTM, et al.Associations of amyloid, tau, and neurodegeneration biomarker profiles with rates of memory decline among individuals without dementia. JAMA2019; 321: 2316–2325.
41.
SinghNAGraff-RadfordJMachuldaMM, et al.Atypical Alzheimer's disease phenotypes with normal or borderline PET biomarker profiles. J Neurol2022; 269: 6613–6626.
42.
TetzloffKAGraff-RadfordJMartinPR, et al.Regional distribution, asymmetry, and clinical correlates of tau uptake on [18F]AV-1451 PET in atypical Alzheimer's disease. J Alzheimers Dis2018; 62: 1713–1724.
43.
SintiniIMartinPRGraff-RadfordJ, et al.Longitudinal tau-PET uptake and atrophy in atypical Alzheimer's disease. Neuroimage Clin2019; 23: 101823.
44.
JanelidzeSPalmqvistSLeuzyA, et al.Detecting amyloid positivity in early Alzheimer's disease using combinations of plasma Abeta42/Abeta40 and p-tau. Alzheimers Dement2022; 18: 283–293.
45.
SchindlerSEBollingerJGOvodV, et al.High-precision plasma beta-amyloid 42/40 predicts current and future brain amyloidosis. Neurology2019; 93: e1647–e1659.
46.
ThijssenEHLa JoieRWolfA, et al.Diagnostic value of plasma phosphorylated tau181 in Alzheimer's disease and frontotemporal lobar degeneration. Nat Med2020; 26: 387–397.
47.
JanelidzeSMattssonNPalmqvistS, et al.Plasma P-tau181 in Alzheimer's disease: relationship to other biomarkers, differential diagnosis, neuropathology and longitudinal progression to Alzheimer's dementia. Nat Med2020; 26: 379–386.
48.
PalmqvistSInselPSStomrudE, et al.Cerebrospinal fluid and plasma biomarker trajectories with increasing amyloid deposition in Alzheimer's disease. EMBO Mol Med2019; 11: e11170.
49.
GuoYHuangYYShenXN, et al.Characterization of Alzheimer's tau biomarker discordance using plasma, CSF, and PET. Alzheimers Res Ther2021; 13: 93.
50.
PyunJMParkYHYounYC, et al.Characteristics of discordance between amyloid positron emission tomography and plasma amyloid-β 42/40 positivity. Transl Psychiatry2024; 14: 88.
51.
PhillipsJSDasSRMcMillanCT, et al.Tau PET imaging predicts cognition in atypical variants of Alzheimer's disease. Hum Brain Mapp2018; 39: 691–708.
52.
OssenkoppeleRSchonhautDRSchollM, et al.Tau PET patterns mirror clinical and neuroanatomical variability in Alzheimer's disease. Brain2016; 139: 1551–1567.
53.
Mila-AlomaMAshtonNJShekariM, et al.Plasma p-tau231 and p-tau217 as state markers of amyloid-beta pathology in preclinical Alzheimer's disease. Nat Med2022; 28: 1797–1801.
54.
SchindlerSEPetersenKKSaefB, et al.Head-to-head comparison of leading blood tests for Alzheimer's disease pathology. Alzheimers Dement2024; 20: 8074–8096.
Supplementary Material
Please find the following supplemental material available below.
For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.
For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.
