The pathological hallmarks of Alzheimer's disease (AD) include the amyloid-β (Aβ) plaques and phosphorylated tau (p-tau) forming neurofibrillary tangles. Understanding the pathophysiological cascade related to Aβ and tau process is crucial.
Objective
To investigate the impact of Aβ positron emission tomography (PET) and cerebrospinal fluid (CSF) p-tau on tau pathology and cognitive decline in AD.
Methods
We analyzed 319 older individuals from the Alzheimer's Disease Neuroimaging Initiative (ADNI) who underwent Aβ (18F-florbetapir or 18F-florbetaben) and tau (18F-flortaucipir) PET scans, along with CSF and cognitive assessments. Aβ positivity (A+) was determined by global standardized uptake value ratio thresholds of ≥1.11 for 18F-florbetapir or ≥1.08 for 18F-florbetaben, while p-tau positivity (T+) was defined as CSF p-tau181 levels ≥23 pg/ml. Linear mixed regression models were used to assess the effects of PET Aβ and CSF p-tau181 levels on tau accumulation in predefined Braak regions and cognitive function over time.
Results
Our results revealed significant differences in PET tau pathology and cognitive decline between A + and A− individuals. We observed that interactions between Aβ and p-tau proteins were associated with tau accumulation and cognitive decline. Additionally, A−/T + individuals exhibited higher levels of tau accumulation in all Braak regions compared to A−/T− counterparts, suggesting a potential independent role of p-tau in tau pathology in the absence of Aβ.
Conclusions
Our findings suggest that Aβ positivity and elevated CSF p-tau181 levels were associated with tau accumulation and cognitive decline, highlighting the relevance of soluble p-tau as a potential biomarker for further investigation.
BatemanRJXiongCBenzingerTLS, et al.Clinical and biomarker changes in dominantly inherited Alzheimer’s disease. N Engl J Med2012; 367: 795–804.
2.
HardyJAHigginsGA. Alzheimer’s disease: the amyloid cascade hypothesis. Science1992; 256: 184–185.
3.
SelkoeDJ. The molecular pathology of Alzheimer’s disease. Neuron1991; 6: 487–498.
4.
OssenkoppeleRSchonhautDRSchöllM, et al.Tau PET patterns mirror clinical and neuroanatomical variability in Alzheimer’s disease. Brain2016; 139: 1551–1567.
5.
PontecorvoMJDevousMDNavitskyM, et al.Relationships between flortaucipir PET tau binding and amyloid burden, clinical diagnosis, age and cognition. Brain2017; 140: 748–763.
6.
GordonBAMcCulloughAMishraS, et al.Cross-sectional and longitudinal atrophy is preferentially associated with tau rather than amyloid β positron emission tomography pathology. Alzheimers Dement (Amst)2018; 10: 245–252.
7.
HanseeuwBJBetenskyRAJacobsHIL, et al.Association of amyloid and tau with cognition in preclinical Alzheimer disease: a longitudinal study. JAMA Neurol2019; 76: 915–924.
8.
JackCRWisteHJBothaH, et al.The bivariate distribution of amyloid-β and tau: relationship with established neurocognitive clinical syndromes. Brain2019; 142: 3230–3242.
9.
CummingsJBlennowKJohnsonK, et al.Anti-tau trials for Alzheimer’s disease: a report from the EU/US/CTAD task force. J Prev Alzheimers Dis2019; 6: 157–163.
10.
LongJMHoltzmanDM. Alzheimer disease: an update on pathobiology and treatment strategies. Cell2019; 179: 312–339.
11.
JackCRBennettDABlennowK, et al.NIA-AA Research framework: toward a biological definition of Alzheimer’s disease. Alzheimers Dement2018; 14: 535–562.
12.
MattssonNZetterbergHHanssonO, et al.CSF Biomarkers and incipient Alzheimer disease in patients with mild cognitive impairment. JAMA2009; 302: 385–393.
13.
BuergerKEwersMPirttiläT, et al.CSF Phosphorylated tau protein correlates with neocortical neurofibrillary pathology in Alzheimer’s disease. Brain2006; 129: 3035–3041.
14.
BrierMRGordonBFriedrichsenK, et al.Tau and Aβ imaging, CSF measures, and cognition in Alzheimer’s disease. Sci Transl Med2016; 8: 338ra66.
15.
ChhatwalJPSchultzAPMarshallGA, et al.Temporal T807 binding correlates with CSF tau and phospho-tau in normal elderly. Neurology2016; 87: 920–926.
16.
SkillbäckTFarahmandBYRosénC, et al.Cerebrospinal fluid tau and amyloid-β1-42 in patients with dementia. Brain2015; 138: 2716–2731.
17.
MattssonNSchöllMStrandbergO, et al.18F-AV-1451 And CSF T-tau and P-tau as biomarkers in Alzheimer’s disease. EMBO Mol Med2017; 9: 1212–1223.
18.
Mattsson-CarlgrenNAnderssonEJanelidzeS, et al.Aβ deposition is associated with increases in soluble and phosphorylated tau that precede a positive Tau PET in Alzheimer’s disease. Sci Adv2020; 6: eaaz2387.
19.
MeyerP-FPichet BinetteAGonneaudJ, et al.Characterization of Alzheimer disease biomarker discrepancies using cerebrospinal fluid phosphorylated tau and AV1451 positron emission tomography. JAMA Neurol2020; 77: 508–516.
20.
BejaninASchonhautDRLa JoieR, et al.Tau pathology and neurodegeneration contribute to cognitive impairment in Alzheimer’s disease. Brain2017; 140: 3286–3300.
21.
OssenkoppeleRSmithROhlssonT, et al.Associations between tau, Aβ, and cortical thickness with cognition in Alzheimer disease. Neurology2019; 92: e601–e612.
22.
HeZGuoJLMcBrideJD, et al.Amyloid-β plaques enhance Alzheimer’s brain tau-seeded pathologies by facilitating neuritic plaque tau aggregation. Nat Med2018; 24: 29–38.
23.
PeeraerEBottelbergsAVan KolenK, et al.Intracerebral injection of preformed synthetic tau fibrils initiates widespread tauopathy and neuronal loss in the brains of tau transgenic mice. Neurobiol Dis2015; 73: 83–95.
24.
FrostBJacksRLDiamondMI. Propagation of tau misfolding from the outside to the inside of a cell. J Biol Chem2009; 284: 12845–12852.
25.
ShawLMVandersticheleHKnapik-CzajkaM, et al.Cerebrospinal fluid biomarker signature in Alzheimer’s disease neuroimaging initiative subjects. Ann Neurol2009; 65: 403–413.
26.
ToledoJBXieSXTrojanowskiJQ, et al.Longitudinal change in CSF Tau and Aβ biomarkers for up to 48 months in ADNI. Acta Neuropathol (Berl)2013; 126: 659–670.
27.
JagustWJLandauSMKoeppeRA, et al.The Alzheimer’s disease neuroimaging initiative 2 PET core: 2015. Alzheimers Dement2015; 11: 757–771.
28.
DesikanRSSégonneFFischlB, et al.An automated labeling system for subdividing the human cerebral cortex on MRI scans into gyral based regions of interest. Neuroimage2006; 31: 968–980.
29.
FranzmeierNNeitzelJRubinskiA, et al.Functional brain architecture is associated with the rate of tau accumulation in Alzheimer’s disease. Nat Commun2020; 11: 347.
30.
OssenkoppeleRRabinoviciGDSmithR, et al.Discriminative accuracy of [18F]flortaucipir positron emission tomography for Alzheimer disease vs other neurodegenerative disorders. JAMA2018; 320: 1151–1162.
31.
JoshiADPontecorvoMJClarkCM, et al.Performance characteristics of amyloid PET with florbetapir F 18 in patients with Alzheimer’s disease and cognitively normal subjects. J Nucl Med2012; 53: 378–384.
32.
MaassALandauSBakerSL, et al.Comparison of multiple tau-PET measures as biomarkers in aging and Alzheimer’s disease. Neuroimage2017; 157: 448–463.
33.
CranePKCarleAGibbonsLE, et al.Development and assessment of a composite score for memory in the Alzheimer’s disease neuroimaging initiative (ADNI). Brain Imaging Behav2012; 6: 502–516.
34.
GibbonsLECarleACMackinRS, et al.A composite score for executive functioning, validated in Alzheimer’s disease neuroimaging initiative (ADNI) participants with baseline mild cognitive impairment. Brain Imaging Behav2012; 6: 517–527.
35.
ChoiS-EMukherjeeSGibbonsLE, et al.Development and validation of language and visuospatial composite scores in ADNI. Alzheimers Dement (N Y)2020; 6: e12072.
36.
MesulamMM. Neuroplasticity failure in Alzheimer’s disease: bridging the gap between plaques and tangles. Neuron1999; 24: 521–529.
37.
LiJ-QSongJ-HSucklingJ, et al.Disease trajectories in older adults with non-AD pathologic change and comparison with Alzheimer’s disease pathophysiology: a longitudinal study. Neurobiol Aging2024; 134: 106–114.
38.
JackCRHoltzmanDM. Biomarker modeling of Alzheimer’s disease. Neuron2013; 80: 1347–1358.
39.
SelkoeDJHardyJ. The amyloid hypothesis of Alzheimer’s disease at 25 years. EMBO Mol Med2016; 8: 595–608.
40.
PradeepkiranJAReddyAPReddyPH. Pharmacophore-based models for therapeutic drugs against phosphorylated tau in Alzheimer’s disease. Drug Discov Today2019; 24: 616–623.
41.
Spires-JonesTLHymanBT. The intersection of amyloid beta and tau at synapses in Alzheimer’s disease. Neuron2014; 82: 756–771.
42.
BuscheMAWegmannSDujardinS, et al.Tau impairs neural circuits, dominating amyloid-β effects, in Alzheimer models in vivo. Nat Neurosci2019; 22: 57–64.
43.
PascoalTAMathotaarachchiSMohadesS, et al.Amyloid-β and hyperphosphorylated tau synergy drives metabolic decline in preclinical Alzheimer’s disease. Mol Psychiatry2017; 22: 306–311.
44.
PascoalTAMathotaarachchiSShinM, et al.Synergistic interaction between amyloid and tau predicts the progression to dementia. Alzheimers Dement2017; 13: 644–653.
45.
SmallSADuffK. Linking Abeta and tau in late-onset Alzheimer’s disease: a dual pathway hypothesis. Neuron2008; 60: 534–542.
46.
DuyckaertsC. Tau pathology in children and young adults: can you still be unconditionally baptist?Acta Neuropathol (Berl)2011; 121: 145–147.
47.
BraakHDel TrediciK. The pathological process underlying Alzheimer’s disease in individuals under thirty. Acta Neuropathol (Berl)2011; 121: 171–181.
48.
JohnsonKASchultzABetenskyRA, et al.Tau positron emission tomographic imaging in aging and early Alzheimer disease. Ann Neurol2016; 79: 110–119.
49.
WangYMandelkowE. Tau in physiology and pathology. Nat Rev Neurosci2016; 17: 5–21.
