Aβ deposition is associated with increases in soluble and phosphorylated tau that precede a positive tau PET in Alzheimer's disease

In the paper

“For CSF tau biomarkers, the percentages of positive individuals did not differ markedly between Aβ+ with milder cognitive deficits and dementia, but for Tau PET, the proportion of positivity increased from milder cognitive deficits to dementia.”

In the paper

“Aβ+ CU had higher CSF P-tau181, P-tau217, and T-tau than Aβ− CU (P ≤ 0.0001), but did not differ on any of the Tau PET measures.”

In the paper

“Aβ+ AD dementia had higher levels of all tau measures compared with all other groups (CSF, P ≤ 0.035; Tau PET, P ≤ 0.0013), except that there was no difference for CSF T-tau between Aβ+ with milder cognitive deficits or dementia.”

In the paper

“A large group of Aβ+ CU were positive for CSF tau biomarkers (ranging from 22% for CSF T-tau to 70% for CSF P-tau217; Table 1), but only one Aβ+ CU was positive for Tau PET [in inferior temporal cortex (ITC)].”

In the paper

“Tau PET measures increased at 18F-flutemetamol 0.772 (ITC) or 0.859 SUVR (Braak V–VI; Fig. 3, D and E).”

In the paper

“In sum, CSF Tau368 levels were slightly increased in Aβ+ individuals with mild cognitive deficits or AD dementia, but Tau368 levels were not significantly increased in Aβ+ CU compared with Aβ− CU, and there were no clear correlations between Tau368 and Tau PET uptake (fig. S7, A to C).”

In the paper

“The ratios also increased over time in Aβ+ CU, and spline models indicated that they started to increase before Amyloid PET became positive (fig. S5).”

In the paper

“When using T-tau instead, the mediation was more modest (41% mediation), and Amyloid PET retained an independent association with Tau PET.”

In the paper

“We confirmed this hypothesis in a set of 12 MAPT mutation carriers (eight with cognitive impairment and four CU controls), where all 12 had normal levels of CSF P-tau, and 10 of 12 had normal levels of CSF T-tau (fig. S1).”

In the paper

“Furthermore, the increase in Tau PET as a function of 18F-flutemetamol was only seen in individuals with high CSF P-tau levels, but not in individuals with low CSF P-tau (Fig. 3, H and I).”

In the paper

“CSF P-tau217, P-tau181, and T-tau started to increase already at 18F-flutemetamol 0.679 SUVR [95% confidence interval (CI), 0.671 to 0.695], 0.684 SUVR (95% CI, 0.675 to 0.703), and 0.695 SUVR (95% CI, 0.682 to 0.721), respectively”

In the paper

“but isolated CSF P-tau positivity was also seen in several cases (28.2 to 51.1%). Isolated Tau PET positivity was very rare (0.8 to 3.1%).”

In the paper

“Among the Aβ+ CU, 18 (56.3%) were positive for CSF P-tau217, 8 (25.0%) for CSF P-tau181, and 3 (9.4%) for CSF T-tau in the early sample.”

In the paper

“These ratios were also changed in Aβ+ CU and were often positive in individuals with negative Tau PET (but the opposite, a positive Tau PET with a negative CSF P-tau/T-tau ratio, was only seen in one individual, for P-tau181/T-tau; fig. S4).”

In the paper

“In contrast to CSF tau, Tau PET increases occurred well into the phase of Amyloid PET positivity and only in individuals who also had increased CSF P-tau levels.”

In the paper

“CSF T-tau levels (we did not measure CSF P-tau since, to our knowledge, there is no assay available to measure P-tau in the CSF of mice) started to increase slightly after extracellular Aβ plaques start to accumulate, and then continued to increase as the Aβ pathology progressed, despite a lack of formation of PHF-tau in these mice (25).”

What the sources say

• Not checked yetcites [25] Oakley H., Cole S. L., Logan S., Maus E., Shao P., Craft J., Guillozet-Bongaarts A., Ohno M., Disterhoft J., Van Eldik L., Berry R., Vassar R., Intraneuronal beta-amyloid aggregates, neurodegeneration, and neuron loss in transgenic mice with five familial Alzheimer’s disease mutations: potential factors in amyloid plaque formation. J. Neurosci. 26, 10129– 10140 (2006). 17021169 PMC6674618 source

In the paper

“This is also in line with our findings that Tau PET, but not CSF tau, predicted longitudinal cognitive decline”

In the paper

“Furthermore, baseline CSF tau (but not baseline Tau PET) predicted future increases in Tau PET in people with cognitive impairment.”

In the paper

“Although changes in T-tau were also seen early, P-tau (especially P-tau217) more strongly mediated the effect of Amyloid PET on Tau PET and was more clearly altered in the earliest stages of the disease (in Aβ+ CU several years before a negative Tau PET scan).”

In the paper

“but correlations between in vivo CSF tau biomarkers and tau aggregates in postmortem tissue are weaker (11).”

What the sources say

• Not checked yetcites [11] Buerger K., Ewers M., Pirttila T., Zinkowski R., Alafuzoff I., Teipel S. J., DeBernardis J., Kerkman D., McCulloch C., Soininen H., Hampel H., CSF phosphorylated tau protein correlates with neocortical neurofibrillary pathology in Alzheimer’s disease. Brain 129, 3035– 3041 (2006). 17012293 source

In the paper

“Cell and animal experiments have verified that Aβ may induce pathologically relevant alterations in neuronal tau, including increased phosphorylation and release of tau (4, 5).”

What the sources say

• Not checked yetcites [4] Stancu I.-C., Vasconcelos B., Terwel D., Dewachter I., Models of β-amyloid induced Tau-pathology: The long and “folded” road to understand the mechanism. Mol. Neurodegener. 9, 51 (2014). 25407337 PMC4255655 source
• Not checked yetcites [5] Maia L. F., Kaeser S. A., Reichwald J., Hruscha M., Martus P., Staufenbiel M., Jucker M., Changes in amyloid-β and Tau in the cerebrospinal fluid of transgenic mice overexpressing amyloid precursor protein. Sci. Transl. Med. 5, 194re2 (2013). 23863834 source

In the paper

“Accumulation of Aβ fibrils is thought to be an initiating factor in AD and necessary for the formation of tau aggregates (1).”

What the sources say

• Not checked yetcites [1] Goedert M., Tau filaments in neurodegenerative diseases. FEBS Lett. 592, 2383– 2391 (2018). 29790176 source

In the paper

“Neuropathological studies have shown that Tau PET correlates strongly to NFT and neuropil threads in the brain (10)”

What the sources say

• Not checked yetcites [10] Smith R., Wibom M., Pawlik D., Englund E., Hansson O., Correlation of in vivo [18F]Flortaucipir with postmortem alzheimer disease tau pathology. JAMA Neurol. 76, 310– 317 (2018). PMC6439731 30508025 source

In the paper

“Cognitive measures (15, 16) and atrophy (15) are more strongly related to Tau PET than to CSF tau biomarkers.”

What the sources say

• Not checked yetcites [15] Mattsson N., Schöll M., Strandberg O., Smith R., Palmqvist S., Insel P. S., Hägerström D., Ohlsson T., Zetterberg H., Jögi J., Blennow K., Hansson O., 18F-AV-1451 and CSF T-tau and P-tau as biomarkers in Alzheimer’s disease. EMBO Mol. Med. 9, 1212– 1223 (2017). 28743782 PMC5582410 source
• Not checked yetcites [16] La Joie R., Bejanin A., Fagan A. M., Ayakta N., Baker S. L., Bourakova V., Boxer A. L., Cha J., Karydas A., Jerome G., Maass A., Mensing A., Miller Z. A., O’Neil J. P., Pham J., Rosen H. J., Tsai R., Visani A. V., Miller B. L., Jagust W. J., Rabinovici G. D., Associations between [18F]AV1451 tau PET and CSF measures of tau pathology in a clinical sample. Neurology 90, e282– e290 (2018). 29282337 PMC5798657

In the paper

“For example, transgenic animal experiments have shown that Aβ aggregates are associated with increased levels of soluble tau and increased tau phosphorylation (5, 6).”

What the sources say

• Not checked yetcites [5] Maia L. F., Kaeser S. A., Reichwald J., Hruscha M., Martus P., Staufenbiel M., Jucker M., Changes in amyloid-β and Tau in the cerebrospinal fluid of transgenic mice overexpressing amyloid precursor protein. Sci. Transl. Med. 5, 194re2 (2013). 23863834 source
• Not checked yetcites [6] Jin M., Shepardson N., Yang T., Chen G., Walsh D., Selkoe D. J., Soluble amyloid β-protein dimers isolated from Alzheimer cortex directly induce Tau hyperphosphorylation and neuritic degeneration. Proc. Natl. Acad. Sci. U.S.A. 108, 5819– 5824 (2011). 21421841 PMC3078381

In the paper

“These previous studies suggest that CSF tau biomarkers and Tau PET reflect different aspects of tau pathology and may become abnormal at different stages of the disease.”

What the sources say

• Not checked yetcites [12] Brier M. R., Gordon B., Friedrichsen K., McCarthy J., Stern A., Christensen J., Owen C., Aldea P., Su Y., Hassenstab J., Cairns N. J., Holtzman D. M., Fagan A. M., Morris J. C., Benzinger T. L. S., Ances B. M., Tau and Aβ imaging, CSF measures, and cognition in Alzheimer’s disease. Sci. Transl. Med. 8, 338ra66 (2016). PMC5267531 27169802 source
• Not checked yetcites [13] Chhatwal J. P., Schultz A. P., Marshall G. A., Boot B., Gomez-Isla T., Dumurgier J., LaPoint M., Scherzer C., Roe A. D., Hyman B. T., Sperling R. A., Johnson K. A., Temporal T807 binding correlates with CSF tau and phospho-tau in normal elderly. Neurology 87, 920– 926 (2016). 27473132 PMC5035159 source
• Not checked yetcites [14] Gordon B. A., Friedrichsen K., Brier M., Blazey T., Su Y., Christensen J., Aldea P., McConathy J., Holtzman D. M., Cairns N. J., Morris J. C., Fagan A. M., Ances B. M., Benzinger T. L. S., The relationship between cerebrospinal fluid markers of Alzheimer pathology and positron emission tomography tau imaging. Brain 139, 2249– 2260 (2016). 27286736 PMC4958902
• Not checked yetcites [15] Mattsson N., Schöll M., Strandberg O., Smith R., Palmqvist S., Insel P. S., Hägerström D., Ohlsson T., Zetterberg H., Jögi J., Blennow K., Hansson O., 18F-AV-1451 and CSF T-tau and P-tau as biomarkers in Alzheimer’s disease. EMBO Mol. Med. 9, 1212– 1223 (2017). 28743782 PMC5582410 source
• Not checked yetcites [16] La Joie R., Bejanin A., Fagan A. M., Ayakta N., Baker S. L., Bourakova V., Boxer A. L., Cha J., Karydas A., Jerome G., Maass A., Mensing A., Miller Z. A., O’Neil J. P., Pham J., Rosen H. J., Tsai R., Visani A. V., Miller B. L., Jagust W. J., Rabinovici G. D., Associations between [18F]AV1451 tau PET and CSF measures of tau pathology in a clinical sample. Neurology 90, e282– e290 (2018). 29282337 PMC5798657

In the paper

“These results demonstrate that CSF tau protein levels and phosphorylation are increased already in Aβ+ CU (in up to 70% of individuals for CSF P-tau217), a stage of the disease when insoluble PHF-tau deposition is rarely detected on Tau PET.”

In the paper

“Studies comparing CSF tau biomarkers with Tau PET have found that they are only moderately correlated, with the strongest correlations in symptomatic stages of AD, and no or weak correlations in cognitively unimpaired (CU) individuals (12–16).”

What the sources say

• Not checked yetcites [12] Brier M. R., Gordon B., Friedrichsen K., McCarthy J., Stern A., Christensen J., Owen C., Aldea P., Su Y., Hassenstab J., Cairns N. J., Holtzman D. M., Fagan A. M., Morris J. C., Benzinger T. L. S., Ances B. M., Tau and Aβ imaging, CSF measures, and cognition in Alzheimer’s disease. Sci. Transl. Med. 8, 338ra66 (2016). PMC5267531 27169802 source
• Not checked yetcites [13] Chhatwal J. P., Schultz A. P., Marshall G. A., Boot B., Gomez-Isla T., Dumurgier J., LaPoint M., Scherzer C., Roe A. D., Hyman B. T., Sperling R. A., Johnson K. A., Temporal T807 binding correlates with CSF tau and phospho-tau in normal elderly. Neurology 87, 920– 926 (2016). 27473132 PMC5035159 source
• Not checked yetcites [14] Gordon B. A., Friedrichsen K., Brier M., Blazey T., Su Y., Christensen J., Aldea P., McConathy J., Holtzman D. M., Cairns N. J., Morris J. C., Fagan A. M., Ances B. M., Benzinger T. L. S., The relationship between cerebrospinal fluid markers of Alzheimer pathology and positron emission tomography tau imaging. Brain 139, 2249– 2260 (2016). 27286736 PMC4958902
• Not checked yetcites [15] Mattsson N., Schöll M., Strandberg O., Smith R., Palmqvist S., Insel P. S., Hägerström D., Ohlsson T., Zetterberg H., Jögi J., Blennow K., Hansson O., 18F-AV-1451 and CSF T-tau and P-tau as biomarkers in Alzheimer’s disease. EMBO Mol. Med. 9, 1212– 1223 (2017). 28743782 PMC5582410 source
• Not checked yetcites [16] La Joie R., Bejanin A., Fagan A. M., Ayakta N., Baker S. L., Bourakova V., Boxer A. L., Cha J., Karydas A., Jerome G., Maass A., Mensing A., Miller Z. A., O’Neil J. P., Pham J., Rosen H. J., Tsai R., Visani A. V., Miller B. L., Jagust W. J., Rabinovici G. D., Associations between [18F]AV1451 tau PET and CSF measures of tau pathology in a clinical sample. Neurology 90, e282– e290 (2018). 29282337 PMC5798657

In the paper

“In AD, tau becomes truncated and hyperphosphorylated (3), which can increase the risk for tau to aggregate into the paired helical filaments (PHF) that are found in neurofibrillary tangles (NFT) and neuropil treads in the brains of patients with AD (1).”

What the sources say

• Not checked yetcites [3] Cicognola C., Brinkmalm G., Wahlgren J., Portelius E., Gobom J., Cullen N. C., Hansson O., Parnetti L., Constantinescu R., Wildsmith K., Chen H.-H., Beach T. G., Lashley T., Zetterberg H., Blennow K., Höglund K., Novel tau fragments in cerebrospinal fluid: Relation to tangle pathology and cognitive decline in Alzheimer’s disease. Acta Neuropathol. 137, 279– 296 (2019). 30547227 PMC6514201 source
• Not checked yetcites [1] Goedert M., Tau filaments in neurodegenerative diseases. FEBS Lett. 592, 2383– 2391 (2018). 29790176 source

In the paper

“Together, these results show that the P-tau217/T-tau and P-tau181/T-tau ratios increase before Tau PET and may link Aβ pathology to deposition of PHF-tau.”

In the paper

“In contrast, CSF tau levels increase in the presence of Aβ, but do not directly reflect an injury process leading to cognitive decline.”

In the paper

“This suggests that Aβ pathology leads to increased neuronal phosphorylation and release of tau, which seems necessary for the formation of tau deposits.”

In the paper

“To our knowledge, this is the first study to demonstrate directly in humans that early Aβ pathology is associated with marked changes in levels and phosphorylation of tau, before deposition of PHF-tau is detected with Tau PET imaging, and that changes in soluble tau mediate the effects of Aβ pathology on downstream deposition of tau aggregates.”

In the paper

“Slope differences were tested in linear regression models, adjusted for age, sex, and time span between the two lumbar punctures.”

In the paper

“These results show that CSF P-tau markers (especially P-tau217) not only start to increase but also, in many cases, reach clearly abnormal levels several years before PHF-tau deposition can be detected by Tau PET.”

In the paper

“This study presents converging results from human individuals in asymptomatic and symptomatic stages of AD, and from an AD mouse model (5xFAD) that increased release and phosphorylation of tau occur in response to fibrillar Aβ deposition, and that these alterations in tau metabolism link the accumulation of Aβ plaques to deposition of PHF-tau as seen by Tau PET in humans, but with a delay of”

In the paper

“Together, these results support a model where Aβ pathology induces a change in brain metabolism of tau, including increased release and phosphorylation of tau at amino acid residues 217 and 181, where phosphorylation at position 217 may be a more pronounced early change, which later leads to accumulation of tau aggregates.”

In the paper

“a recent mass spectrometry–based study found increased degree of phosphorylation at position 217 compared with position 181 in CSF from patients with AD (9).”

What the sources say

• Not checked yetcites [9] Barthélemy N. R., Mallipeddi N., Moiseyev P., Sato C., Bateman R. J., Tau phosphorylation rates measured by mass spectrometry differ in the intracellular brain vs. extracellular cerebrospinal fluid compartments and are differentially affected by alzheimer’s disease. Front. Aging Neurosci. 11, 121 (2019). 31178717 PMC6537657 source

In the paper

“These findings strengthen the amyloid cascade hypothesis and demonstrate in humans with sporadic (non–autosomal dominant) forms of AD that metabolism of soluble tau is altered in the presence of Aβ, and that this foreshadows significant tau deposition by several years.”

In the paper

“A recently presented framework for AD research (the “ATN” framework) has suggested that Tau PET and CSF P-tau can be used to define tau pathology (“T”), while CSF T-tau can be used to define neurodegeneration (“N”) in AD (18).”

What the sources say

• Not checked yetcites [18] Jack C. R. Jr., Bennett D. A., Blennow K., Carrillo M. C., Dunn B., Haeberlein S. B., Holtzman D. M., Jagust W., Jessen F., Karlawish J., Liu E., Molinuevo J. L., Montine T., Phelps C., Rankin K. P., Rowe C. C., Scheltens P., Siemers E., Snyder H. M., Sperling R., Contributors, NIA-AA Research Framework: Toward a biological definition of Alzheimer’s disease. Alzheimers Dement. 14, 535– 562 (2018). 29653606 PMC5958625 source

In the paper

“not only CSF P-tau217 but also P-tau181 may be increased very early (in preclinical stages) and then reach a plateau [and in very late stages, perhaps even a decrease, as has also been suggested by findings from autosomal dominant AD (35)].”

What the sources say

• Not checked yetcites [35] McDade E., Wang G., Gordon B. A., Hassenstab J., Benzinger T. L. S., Buckles V., Fagan A. M., Holtzman D. M., Cairns N. J., Goate A. M., Marcus D. S., Morris J. C., Paumier K., Xiong C., Allegri R., Berman S. B., Klunk W., Noble J., Ringman J., Ghetti B., Farlow M., Sperling R. A., Chhatwal J., Salloway S., Graff-Radford N. R., Schofield P. R., Masters C., Rossor M. N., Fox N. C., Levin J., Jucker M., Bateman R. J.; Dominantly inherited alzheimer network, Longitudinal cognitive and biomarker changes in dominantly inherited alzheimer disease. Neurology 91, e1295– e1306 (2018). 30217935 PMC61772 source

In the paper

“Tau PET may continue to increase throughout the disease course, which gives it a very high diagnostic accuracy during the later stage of the disease (36).”

What the sources say

• Not checked yetcites [36] Ossenkoppele R., Rabinovici G. D., Smith R., Cho H., Schöll M., Strandberg O., Palmqvist S., Mattsson N., Janelidze S., Santillo A., Ohlsson T., Jögi J., Tsai R., La Joie R., Kramer J., Boxer A. L., Gorno-Tempini M. L., Miller B. L., Choi J. Y., Ryu Y. H., Lyoo C. H., Hansson O., Discriminative accuracy of [18F]flortaucipir positron emission tomography for alzheimer disease vs other neurodegenerative disorders. JAMA 320, 1151– 1162 (2018). 30326496 PMC6233630 source

In the paper

“The first tau deposits that are initiated by Aβ may occur in dystrophic neurites surrounding the Aβ plaques, with the formation of widespread tangle pathology coming later (29), potentially spreading through functionally connected neurons.”

What the sources say

• Not checked yetcites [29] He Z., Guo J. L., McBride J. D., Narasimhan S., Kim H., Changolkar L., Zhang B., Gathagan R. J., Yue C., Dengler C., Stieber A., Nitla M., Coulter D. A., Abel T., Brunden K. R., Trojanowski J. Q., Lee V. M.-Y., Amyloid-β plaques enhance Alzheimer’s brain tau-seeded pathologies by facilitating neuritic plaque tau aggregation. Nat. Med. 24, 29– 38 (2018). 29200205 PMC5760353 source

In the paper

“comparisons of in vivo Tau PET versus neuropathology data have shown good correlations between Tau PET signal and tau neuropathology quantifications, although we note that individuals in those studies had substantial tau accumulation (10).”

What the sources say

• Not checked yetcites [10] Smith R., Wibom M., Pawlik D., Englund E., Hansson O., Correlation of in vivo [18F]Flortaucipir with postmortem alzheimer disease tau pathology. JAMA Neurol. 76, 310– 317 (2018). PMC6439731 30508025 source

In the paper

“changes in CSF P-tau217 and P-tau181 would indicate “disease state,” i.e., the presence of a pathological process associated with AD from very early on in the disease, while the continuous increase in Tau PET [and the strong correlations between Tau PET and atrophy and cognitive decline; (39)] would make Tau PET a marker of “disease stage” throughout the symptomatic phases of AD.”

What the sources say

• Not checked yetcites [38] Blennow K., Hampel H., CSF markers for incipient Alzheimer’s disease. Lancet Neurol. 2, 605– 613 (2003). 14505582 source
• Not checked yetcites [39] Mattsson N., Insel P. S., Donohue M., Jögi J., Ossenkoppele R., Olsson T., Schöll M., Smith R., Hansson O., Predicting diagnosis and cognition with 18F-AV-1451 tau PET and structural MRI in Alzheimer’s disease. Alzheimers Dement. 15, 570– 580 (2019). 30639421 source

In the paper

“T-tau levels may be increased also in other conditions with brain injury without tau aggregation (17).”

What the sources say

• Not checked yetcites [17] Hesse C., Rosengren L., Vanmechelen E., Vanderstichele H., Jensen C., Davidsson P., Blennow K., Cerebrospinal fluid markers for Alzheimer’s disease evaluated after acute ischemic stroke. J. Alzheimers Dis. 2, 199– 206 (2000). 12214084

In the paper

“The change in soluble tau metabolism (including hyperphosphorylation) is a link between the accumulation of Aβ and the widespread deposition of insoluble tau aggregates detectable by Tau PET imaging, with the latter following several years after detection of the first changes in soluble tau.”

In the paper

“Limitations of the study include the lack of neuropathology to verify the correlations between the different tau measures and neuropathological changes in the brain.”

In the paper

“Another limitation was that the longitudinal part of the study was relatively small and differed between CSF and Tau PET measures.”

In the paper

“The CSF Aβ42/Aβ40 ratio (using EUROIMMUN data) was used to define Aβ status, with a previously defined cut point (<0.1) to define positivity (42).”

What the sources say

• Not checked yetcites [42] Janelidze S., Zetterberg H., Mattsson N., Palmqvist S., Vanderstichele H., Lindberg O., van Westen D., Stomrud E., Minthon L., Blennow K.; Swedish BioFINDER study group, Hansson O., CSF Aβ42/Aβ40 and Aβ42/Aβ38 ratios: Better diagnostic markers of Alzheimer disease. Ann. Clin. Transl. Neurol. 3, 154– 165 (2016). 27042676 PMC4774260 source

In the paper

“Our results therefore support that Aβ aggregation leads to both increased tau release (as shown in both the human individuals and the mouse model data) and phosphorylation, but it is primarily the altered tau hyperphosphorylation that is associated with the deposition of tau aggregates in humans.”

In the paper

“A cut point for this global uptake was defined in a cohort of 428 BioFINDER participants using mixture modeling analysis as described elsewhere (SUVR 0.743; Mattsson, Leuzy et al., in press, Neurology).”

In the paper

“Analyses were done using a priori defined ROIs.”

In the paper

“All regression models were adjusted for age, sex, and (when appropriate) the time-lag between lumbar puncture and Tau PET scan.”

In the paper

“We defined cut points for tau biomarkers based on the mean levels plus two SDs of the respective biomarker in independent cohorts of Aβ− CU.”

In the paper

“Post hoc analysis for group comparisons between the youngest group and all other groups was performed using the Mann-Whitney U test, and corrected for multiple comparisons using the Bonferroni method.”