The DOI matches its Crossref record; 38 of the 38 references it cites were found in a registry or an index; none of the 32 sources its claims cite is checked for support yet.
Association Between Amyloid and Tau Accumulation in Young Adults With Autosomal Dominant Alzheimer Disease
Open accessAbstract
Importance: It is critically important to improve our ability to diagnose and track Alzheimer disease (AD) as early as possible. Individuals with autosomal dominant forms of AD can provide clues as to which and when biological changes are reliably present prior to the onset of clinical symptoms. Objective: To characterize the associations between amyloid and tau deposits in the brains of cognitively unimpaired and impaired carriers of presenilin 1 (PSEN1) E280A mutation. Design, Setting, and Participants: In this cross-sectional imaging study, we leveraged data from a homogeneous autosomal dominant AD kindred, which allowed us to examine measurable tau deposition as a function of individuals' proximity to the expected onset of dementia. Cross-sectional measures of carbon 11-labeled Pittsburgh Compound B positron emission tomography (PET) and flortaucipir F 18 (previously known as AV 1451, T807) PET imaging were assessed in 24 PSEN1 E280A kindred members (age range, 28-55 years), including 12 carriers, 9 of whom were cognitively unimpaired and 3 of whom had mild cognitive impairment, and 12 cognitively unimpaired noncarriers. Main Outcomes and Measures: We compared carbon 11-labeled Pittsburgh Compound B PET cerebral with cerebellar distribution volume ratios as well as flortaucipir F 18 PET cerebral with cerebellar standardized uptake value ratios in mutation carriers and noncarriers. Spearman correlations characterized the associations between age and mean cortical Pittsburgh Compound B distribution volume ratio levels or regional flortaucipir standardized uptake value ratio levels in both groups. Results: Of the 24 individuals, the mean (SD) age was 38.0 (7.4) years, or approximately 6 years younger than the expected onset of clinical symptoms in carriers. Compared with noncarriers, cognitively unimpaired mutation carriers had elevated mean cortical Pittsburgh Compound B distribution volume ratio levels in their late 20s, and 7 of 9 carriers older than 30 years reached the threshold for amyloidosis (distribution volume ratio level > 1.2). Elevated levels of tau deposition were seen within medial temporal lobe regions in amyloid-positive mutation carriers 6 years before clinical onset of AD in this kindred. Substantial tau deposition in the neocortex was only observed in 1 unimpaired carrier and in those with mild cognitive impairment. β-Amyloid uptake levels were diffusely elevated in unimpaired carriers approximately 15 years prior to expected onset of mild cognitive impairment. In carriers, higher levels of tau deposition were associated with worse performance on the Mini-Mental State Examination (entorhinal cortex: r = -0.60; P = .04; inferior temporal lobe: r = -0.54; P = .06) and the Consortium to Establish a Registry for Alzheimer Disease Word List Delayed Recall (entorhinal cortex: r = -0.86; P < .001; inferior temporal lobe: r = -0.70; P = .01). Conclusions and Relevance: The present findings add to the growing evidence that molecular markers can characterize biological changes associated with AD in individuals who are still cognitively unimpaired. The findings also suggest that tau PET imaging may be useful as a biomarker to distinguish individuals at high risk to develop the clinical symptoms of AD and to track disease progression.
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40 Own result · 26 Not checked yet · 9 Own method · 9 Own interpretation · 4 No basis given
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In the paper
“followed by unimpaired mutation carriers (mean [SD], 1.21 [0.14]; 95% CI, -0.24 to -0.08)”
§ Association Between Amyloid and Tau Accumulation in Young Adults With Autosomal Dominant Alzheimer Disease > Carbon 11-Labeled PiB DVR in PSEN1 Mutation Carriers
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: Carbon 11-labeled PiB selectively binds amyloid deposits.
None of the sources cited for this claim have been checked yet.
In the paper
“β-Amyloid uptake levels were diffusely elevated in unimpaired carriers approximately 15 years prior to expected onset of MCI, consistent with our previous report 29 of increased mean cortical 18F florbetapir SUVR levels in individuals from the same kindred.”
- Also stated in: § Downloaded From: https://jamanetwork.com/ on 07/13/2023 · hedged
“This result is consistent with the present study and another one based on the Colombian kindred, 6 both of which showed that PiB levels begin to be elevated approximately 15 years prior to estimated onset of MCI.”
§ Association Between Amyloid and Tau Accumulation in Young Adults With Autosomal Dominant Alzheimer Disease > Downloaded From: https://jamanetwork.com/ on 07/13/2023
What the sources say
- Not checked yetcites [29] 29. Sepulveda-Falla D, Matschke J, Bernreuther C, et al. Deposition of hyperphosphorylated tau in cerebellum of PS1 E280A Alzheimer's disease. Brain Pathol. 2011;21(4):452-463.
- Not checked yetcites [6] 6. Fleisher AS, Chen K, Quiroz YT, et al. Associations between biomarkers and age in the presenilin 1 E280A autosomal dominant Alzheimer disease kindred: a cross-sectional study. JAMA Neurol. 2015;72(3):316-324.
plain- Asserted: passes — The authors put it forward as true.
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- Also stated in: § Downloaded From: https://jamanetwork.com/ on 07/13/2023 · hedged
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“who in turn showed higher carbon 11-labeled PiB DVR than noncarriers (mean [SD], 1.04 [0.02]; P < .001).”
§ Association Between Amyloid and Tau Accumulation in Young Adults With Autosomal Dominant Alzheimer Disease > Carbon 11-Labeled PiB DVR in PSEN1 Mutation Carriers
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: Carbon 11-labeled PiB selectively binds amyloid deposits.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“and the Consortium to Establish a Registry for Alzheimer Disease Word List Delayed Recall (entorhinal cortex: r = -0.86;P < .001;inferior temporal lobe: r = -0.70;P = .01).”
§ Association Between Amyloid and Tau Accumulation in Young Adults With Autosomal Dominant Alzheimer Disease > Abstract
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: Flortaucipir F 18 selectively binds tau aggregates.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“hippocampus (mean [SD] SUVR, 1.37 [0.30] vs 1.12 [0.08]; mean difference, -0.25; 95% CI, -0.49 to -0.03; P = .03)”
§ Association Between Amyloid and Tau Accumulation in Young Adults With Autosomal Dominant Alzheimer Disease > Regional 18F FTP Binding in PSEN1 Mutation Carriers
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: Flortaucipir F 18 selectively binds tau aggregates.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Inferior temporal lobe 18F FTP binding was associated with higher mean cortical PiB retention in mutation carriers (r = 0.67; P = .02).”
§ Association Between Amyloid and Tau Accumulation in Young Adults With Autosomal Dominant Alzheimer Disease > 18F FTP and PiB Binding in Relation to Each Other
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: Flortaucipir F 18 selectively binds tau aggregates.
- Rests on an assumption: Carbon 11-labeled PiB selectively binds amyloid deposits.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Furthermore, 18F FTP SUVR levels were correlated with clinical measures.”
§ Association Between Amyloid and Tau Accumulation in Young Adults With Autosomal Dominant Alzheimer Disease > Downloaded From: https://jamanetwork.com/ on 07/13/2023
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Compared with noncarriers, cognitively unimpaired mutation carriers had elevated mean cortical Pittsburgh Compound B distribution volume ratio levels in their late 20s”
§ Association Between Amyloid and Tau Accumulation in Young Adults With Autosomal Dominant Alzheimer Disease > Abstract
plaincorrelationaln = 24- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: Carbon 11-labeled PiB selectively binds amyloid deposits.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In mutation carriers, greater age was associated with both higher cortical PiB DVR (r = 0.88; P < .001)”
§ Association Between Amyloid and Tau Accumulation in Young Adults With Autosomal Dominant Alzheimer Disease > Associations Among PET Measures, Age, and Cognitive Measures
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: Carbon 11-labeled PiB selectively binds amyloid deposits.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Individual threshold-based anatomic assessments showed that unimpaired carriers with the highest PiB DVR values also had the highest FTP binding in the medial temporal lobe and inferior temporal regions.”
§ Association Between Amyloid and Tau Accumulation in Young Adults With Autosomal Dominant Alzheimer Disease > Regional 18F FTP Binding in PSEN1 Mutation Carriers
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: Flortaucipir F 18 selectively binds tau aggregates.
- Rests on an assumption: Carbon 11-labeled PiB selectively binds amyloid deposits.
- It may state two separate claims as one. 14
- Probably not a substantial claim. 16
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The youngest mutation carrier, aged 28 years, showed no PIB elevation (PiB = 1.02)”
§ Association Between Amyloid and Tau Accumulation in Young Adults With Autosomal Dominant Alzheimer Disease > Carbon 11-Labeled PiB DVR in PSEN1 Mutation Carriers
plainSingle case- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Rests on an assumption: Carbon 11-labeled PiB selectively binds amyloid deposits.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“No elevated amyloid accumulation was seen in any noncarriers, as expected (PiB DVR < 1.1 in all individuals).”
§ Association Between Amyloid and Tau Accumulation in Young Adults With Autosomal Dominant Alzheimer Disease > Carbon 11-Labeled PiB DVR in PSEN1 Mutation Carriers
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Rests on an assumption: Carbon 11-labeled PiB selectively binds amyloid deposits.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Compared with unimpaired mutation carriers, cognitively impaired mutation carriers were older and had significantly lower neuropsychological test scores.”
§ Association Between Amyloid and Tau Accumulation in Young Adults With Autosomal Dominant Alzheimer Disease > Demographic Information
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“but beginning at age 29 years, mutation carriers showed elevated PiB uptake (PiB DVR > 1.1 in all but 1 individual).”
§ Association Between Amyloid and Tau Accumulation in Young Adults With Autosomal Dominant Alzheimer Disease > Carbon 11-Labeled PiB DVR in PSEN1 Mutation Carriers
plainn = 9- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Rests on an assumption: Carbon 11-labeled PiB selectively binds amyloid deposits.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Additionally, the study of tau PET in combination with Pittsburgh Compound B (PiB) PET measures can reveal the extent to which amyloidtau relations in ADAD differ from those seen in sporadic AD.”
§ Association Between Amyloid and Tau Accumulation in Young Adults With Autosomal Dominant Alzheimer Disease > Abstract
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“All data were acquired by investigators who were masked to the participants' genetic status.”
§ Association Between Amyloid and Tau Accumulation in Young Adults With Autosomal Dominant Alzheimer Disease > Study Design and Participants
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“Presenilin 1 (PSEN1; OMIM, 104311) mutations predispose individuals to develop autosomal dominant Alzheimer disease (ADAD), usually relatively early in adulthood.5”
§ Association Between Amyloid and Tau Accumulation in Young Adults With Autosomal Dominant Alzheimer Disease > Abstract
What the sources say
- Not checked yetcites [5] 5. Lopera F, Ardilla A, Martínez A, et al. Clinical features of early-onset Alzheimer disease in a large kindred with an E280A presenilin-1 mutation. JAMA. 1997;277(10):793-799.
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Positron emission tomography data were not partial volume corrected.”
§ Association Between Amyloid and Tau Accumulation in Young Adults With Autosomal Dominant Alzheimer Disease > Image Acquisition and Processing
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“The cognitively unimpaired mutation carrier and noncarrier groups did not differ significantly in their age, sex, education, or neuropsycho-logical test scores.”
§ Association Between Amyloid and Tau Accumulation in Young Adults With Autosomal Dominant Alzheimer Disease > Demographic Information
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“A lzheimer disease (AD) is defined at the neuropathological molecular level by amyloid plaques and neurofibrillary tangles.1,2”
§ Association Between Amyloid and Tau Accumulation in Young Adults With Autosomal Dominant Alzheimer Disease > Abstract
What the sources say
- Not checked yetcites [1] 1. Iqbal K, Grundke-Iqbal I. Neurofibrillary pathology leads to synaptic loss and not the other way around in Alzheimer disease. J Alzheimers Dis. 2002;4(3):235-238.
- Not checked yetcites [2] 2. Crews L, Masliah E. Molecular mechanisms of neurodegeneration in Alzheimer's disease. Hum Mol Genet. 2010;19(R1):R12-R20.
plain- Asserted: passes — The authors put it forward as true.
- Checkable: fails — It may be too vague to check against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. It may be too vague to check against evidence. The paper’s conclusions may not depend on it.
In the paper
“Approximately 30% of living mutation carriers from this kindred are currently experiencing symptoms of AD, with median ages of 44 years (95% CI, 43-45) at onset of mild cognitive impairment (MCI) and 49 years (49-50) at onset of dementia.9”
§ Association Between Amyloid and Tau Accumulation in Young Adults With Autosomal Dominant Alzheimer Disease > Abstract
What the sources say
- Not checked yetcites [9] 9. Acosta-Baena N, Sepulveda-Falla D, Lopera-Gómez CM, et al. Pre-dementia clinical stages in presenilin 1 E280A familial early-onset Alzheimer's disease: a retrospective cohort study. Lancet Neurol. 2011;10(3):213-220.
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“This neuropathology generally follows a characteristic spatial distribution, with amyloid plaques beginning in neocortical association regions and tangles beginning in the medial temporal lobe and then spreading into adjacent association cortices with subsequent pancortical extension.3,4”
§ Association Between Amyloid and Tau Accumulation in Young Adults With Autosomal Dominant Alzheimer Disease > Abstract
What the sources say
- Not checked yetcites [3] 3. Arnold SE, Hyman BT, Flory J, Damasio AR, Van Hoesen GW. The topographical and neuroanatomical distribution of neurofibrillary tangles and neuritic plaques in the cerebral cortex of patients with Alzheimer's disease. Cereb Cortex. 1991;1(1):103-116.
- Not checked yetcites [4] 4. Braak H, Braak E. Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol. 1991; 82(4):239-259.
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“Residing in Antioquia, Colombia, this kindred is estimated to have approximately 5000 living members, including approximately 1800 mutation carriers.9”
§ Association Between Amyloid and Tau Accumulation in Young Adults With Autosomal Dominant Alzheimer Disease > Abstract
What the sources say
- Not checked yetcites [9] 9. Acosta-Baena N, Sepulveda-Falla D, Lopera-Gómez CM, et al. Pre-dementia clinical stages in presenilin 1 E280A familial early-onset Alzheimer's disease: a retrospective cohort study. Lancet Neurol. 2011;10(3):213-220.
hedged- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The findings also suggest that tau PET imaging may be useful as a biomarker to distinguish individuals at high risk to develop the clinical symptoms of AD and to track disease progression.”
§ Association Between Amyloid and Tau Accumulation in Young Adults With Autosomal Dominant Alzheimer Disease > Abstract
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Rests on an assumption: Flortaucipir F 18 selectively binds tau aggregates.
- Rests on an assumption: Cross-sectional differences by age reflect the temporal sequence of tau and amyloid accumulation.
In the paper
“Flortaucipir F 18 was prepared at Massachusetts General Hospital with a mean (SD) radiochemical yield of 14% (3%) and a mean (SD) specific activity of 216 (60) GBq/μmol at the end of synthesis (60 min) and was validated for human use.16”
§ Association Between Amyloid and Tau Accumulation in Young Adults With Autosomal Dominant Alzheimer Disease > Image Acquisition and Processing
What the sources say
- Not checked yetcites [16] 16. Shoup TM, Yokell DL, Rice PA, et al. A concise radiosynthesis of the tau radiopharmaceutical, [(18)
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Positron emission tomography images were reconstructed and attenuation-corrected, and each frame was evaluated to verify adequate count statistics and absence of head motion.”
§ Association Between Amyloid and Tau Accumulation in Young Adults With Autosomal Dominant Alzheimer Disease > Image Acquisition and Processing
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Cognitively unimpaired mutation carriers and noncarriers were matched for sex, age, and education.”
§ Association Between Amyloid and Tau Accumulation in Young Adults With Autosomal Dominant Alzheimer Disease > Study Design and Participants
plainn = 9- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Results with white matter were very similar to the results using the cerebellum (eg, the statistical differences observed with cerebellum as the reference region were also observed with white matter as the reference).”
§ Association Between Amyloid and Tau Accumulation in Young Adults With Autosomal Dominant Alzheimer Disease > Carbon 11-Labeled PiB DVR in PSEN1 Mutation Carriers
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“To account for possible 18F FTP off-target binding in choroid plexus, which may confound hippocampal signal, we used a linear regression to regress the choroid plexus, as previously reported.21”
§ Association Between Amyloid and Tau Accumulation in Young Adults With Autosomal Dominant Alzheimer Disease > Image Acquisition and Processing
What the sources say
- Not checked yetcites [21] 21. Chien DT, Bahri S, Szardenings AK, et al. Early clinical PET imaging results with the novel PHF-tau radioligand [F-18]-T807. J Alzheimers Dis. 2013;34 (2):457-468.
hedged- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
In the paper
“While the pathogenesis of ADAD may be different from late-onset AD (LOAD) and some clinical features may differ, these conditions are markedly similar in terms of their biological profiles, including abnormalities in amyloid biomarkers, brain structure, and brain activity.6”
§ Association Between Amyloid and Tau Accumulation in Young Adults With Autosomal Dominant Alzheimer Disease > Abstract
What the sources say
- Not checked yetcites [6] 6. Fleisher AS, Chen K, Quiroz YT, et al. Associations between biomarkers and age in the presenilin 1 E280A autosomal dominant Alzheimer disease kindred: a cross-sectional study. JAMA Neurol. 2015;72(3):316-324.
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“They also suggest that tau PET imaging may be useful as a biomarker to distinguish individuals at high risk to develop the clinical symptomatology of AD, track progression of the disease, and evaluate response to disease-modifying treatments.”
§ Association Between Amyloid and Tau Accumulation in Young Adults With Autosomal Dominant Alzheimer Disease > Conclusions
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Because age is predictive of clinical onset in the PSEN1 E280A mutation kindred, cross-sectional assessments across a wide age range in this well-defined cohort are perhaps analogous to what might be expected from the assessment of longitudinal trajectories of biomarker change.”
§ Association Between Amyloid and Tau Accumulation in Young Adults With Autosomal Dominant Alzheimer Disease > Limitations
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
- Rests on an assumption: Age is predictive of clinical onset in the PSEN1 E280A mutation kindred.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“In addition, the present results are based on a relatively small sample size compared with studies of LOAD.”
§ Association Between Amyloid and Tau Accumulation in Young Adults With Autosomal Dominant Alzheimer Disease > Limitations
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“These findings will inform ongoing preclinical trials with ADAD, such as the Alzheimer Prevention Initiative treatment trial of an Aβ-modifying agent.35”
§ Association Between Amyloid and Tau Accumulation in Young Adults With Autosomal Dominant Alzheimer Disease > Conclusions
What the sources say
- Not checked yetcites [35] 35. Benzinger T, Friedrichsen K, Sul Y, et al. Patterns of tau deposition using [18F]-AV-1451 in autosomal dominant Alzheimer's disease: results from the DIAN. Paper presented at: Human Amyloid Imaging 2016; January 14, 2016; Miami, FL.
plain- Asserted: passes — The authors put it forward as true.
- Checkable: fails — It may be too vague to check against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. It may be too vague to check against evidence. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Overall, the results from the Colombia kindred agree with those from DIAN for both FTP and PiB imaging.”
§ Association Between Amyloid and Tau Accumulation in Young Adults With Autosomal Dominant Alzheimer Disease > Downloaded From: https://jamanetwork.com/ on 07/13/2023
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“As such, the temporal differences observed between amyloid and tau pathology in this study may be explained in part by limited detection of pathology by PET methods.”
§ Association Between Amyloid and Tau Accumulation in Young Adults With Autosomal Dominant Alzheimer Disease > Limitations
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Most importantly, there is uncertainty regarding the extent to which the findings will generalize to LOAD and to other AD-causing mutations.”
§ Association Between Amyloid and Tau Accumulation in Young Adults With Autosomal Dominant Alzheimer Disease > Limitations
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
The paper relies on this without support.
Tau imaging had not been extensively tested in autosomal dominant Alzheimer disease before this study.
“To our knowledge, tau imaging has not been extensively tested in ADAD to date.”
The paper relies on this without support.
Flortaucipir F 18 selectively binds tau aggregates.
“flortaucipir F 18 (18F FTP; previously known as AV 1451, T807), which selectively binds tau aggregates”
The paper relies on this without support.
Carbon 11-labeled PiB selectively binds amyloid deposits.
“carbon 11labeled PiB, which selectively binds amyloid deposits”
The paper relies on this without support.
Tau PET imaging holds promise for detecting Alzheimer disease in the preclinical stage.
“This novel biomarker holds promise for detecting AD in the preclinical stage.”
The paper relies on this without support.
Cross-sectional differences by age reflect the temporal sequence of tau and amyloid accumulation.
“In this study, we characterized the spatial pattern and temporal lag cross-sectionally of tau and amyloid deposition in the brains of 24 PSEN1 E280A mutation carriers and noncarriers from the largest known kindred with ADAD.”
The paper relies on this without support.
PSEN1 mutation carriers will go on to develop Alzheimer disease with virtual certainty.
“Studies of PSEN1 mutation carriers allow us to examine cognitively unimpaired individuals who will go on to develop AD in the future with virtual certainty.”
The paper relies on this without support.
Age is predictive of clinical onset in the PSEN1 E280A mutation kindred.
“Because age is predictive of clinical onset in the PSEN1 E280A mutation kindred, cross-sectional assessments across a wide age range in this well-defined cohort are perhaps analogous to what might be expected from the assessment of longitudinal trajectories of biomarker change.”
The paper relies on this without support.
The present study is the first to investigate tau aggregation using PET imaging in this kindred.
“To our knowledge, the present study is the first to investigate tau aggregation using PET imaging in this kindred.”
The paper relies on this without support.
The present sample represents one of the largest of its kind with amyloid and tau PET data in carriers of a single ADAD mutation.
“However, because of the rarity of these mutations, the present sample represents, to our knowledge, one of the largest of its kind with amyloid and tau PET data in carriers of a single ADAD mutation.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The cited source says what the claim attributes to it.
In the citing paper
“The reported patient was protected from the clinical effects of PSEN1-E280A, a highly penetrant mutation causing EOAD dementia41,42, for 28 years by the homozygous APOE3-R136S mutation36.”
From The APOE-R136S mutation protects against APOE4-driven tau pathology, neurodegeneration, and neuroinflammation (2023) · cites this paper as [41]
The check wasn’t confident either way, so it gives no verdict — never disputed.
In the citing paper
“However, he had relatively limited Tau pathology in the entorhinal cortex (ERC) (SUVR = 1.34; Fig. 1a,c) and in other neocortical regions, such as the posterior cingulate cortex (PCC) and precuneus (SUVR PCC = 1.51; SUVR precuneus = 1.49; Fig. 1a)”
From Resilience to autosomal dominant Alzheimer’s disease in a Reelin-COLBOS heterozygous man (2023) · cites this paper as [3]
Experimental — accuracy not yet measuredIn the citing paper
“In contrast, the more appropriate longitudinal measures indicate that soluble tau phosphorylation occupancy decreases during the time of tau increase25, at least in DIAD, demonstrating an inverse correlation.”
From A soluble phosphorylated tau signature links tau, amyloid and the evolution of stages of dominantly inherited Alzheimer’s disease (2020) · cites this paper as [25]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ Association Between Amyloid and Tau Accumulation in Young Adults With Autosomal Dominant Alzheimer Disease > Abstract
“inferior temporal lobe: r = -0.54;P = .06”
§ Association Between Amyloid and Tau Accumulation in Young Adults With Autosomal Dominant Alzheimer Disease > Discussion
“FTP SUVR (Inferior-Temporal) r = -0.54P = .07”
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Cited by
Sorted by citations
The Amyloid-β Pathway in Alzheimer’s Disease
Hampel, H., Hardy, J., Blennow, K., Chen, C., Perry, G., Kim, S. H., Villemagne, V. L., Aisen, P., Vendruscolo, M., Iwatsubo, T., et al. (2021) · Molecular Psychiatry · doi:10.1038/s41380-021-01249-0 · Cited by 1,952
Palmqvist, S., Janelidze, S., Quiroz, Y. T., Zetterberg, H., Lopera, F., Stomrud, E., Su, Y., Chen, Y., Serrano, G. E., Leuzy, A., et al. (2020) · JAMA · doi:10.1001/jama.2020.12134 · Cited by 1,603
Self-citationthe Dominantly Inherited Alzheimer Network, Barthélemy, N. R., Li, Y., Joseph-Mathurin, N., Gordon, B. A., Hassenstab, J., Benzinger, T. L. S., Buckles, V., Fagan, A. M., Perrin, R. J., et al. (2020) · Nature Medicine · doi:10.1038/s41591-020-0781-z · Cited by 651
Imaging the evolution and pathophysiology of Alzheimer disease
Jagust, W. (2018) · Nature Reviews Neuroscience · doi:10.1038/s41583-018-0067-3 · Cited by 604
Arboleda-Velasquez, J. F., Lopera, F., O’Hare, M., Delgado-Tirado, S., Marino, C., Chmielewska, N., Saez-Torres, K. L., Amarnani, D., Schultz, A. P., Sperling, R. A., et al. (2019) · Nature Medicine · doi:10.1038/s41591-019-0611-3 · Cited by 598
Self-citationAmyloid-β-independent regulators of tau pathology in Alzheimer disease
van der Kant, R., Goldstein, L. S. B., & Ossenkoppele, R. (2020) · Nature reviews. Neuroscience · doi:10.1038/s41583-019-0240-3 · Cited by 580
Tau impairs neural circuits, dominating amyloid-β effects, in Alzheimer models in vivo
Busche, M. A., Wegmann, S., Dujardin, S., Commins, C., Schiantarelli, J., Klickstein, N., Kamath, T. V., Carlson, G. A., Nelken, I., & Hyman, B. T. (2019) · Nature Neuroscience · doi:10.1038/s41593-018-0289-8 · Cited by 413
Suárez‐Calvet, M., Karikari, T. K., Ashton, N. J., Lantero Rodríguez, J., Milà‐Alomà, M., Gispert, J. D., Salvadó, G., Minguillon, C., Fauria, K., Shekari, M., et al. (2020) · EMBO Molecular Medicine · doi:10.15252/emmm.202012921 · Cited by 401
“…studies on the timing of the biomarker’s changes in sporadic or autosomaldominant AD suggest that CSF p-tau increases earlier in the disease than tau PET (Bateman et al, 2012; Toledo et al, 2013; Johnson et al, 2016; Quiroz et al, 2018; Gordon et al, 2019; Jack et al, 2019; Mattsson et al, 2019).”
BackgroundThe complexity of tau in Alzheimer’s disease
Naseri, N. N., Wang, H., Guo, J. D., Sharma, M., & Luo, W. (2019) · Neuroscience Letters · doi:10.1016/j.neulet.2019.04.022 · Cited by 393
“the neocortex was associated with mild cognitive impairment and worse scores on cognitive tests [287].”
BackgroundAntisense Oligonucleotide Therapies for Neurodegenerative Diseases
Bennett, C. F., Krainer, A. R., & Cleveland, D. W. (2019) · Annual Review of Neuroscience · doi:10.1146/annurev-neuro-070918-050501 · Cited by 353
“With newer in vivo imaging techniques and CSF measurements of β-amyloid and tau in a genetically predisposed patient population, the temporal relationship between these two pathologies has become better defined (Fleisher et al. 2015, McDade & Bateman 2018, McDade et al. 2018, Quiroz et al. 2018).”
BackgroundRadiopharmaceuticals for PET and SPECT Imaging: A Literature Review over the Last Decade
Crișan, G., Moldovean‐Cioroianu, N. S., Timaru, D.-G., Andrieș, G., Cainap, C. I., & Chiş, V. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23095023 · Cited by 386
A walk through tau therapeutic strategies
Jadhav, S., Ávila, J., Schöll, M., Kovács, G. G., Kövari, E., Škrabana, R., Evans, L., Kontseková, E., Malawska, B., de Silva, R., et al. (2019) · Acta Neuropathologica Communications · doi:10.1186/s40478-019-0664-z · Cited by 299
Therriault, J., Vermeiren, M. R., Servaes, S., Tissot, C., Ashton, N. J., Benedet, A. L., Karikari, T. K., Lantero‐Rodriguez, J., Brum, W. S., Lussier, F. Z., et al. (2022) · JAMA Neurology · doi:10.1001/jamaneurol.2022.4485 · Cited by 278
Leuzy, A., Smith, R., Ossenkoppele, R., Santillo, A., Borroni, E., Klein, G., Ohlsson, T., Jögi, J., Palmqvist, S., Mattsson-Carlgren, N., et al. (2020) · JAMA Neurology · doi:10.1001/jamaneurol.2020.0989 · Cited by 222
Schöll, M., Maaß, A., Mattsson, N., Ashton, N. J., Blennow, K., Zetterberg, H., & Jagust, W. J. (2018) · Molecular and Cellular Neuroscience · doi:10.1016/j.mcn.2018.12.001 · Cited by 248
“Data from studies in early-onset familial/autosomal-dominant AD are limited, suggesting earliest FTP uptake in the MTL of Aβ-positive presymptomatic mutation carriers but high cortical uptake, spatially comparable to sporadic EOAD cases in later symptomatic stages (Quiroz et al., 2018; Schöll et al., 2017a).”
ResultMorris, G. P., Clark, I. A., & Vissel, B. (2018) · Acta Neuropathologica · doi:10.1007/s00401-018-1918-8 · Cited by 212
Resilience to autosomal dominant Alzheimer’s disease in a Reelin-COLBOS heterozygous man
Lopera, F., Marino, C., Chandrahas, A. S., O’Hare, M., Villalba-Moreno, N. D., Aguillon, D., Baena, A., Sanchez, J. S., Vila-Castelar, C., Ramirez Gomez, L., et al. (2023) · Nature Medicine · doi:10.1038/s41591-023-02318-3 · Cited by 192
Self-citationSanchez, J. S., Becker, J. A., Jacobs, H. I. L., Hanseeuw, B. J., Jiang, S., Schultz, A. P., Properzi, M. J., Katz, S. R., Beiser, A., Satizabal, C. L., et al. (2021) · Science Translational Medicine · doi:10.1126/scitranslmed.abc0655 · Cited by 200
Self-citationGordon, B. A., Blazey, T. M., Christensen, J., Dincer, A., Flores, S., Keefe, S., Chen, C., Su, Y., McDade, E. M., Wang, G., et al. (2019) · Brain · doi:10.1093/brain/awz019 · Cited by 180
“While tau PET has been examined in ADAD (Smith et al., 2016; Quiroz et al., 2018), this work had very small samples of impaired individuals (53), and had limited additional biomarkers.”
BackgroundResultQuiroz, Y. T., Zetterberg, H., Reiman, E. M., Chen, Y., Su, Y., Fox-Fuller, J. T., Garcia, G., Villegas, A., Sepulveda-Falla, D., Villada, M., et al. (2020) · The Lancet Neurology · doi:10.1016/s1474-4422(20)30137-x · Cited by 159
Self-citationDissecting the clinical heterogeneity of early-onset Alzheimer’s disease
Sirkis, D. W., Bonham, L. W., Johnson, T. P., La Joie, R., & Yokoyama, J. S. (2022) · Molecular Psychiatry · doi:10.1038/s41380-022-01531-9 · Cited by 151
Dementia in Latin America: Paving the way toward a regional action plan
Parra, M. A., Báez, S., Sedeño, L., Campo, C. G., Santamaría‐García, H. A., Aprahamian, I., Bertolucci, P. H. F., Bustin, J., Bicalho, M. A. C., Cano, C. A., et al. (2020) · Alzheimer s & Dementia · doi:10.1002/alz.12202 · Cited by 155
Self-citationMiao, J., Shi, R., Li, L., Chen, F., Zhou, Y., Tung, Y. C., Hu, W. H., Gong, C., Iqbal, K., & Liu, F. (2019) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2019.00034 · Cited by 125
“plaques, correlates with the degree of dementia in AD patients (Tomlinson et al., 1970; Alafuzoff et al., 1987; Arriagada et al., 1992; Quiroz et al., 2018).”
BackgroundUddin, M. S., Kabir, M. T., Rahman, M. S., Behl, T., Jeandet, P., Ashraf, G. M., Najda, A., Bin-Jumah, M. N., El-Seedi, H. R., & Abdel‐Daim, M. M. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21165858 · Cited by 131
“[45] revealed that increased levels of tau were observed in medial temporal lobe areas in carriers of unimpaired PSEN1 E280A mutation in their late 30s, and that noticeable formation of tau tangle in neocortical areas was seen in one cognitively unaffected carrier as well as in individuals with mild cognitive impairme…”
BackgroundMcCluskey, S. P., Plisson, C., Rabiner, E. A., & Howes, O. D. (2019) · European Journal of Nuclear Medicine and Molecular Imaging · doi:10.1007/s00259-019-04488-0 · Cited by 127
Nelson, M. R., Liu, P., Agrawal, A., Yip, O., Blumenfeld, J., Traglia, M., Kim, M. J., Koutsodendris, N., Rao, A., Grone, B., et al. (2023) · Nature Neuroscience · doi:10.1038/s41593-023-01480-8 · Cited by 120
“The reported patient was protected from the clinical effects of PSEN1-E280A, a highly pene-trant mutation causing EOAD dementia 41,42 , for 28 years by the homozygous APOE3-R136S mutation 36 .”
BackgroundSelf-citationMilligan Armstrong, A., Porter, T., Quek, H., White, A., Haynes, J., Jackaman, C., Villemagne, V., Munyard, K., Laws, S. M., Verdile, G., et al. (2021) · Biological Reviews · doi:10.1111/brv.12750 · Cited by 116
Kalaria, R. N., Maestre, G. E., Mahinrad, S., Acosta, D. M., Akinyemi, R., Alladi, S., Allegri, R., Arshad, F., Babalola, D. O., Baiyewu, O., et al. (2024) · Alzheimer s & Dementia · doi:10.1002/alz.13836 · Cited by 110
“153 In addition, PSEN1 E280A carriers have low levels of cerebrospinal fluid (CSF) A β 1-42 154 and high levels of plasma tau phosphorylated at threonine 217 (p-tau217) and neurofilament light (NfL) up to 20 years before the first symptoms of MCI.”
Sepulveda-Falla, D., Sanchez, J. S., Almeida, M. C., Boassa, D., Acosta-Uribe, J., Vila-Castelar, C., Ramirez-Gomez, L., Baena, A., Aguillon, D., Villalba-Moreno, N. D., et al. (2022) · Acta Neuropathologica · doi:10.1007/s00401-022-02467-8 · Cited by 92
“Structural MRI, 11C-Pittsburgh Compound B (PiB) and 18F-Flortaucipir (FTP) PET data were acquired at Massachusetts General Hospital, as previously described [29].”
MethodSelf-citationGuzmán‐Vélez, E., Diez, I. P., Schoemaker, D., Pardilla‐Delgado, E., Vila‐Castelar, C., Fox‐Fuller, J. T., Baena, A. Y., Sperling, R. A., Johnson, K. A., Lopera, F. J., et al. (2022) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2113641119 · Cited by 95
“, the preclinical stage)(1, 2) and follows distinct spatio-temporal patterns(3, 4).”
BackgroundSelf-citationLongitudinal tau-PET uptake and atrophy in atypical Alzheimer's disease
Sintini, I., Martin, P. R., Graff‐Radford, J., Senjem, M. L., Schwarz, C. G., Machulda, M. M., Spychalla, A. J., Drubach, D. A., Knopman, D. S., Petersen, R. C., et al. (2019) · NeuroImage Clinical · doi:10.1016/j.nicl.2019.101823 · Cited by 87
“According to the amyloid cascade model, the formation of Aβ plaques triggers the biological events that subsequently cause tauopathy, which is followed by neurodegeneration and, lastly, by the clinical symptoms of dementia (Jack Jr. et al., 2013; Jack et al., 2010; Quiroz et al., 2018).”
BackgroundRelevance of biomarkers across different neurodegenerative diseases
Ehrenberg, A. J., Khatun, A., Coomans, E. M., Betts, M. J., Capraro, F., Thijssen, E. H., Senkevich, K. A., Bharucha, T., Jafarpour, M., Young, P. N. E., et al. (2020) · Alzheimer s Research & Therapy · doi:10.1186/s13195-020-00601-w · Cited by 81
“For example, positron emission tomography (PET) imaging studies of familial AD cases have suggested that brain Aβ deposition begins up to 20 years before clinical symptoms, while cortical tau deposition arises roughly 6 years before onset [39, 40].”
BackgroundCurrent directions in tau research: Highlights from Tau 2020
Sexton, C. E., Snyder, H. M., Beher, D., Boxer, A. L., Brannelly, P., Brion, J., Buée, L., Cacace, A. M., Chételat, G., Citron, M., et al. (2021) · Alzheimer s & Dementia · doi:10.1002/alz.12452 · Cited by 89
Self-citationFranzmeier, N., Koutsouleris, N., Benzinger, T. L. S., Goate, A., Karch, C. M. M., Fagan, A. M., McDade, E., Duering, M., Dichgans, M., Levin, J., et al. (2020) · Alzheimer s & Dementia · doi:10.1002/alz.12032 · Cited by 76
“43,44 Further, predictive regions included posterior parietal and medial temporal regions for MRI and posterior parietal and lateral frontal regions for FDG-PET, that is, AD-typical predilection sites.”
Sintini, I., Schwarz, C. G., Martin, P. R., Graff‐Radford, J., Machulda, M. M., Senjem, M. L., Reid, R. I., Spychalla, A. J., Drubach, D. A., Lowe, V. J., et al. (2018) · Human Brain Mapping · doi:10.1002/hbm.24473 · Cited by 75
“symptoms of cognitive decline, which are directly caused by neurodegeneration, and tau accumulation happens in between the two (Jack et al., 2013; Quiroz et al., 2018).”
BackgroundInsights into Computational Drug Repurposing for Neurodegenerative Disease
Paranjpe, M. D., Taubes, A. L., & Sirota, M. (2019) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2019.06.003 · Cited by 72
Pan, S., Ding, A., Li, Y., Sun, Y., Zhan, Y., Ye, Z., Song, N., Peng, B., Li, L., Huang, W., et al. (2023) · Chemical Society Reviews · doi:10.1039/d3cs00056g · Cited by 71
d’Abramo, C., D'adamio, L., & Giliberto, L. (2020) · Journal of Personalized Medicine · doi:10.3390/jpm10030116 · Cited by 71
Translational approaches to understanding resilience to Alzheimer’s disease
Neuner, S. M., Telpoukhovskaia, M., Menon, V., O’Connell, K. M. S., Hohman, T. J., & Kaczorowski, C. C. (2022) · Trends in Neurosciences · doi:10.1016/j.tins.2022.02.005 · Cited by 68
“Carriers of the PSEN1 E280A mutation exhibit an average age of dementia onset at 49 years [21,22], so this individual seemed highly resilient to the typically deleterious effects of the mutation [20].”
BackgroundThe complex pathway between amyloid β and cognition: implications for therapy
Jagust, W. J., Teunissen, C. E., & DeCarli, C. S. (2023) · The Lancet Neurology · doi:10.1016/s1474-4422(23)00128-x · Cited by 69
Alzheimer's disease neuroimaging
Whitwell, J. L. (2018) · Current Opinion in Neurology · doi:10.1097/wco.0000000000000570 · Cited by 67
Sanchez, J. S., Hanseeuw, B. J., Lopera, F., Sperling, R. A., Baena, A., Bocanegra, Y., Aguillon, D., Guzmán-Vélez, E., Pardilla-Delgado, E., Ramirez-Gomez, L., et al. (2021) · Alzheimer's Research & Therapy · doi:10.1186/s13195-020-00765-5 · Cited by 58
“EC tau levels were significantly elevated in all impaired carriers and in unimpaired carriers as early as 9 EYO— younger than we previously reported in this cohort [18].”
BackgroundResultSelf-citationFuller, J. T., Cronin-Golomb, A., Gatchel, J. R., Norton, D. J., Guzmán-Vélez, E., Jacobs, H. I. L., Hanseeuw, B., Pardilla-Delgado, E., Artola, A., Baena, A., et al. (2019) · The Journal of Prevention of Alzheimer's Disease · doi:10.14283/jpad.2019.6 · Cited by 57
“Flortaucipir PET imaging of tau in the brain of carriers has shown progressive accumulation of tau in the entorhinal cortex and inferior temporal lobe an average of -6 EYO, and an estimated 10 years after the first evidence of cortical Aβ1-42 (37).”
InfluentialSelf-citationBiphasic cortical macro‐ and microstructural changes in autosomal dominant Alzheimer's disease
Montal, V., Vilaplana, E., Pegueroles, J., Bejanin, A., Alcolea, D. A., Carmona‐Iragui, M., Clarimón, J., Levin, J., Cruchaga, C., Graff‐Radford, N. R., et al. (2020) · Alzheimer s & Dementia · doi:10.1002/alz.12224 · Cited by 54
“Thereafter, when comparing mutation carriers and non–carriers with EYO in the A+T CSF + phase, we did not see differences until the earliest reported alterations in tau PET, which occur 6 years before the symptoms onset 32 .”
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“Early presymptomatic accumulations of Aβ are a signature of fAD [1].”
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“…2004; Bolmont et al. , 2007) and that an enhanced neuropathology occurs following in vivo interaction between A b and tau (Gotz et al. , 2001; Lewis et al. , 2001; Hurtado et al. , 2010; Bennett et al. , 2017; Pontecorvo et al. , 2017; He et al. , 2018; Jacobs et al. , 2018; Quiroz et al. , 2018).”
Neuronal levels and sequence of tau modulate the power of brain rhythms
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Self-citationTesting the amyloid cascade hypothesis: Prevention trials in autosomal dominant Alzheimer disease
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“As a consequence of the late onset of tau pathology in the PSEN1-E280A brain, such may account for the early and widespread distribution of NFTs in the temporal cortex and perhaps their association with aluminum [35, 36].”
BackgroundInfluentialBarthélemy, N. R., Toth, B., Manser, P. T., Sanabria-Bohórquez, S., Teng, E., Keeley, M., Bateman, R. J., Weimer, R. M., & Wildsmith, K. R. (2021) · Journal of Alzheimer s Disease · doi:10.3233/jad-210677 · Cited by 34
“CSF total tau (t-tau) and phosphorylated tau (p-tau) levels, which reflect the circulating pool of soluble tau released by central nervous system cells [17], may enable earlier assessment of tau abnormalities prior to the deposition of NFTs in brain parenchyma [18, 19].”
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“8 In people with Down syndrome, amyloid accumulates about 17 years before symptom onset, 2 and evidence suggests that tau might begin to accumulate before people with Down syndrome become amyloid positive.”
Self-citationMiR-29c-3p May Promote the Progression of Alzheimer’s Disease through BACE1
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“Dementia appears at an average age of 49 years but brain imaging of their brains shows amyloid 15 years before and tau deposition 6 years before the dementia [3].”
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“Notably, deposition of tau was evident many years before clinical symptoms appeared (Quiroz et al., 2018), and the extent of tau lesions in the brain has been shown to be closely related to the severity of dementia in AD patients (Braak and Braak, 1991).”
BackgroundStriatal amyloid is associated with tauopathy and memory decline in familial Alzheimer’s disease
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“FTP-SUVRs were characterized in the entorhinal cortex ROI, since this region was found to be associated with early FTP-SUVR increases over age in our PSEN1-E280A kindred [3].”
InfluentialSelf-citationBiomarkers of neurodegeneration across the Global South
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“Similar to the majority of dominant-negative PSEN1 mutations [15, 16], PSEN1 E280A produces increased Aβ42 deposition [17], hippocampal neuron loss [18], and Aβ/TAU accumulation in young adults [19, 20].”
BackgroundSelf-citationGenetic origin of a large family with a novel PSEN1 mutation (Ile416Thr)
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“11C Pittsburgh compound B PET data were expressed as the distribution volume ratio with cerebellar gray as reference tissue, using a large cortical Region of Interest aggregate that included frontal, lateral temporal, and retrosplenial cortices as described previously [23].”
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“Donors from the Colombian PSEN1-E280A fAD cohort are known to develop tauopathies later in life, as has been demonstrated by positron emission tomography (PET), in living patients [55].”
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“Cognitive assessments were done within 1–3 months of the brain scans for the API ADAD cohort and two months for the COLBOS cohort (Quiroz et al., 2018).”
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“…form or ADAD is caused by mutations in the genes coding for the amyloid precursor protein (APP), the precursor of Aβ peptide, or in the genes coding for presenilin 1 and 2 (PSEN1 and PSEN2), protease enzymes directly regulating the γ-secretase enzyme complex, cleaving the Aβ peptide from APP [5].”
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“These findings essentially reveal that the formation ofA (cid:2) peptideaccumulationinthebrainisalateevent, unlikely to be the primary cause of AD [2, 47, 51], or that its accumulation triggers or precedes NFTs, as previously argued in the amyloid cascade hypothesis [45, 47, 52, 53].”
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Early molecular events of autosomal‐dominant Alzheimer's disease in marmosets with PSEN1 mutations
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“…mutation carriers, with elevated cortical amyloid accumulation 15 years before clinical symptom onset (i.e., mild cognitive impairment) and elevated levels of tau in medial temporal lobe regions (i.e., entorhinal cortex and inferior temporal lobe) 6 years before clinical symptom onset [17, 20, 21].”
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“…0.05, p< 0.05, ^^p< 0.01. determine the pharmacokinetic parameters of the drug in vivo, but also provide the drug concentration data for pharmacodynamics and toxicology evaluations, and provide the basis for optimising the dosage regimen in clinical research (Quiroz et al. 2018; Wei et al. 2019).”
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An Overview of Experimental and Clinical Spinal Cord Findings in Alzheimer’s Disease
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“These pathological features not only occur in brain tissue but also involve the spinal cord (Figure 2) [58,59].”
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“, [13,14]), there are no efficient therapies to date.”
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Self-citationAccelerating Alzheimer’s disease drug discovery and development: what’s the way forward?
Imbimbo, B. P., Ippati, S., Watling, M. I. L., & Balducci, C. (2021) · Expert Opinion on Drug Discovery · doi:10.1080/17460441.2021.1887132 · Cited by 18
“and biomarker features that are similar to those of SAD and usually occurs at a younger age [2], but can also emerge at later ages [3].”
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“As the majority of dominant-negative PSEN1 mutations [11], PSEN1 E280A produces increased A 42 deposition [12], hippocampal neuron loss [13], and A /tau accumulation in young adults [14, 15].”
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Self-citationIn vivo Brainstem Imaging in Alzheimer’s Disease: Potential for Biomarker Development
Braun, D. J., & Eldik, L. J. V. (2018) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2018.00266 · Cited by 16
“It can also measure functional parameters relevant to AD pathology such as tissue perfusion (Wolk and Detre, 2012) or blood brain barrier (BBB) integrity (Raja et al., 2017); however, these methods have yet to be validated for biomarker use.”
Background
Metadata
- Authors
- Quiroz, Y. T., Sperling, R. A., Norton, D. J., Baena, A., Arboleda-Velasquez, J. F., Cosio, D., Schultz, A., Lapoint, M., Guzman-Velez, E., Miller, J. B., Kim, L. A., Chen, K., Tariot, P. N., Lopera, F., Reiman, E. M., & Johnson, K. A.
- Affiliations
- Harvard University (US)
- Brigham and Women's Hospital (US)
- Universidad de Antioquia (CO)
- Schepens Eye Research Institute of Massachusetts Eye and Ear, Harvard Medical School, Boston
- Massachusetts General Hospital, Harvard Medical School, Boston
- Massachusetts Eye and Ear Infirmary (US)
- Banner Alzheimer’s Institute (US)
- Corresponding author
- Quiroz, Yakeel T.
- ORCID
- Venue
- JAMA Neurology
- Publisher
- American Medical Association (AMA)
- Published
- 2018-05-01
- Volume
- 75
- Issue
- 5
- Pages
- 548
- ISSN
- 2168-6149 (ISSN-L)
- PMC
- PMC5885174
- OpenAlex
- W2793496929
- Cited by
- 186
- References
- 38
- Citations by year
- 2026: 7 · 2025: 17 · 2024: 18 · 2023: 20 · 2022: 19 · 2021: 30 · 2020: 34 · 2019: 29 · 2018: 12
- FWCI
- 20.51
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- JAMA Neurology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Institutional Repository University of Antioquia (University of Antioquia) (publishedVersion, cc-by-nc-nd)
- Repositorio Digital - Academia Colombiana de Ciencias Exactas, Fisicas y Naturales (submittedVersion, other-oa)
- Funders
- National Institutes of Health (DP5OD019833)
- National Institute on Aging (K24AG035007, R01AG055444, R01AG046396, R01AG027435, P30AG019610, P50AG005134, P01AG036694, P30AG062421)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Clinical Neurology › Amyotrophic Lateral Sclerosis Research
- Keywords
- autosomal dominant Alzheimer's disease, PSEN1 E280A mutation, presenilin 1, amyloid accumulation, tau accumulation, Pittsburgh compound B PET, flortaucipir PET, preclinical Alzheimer's disease, young adults, medial temporal lobe, neocortex, mild cognitive impairment
- MeSH terms
- Mental Status and Dementia Tests, Adult, Age Factors, Alzheimer Disease, Amyloid, Aniline Compounds, Brain, Carbolines, Cognition Disorders, Colombia, Cross-Sectional Studies, Female, Humans, Magnetic Resonance Imaging, Male, Middle Aged, Mutation, Neuropsychological Tests, Thiazoles, tau Proteins, Positron-Emission Tomography, Presenilin-1
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