Earliest accumulation of β-amyloid occurs within the default-mode network and concurrently affects brain connectivity

May combine two claims.

Early Aβ accumulation predominantly overlapped with the DMN (Jaccard coefficient 0.14), but also with the frontoparietal network (JC 0.07).

“Figure 2 shows that early Aβ accumulation predominantly overlapped with the DMN (Jaccard coefficient, JC, 0.14), but also with the frontoparietal network (JC 0.07).”

• cites [15] Yeo, B. T. et al. The organization of the human cerebral cortex estimated by intrinsic functional connectivity. J. Neurophysiol. 106, 1125–1165 (2011). sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Adjusting for APOE genotype did not change the early Aβ pattern; the same regions as in Table 2 were found.

“Finally, we adjusted for APOE genotype to examine if different early Aβ patterns were observed depending on whether one carried an APOE ε4 allele, but the same regions as in Table 2 were found (details shown in Supplementary Table 1).”

May combine two claims.

The earliest Aβ accumulation is associated with hypoconnectivity within the DMN and between the DMN and the frontoparietal network, but not with brain atrophy or glucose hypometabolism.

“The earliest Aβ accumulation is further associated with hypoconnectivity within the DMN and between the DMN and the frontoparietal network, but not with brain atrophy or glucose hypometabolism.”

May combine two claims.

No significant increase was seen in these regions among non-converters; mean rates were +0.3% (95% CI −0.24 to +0.90%) and +0.3% (95% CI −0.7 to +1.2%).

“No significant increase was seen in these regions among the non-converters and the corresponding mean rates were +0.3% (95% CI −0.24 to +0.90%) and +0.3% (95% CI −0.7 to +1.2%).”

May combine two claims.

The significant hypoconnectivity component in the CSF+/PET− group predominantly consisted of intra-DMN links, but also links between the DMN and the frontoparietal network.

“The component predominantly consisted of intra-DMN links, but also links between the DMN and the frontoparietal network (Fig. 6a).”

• Also stated in: § Discussion · plain

  “When we correlated whole-brain functional connectivity and CSF Aβ42 levels in the early stage Aβ accumulators (CSF+/PET−), we found a decreased connectivity in intra-DMN connections and between DMN and the frontoparietal network as CSF Aβ42 decreased (Fig. 6a).”

May combine two claims.

In BioFINDER, the highest significance for early Aβ regions was around the posterior regions of the cingulate cortex and the orbitofrontal cortex, similar to ADNI.

“The highest significance was seen around the posterior regions of the cingulate cortex and the orbitofrontal cortex similar to the results in ADNI (Fig. 1a, b).”

May combine two claims.

In BioFINDER, the significant network component associated with CSF Aβ42 was qualitatively similar for the CSF+/PET− and CSF-low/PET− groups and consisted mostly of intra- and inter-DMN connections.

“The connectograms show that the significant network component associated with CSF Aβ42 was qualitatively similar for the CSF+/PET− (a) and CSF-low/PET− (b) groups and consisted mostly of intra- and inter-DM connections.”

May combine two claims.

Although the core DMN was the most prominent network with anatomical overlap with early Aβ regions, involvement of other networks was also evident, especially the frontoparietal network.

“Although the core DMN was the most prominent network that we found that had anatomical overlap with the early Aβ regions, we want to point out that involvement of other networks was also evident in the early Aβ accumulation, especially the frontoparietal network (Fig. 2).”

May combine two claims.

Voxelwise comparisons between early and late accumulators highlighted similar late regions, with greatest significant difference in the sensorimotor cortex and parts of the occipital lobe.

“The corresponding voxelwise comparisons between early and late accumulators are shown in Fig. 3 and highlight similar late regions (greatest significant difference in the sensorimotor cortex and parts of the occipital lobe).”

May combine two claims.

The summed connectivity on the significant correlation component changed most drastically when CSF Aβ42 levels were closer to the cut-off (400-516 ng/L for the INNOTEST ELISA) and seemed to reach a floor effect as Aβ42 reached levels of around 350 ng/L.

“The summed connectivity on the significant correlation component changed most drastically when CSF Aβ42 levels were closer to the cut-off (400–516 ng/L for the INNOTEST ELISA) and seemed to reach a floor effect as Aβ42 reached levels of around 350 ng/L.”

May combine two claims.

The most prominent early Aβ-accumulating regions were the precuneus, posterior cingulate cortex, and the medial orbitofrontal cortex, possibly with an overlap to the anterior cingulate.

“The most prominent early Aβ-accumulating regions were the precuneus, posterior cingulate cortex, and the medial orbitofrontal cortex, possibly with an overlap to the anterior cingulate.”

Probably not a substantial claim: may not pass S3 (load-bearing).

The mean difference between baseline CSF sampling and the florbetapir PET scan was 9.6 days (range 0-110 days).

“The mean difference between baseline CSF sampling and the florbetapir PET scan was 9.6 days (ranging from 0 to 110 days).”

Classified as probably not a substantial claim.

In BioFINDER, mixture modeling determined the cut-offs for abnormal CSF Aβ42 (<517 ng/L) and abnormal Aβ PET (>0.759 SUVR).

“Mixture modeling was performed in the sample to determine the cut-offs for abnormal CSF Aβ42 (<517 ng/L) and abnormal Aβ PET (>0.759 SUVR).”

Classified as probably not a substantial claim.

To account for atrophy as a confounding factor, all significant models were adjusted for the annual change in cortical thickness of each ROI.

“To account for atrophy as a confounding factor, we also adjusted all significant models for the annual change in cortical thickness of each ROI.”

Classified as probably not a substantial claim.

Accumulation of aggregated Aβ in the brain is believed to be the first pathological mechanism of Alzheimer's disease.

“Accumulation of aggregated amyloid-β (Aβ) in the brain is believed to be the first pathological mechanism of Alzheimer’s disease (AD)1.”

• cites [1] Jack, C. R. Jr. et al. Tracking pathophysiological processes in Alzheimer’s disease: an updated hypothetical model of dynamic biomarkers. Lancet Neurol. 12, 207–216, (2013). sourceNot checked yet

  Not checked in the free run.

Classified as probably not a substantial claim.

In AD mutation-carriers, most cortical areas except the sensorimotor cortex show Aβ accumulation as early as 15 years before expected symptom onset.

“when analyzing the earliest data from AD mutation-carriers, most cortical areas except for the sensorimotor cortex showed Aβ accumulation as early as 15 years before the expected onset of symptoms6.”

• cites [6] Benzinger, T. L. et al. Regional variability of imaging biomarkers in autosomal dominant Alzheimer’s disease. Proc. Natl Acad. Sci. USA 110, E4502–4509 (2013). sourceNot checked yet

  Not checked in the free run.

Classified as probably not a substantial claim.

All results were corrected for multiple comparisons and adjusted for gender, age, and time between PET scans.

“All results were corrected for multiple comparisons and adjusted for gender, age, and time between PET scans.”

Classified as probably not a substantial claim.

Cerebral deposition of Aβ fibrils can occur for decades before an individual with AD reaches the dementia stage.

“Previous studies have shown that cerebral deposition of Aβ fibrils can occur for decades before an individual with AD reaches the dementia stage2.”

• cites [2] Sperling, R., Mormino, E. & Johnson, K. The evolution of preclinical Alzheimer’s disease: implications for prevention trials. Neuron 84, 608–622 (2014). sourceNot checked yet

  Not checked in the free run.

May combine two claims.

In a prior longitudinal cohort of more than 400 non-demented individuals, those with abnormally low CSF Aβ42 but normal Aβ PET (CSF+/PET−) accumulated Aβ fibrils longitudinally at a similar rate as CSF+/PET+ and four times higher than CSF−/PET−.

“those with abnormally low CSF levels of Aβ42, but with still normal Aβ levels detected by PET (CSF+/PET−), accumulated Aβ fibrils longitudinally at a similar rate as those who had both abnormal CSF levels of Aβ42 and abnormal levels of Aβ detected by PET (CSF+/PET+) and four times higher than those with normal biomarker results on both parameters (CSF−/PET−)12.”

• cites [12] Palmqvist, S., Mattsson, N., Hansson, O. & Alzheimer’s Disease Neuroimaging Initiative Cerebrospinal fluid analysis detects cerebral amyloid-beta accumulation earlier than positron emission tomography. Brain 139, 1226–1236 (2016). sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing).

The widespread cerebral distribution of Aβ in later AD stages is well-established.

“The widespread cerebral distribution of Aβ in later AD stages is well-established3, 4”

• cites [3] Suva, D. et al. Primary motor cortex involvement in Alzheimer disease. J Neuropathol. Exp. Neurol. 58, 1125–1134 (1999). sourceNot checked yet

  Not checked in the free run.

• cites [4] Villain, N. et al. Regional dynamics of amyloid-beta deposition in healthy elderly, mild cognitive impairment and Alzheimer’s disease: a voxelwise PiB-PET longitudinal study. Brain 135, 2126–2139 (2012). sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing).

The first neuropathological phase of Aβ in AD is characterized by Aβ deposits throughout the frontal, parietal, temporal, and occipital neocortex.

“it has been shown that the first phase is characterized by Aβ deposits throughout the frontal, parietal, temporal, and occipital neocortex5.”

• cites [5] Thal, D. R., Rub, U., Orantes, M. & Braak, H. Phases of A beta-deposition in the human brain and its relevance for the development of AD. Neurology 58, 1791–1800 (2002). sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Aβ fibrils start to accumulate predominantly within certain parts of the DMN in preclinical AD and already then affect brain connectivity.

“Our results suggest that Aβ fibrils start to accumulate predominantly within certain parts of the DMN in preclinical AD and already then affect brain connectivity.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

The early Aβ regions are derived from group analyses, which show where Aβ is prone to start accumulating but do not exclude the possibility that accumulation might start in other regions in some individuals.

“It should be noted that the early Aβ regions are derived from group analyses, which show where Aβ is prone to start accumulating but they do not exclude the possibility that the accumulation might start in other regions in some individuals.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

In BioFINDER, the voxelwise comparison in Fig. 5 used a two-sample t-test with significance threshold p < 0.001 and was adjusted for age and gender.

“Voxelwise two-sample t-test was used. The significance threshold was set at p < 0.001 and the comparison was adjusted for age and gender.”

Probably not a substantial claim: may not pass S3 (load-bearing).

Another cross-sectional study found an initial Aβ region involving the areas in Fig. 1a, but also affecting middle and inferior temporal regions, and superior and middle frontal regions.

“By assuming that earlier regions would show increased Aβ PET signal in a greater number of subjects, they found an initial Aβ region involving the areas in Fig. 1a, but also affecting middle and inferior temporal regions, and superior and middle frontal regions.”

• cites [18] Cho, H. et al. In vivo cortical spreading pattern of tau and amyloid in the Alzheimer disease spectrum. Ann. Neurol. 80, 247–258 (2016). sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

The BioFINDER analysis included cross-sectional data and fewer subjects than ADNI, resulting in less statistical power.

“Note that the BioFINDER analysis included cross-sectional data and fewer subjects compared to ADNI, which results in less statistical power.”

May combine two claims.

Previous longitudinal studies have either failed to detect an early increase in regional Aβ deposition or identified a rather large early stage Aβ region including the posterior temporal, inferior parietal, posterior cingulate, precuneus, and occipital areas.

“Previous longitudinal studies have either failed to detect an early increase in regional Aβ deposition16 or identified a rather large early stage Aβ region including the posterior temporal, inferior parietal, posterior cingulate, precuneus, and occipital areas4.”

• cites [16] Villemagne, V. L. et al. Longitudinal assessment of Abeta and cognition in aging and Alzheimer disease. Ann. Neurol. 69, 181–192 (2011). sourceNot checked yet

  Not checked in the free run.

• cites [4] Villain, N. et al. Regional dynamics of amyloid-beta deposition in healthy elderly, mild cognitive impairment and Alzheimer’s disease: a voxelwise PiB-PET longitudinal study. Brain 135, 2126–2139 (2012). sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing).

The binding affinity of current PET ligands could explain some of the differences with neuropathological studies that use silver technique or anti-Aβ antibodies.

“The binding affinity of current PET ligands could explain some of the differences with neuropathological studies that either use silver technique19, which stain not only Aβ but also tau, or anti-Aβ antibodies5 that bind to specific Aβ epitopes and stain different Aβ forms.”

• cites [19] Braak, H. & Braak, E. Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol. 82, 239–259 (1991). sourceNot checked yet

  Not checked in the free run.

• cites [5] Thal, D. R., Rub, U., Orantes, M. & Braak, H. Phases of A beta-deposition in the human brain and its relevance for the development of AD. Neurology 58, 1791–1800 (2002). sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

The voxelwise analyses in Fig. 4 were adjusted for age and gender, and the VBM analysis was additionally adjusted for total intracranial volume.

“all results in a–d were adjusted for age and gender. The VBM analysis was also adjusted for total intracranial volume.”

Probably not a substantial claim: may not pass S3 (load-bearing).

The DMN has a core network located in the posterior cingulate cortex, precuneus, and medial prefrontal cortex.

“The DMN has a core network located in the posterior cingulate cortex, precuneus, and medial prefrontal cortex20.”

• cites [20] Andrews-Hanna, J. R., Smallwood, J. & Spreng, R. N. The default network and self-generated thought: component processes, dynamic control, and clinical relevance. Ann. N. Y. Acad. Sci. 1316, 29–52 (2014). sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing).

An alternative explanation is that Aβ accumulation is caused by high metabolic demand and metabolic stress in these neurons and not neuronal activation per se.

“An alternative explanation is that Aβ accumulation is caused by the high metabolic demand and metabolic stress in these neurons (high energy consumption and frequent fluctuations in activation and deactivation) and not the neuronal activation per se30.”

• cites [30] Lehmann, M. et al. Intrinsic connectivity networks in healthy subjects explain clinical variability in Alzheimer’s disease. Proc. Natl Acad. Sci. USA 110, 11606–11611 (2013). sourceNot checked yet

  Not checked in the free run.

May combine two claims.

In a recent study, CSF+/PET− subjects accumulated Aβ at a similar rate as CSF+/PET+ subjects and about four times higher than CSF−/PET− subjects.

“In a recent study, we also showed that CSF+/PET− subjects accumulated Aβ at a similar rate as CSF+/PET+ subjects and about four times higher than CSF−/PET− subjects12.”

• cites [12] Palmqvist, S., Mattsson, N., Hansson, O. & Alzheimer’s Disease Neuroimaging Initiative Cerebrospinal fluid analysis detects cerebral amyloid-beta accumulation earlier than positron emission tomography. Brain 139, 1226–1236 (2016). sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing).

A certain overlap between the DMN and the distribution of Aβ fibrils in AD has been noted in previous publications.

“A certain overlap between the DMN and the distribution of Aβ fibrils in AD has also been noted in previous publications23–26.”

• cites [23] Buckner, R. L. et al. Molecular, structural, and functional characterization of Alzheimer’s disease: evidence for a relationship between default activity, amyloid, and memory. J. Neurosci. 25, 7709–7717 (2005). sourceNot checked yet

  Not checked in the free run.

• cites [24] Sperling, R. A. et al. Amyloid deposition is associated with impaired default network function in older persons without dementia. Neuron 63, 178–188 (2009). sourceNot checked yet

  Not checked in the free run.

• cites [25] Myers, N. et al. Within-patient correspondence of amyloid-beta and intrinsic network connectivity in Alzheimer’s disease. Brain 137, 2052–2064 (2014). sourceNot checked yet

  Not checked in the free run.

• cites [26] Sepulcre, J., Sabuncu, M. R., Becker, A., Sperling, R. & Johnson, K. A. In vivo characterization of the early states of the amyloid-beta network. Brain 136, 2239–2252 (2013). sourceNot checked yet

  Not checked in the free run.

May combine two claims.

These adjustments show that the results were not confounded by differences in atrophy between the groups or differences between healthy controls and MCI subjects.

“These adjustments show that the results were not confounded by differences in atrophy between the groups or differences between healthy controls and MCI subjects (discussed further in the Methods section).”

May combine two claims.

The correlation between disruption of functional connectivity and Aβ pathology has recently been described in AD, but this study is the first to show that this association is present already at the very earliest preclinical stages of AD when Aβ fibrils are just starting to accumulate.

“This correlation between the disruption of functional connectivity and Aβ pathology has recently been described in AD32, 33, but to our knowledge the present study is the first to show that this association is present already at the very earliest preclinical stages of AD when Aβ fibrils are just starting to accumulate.”

• cites [32] Elman, J. A. et al. Effects of beta-amyloid on resting state functional connectivity within and between networks reflect known patterns of regional vulnerability. Cereb. Cortex 26, 695–707 (2016).Not checked yet

  Not checked in the free run.

• cites [33] Koch, K. et al. Disrupted intrinsic networks link amyloid-beta pathology and impaired cognition in prodromal Alzheimer’s disease. Cereb. Cortex 25, 4678–4688 (2015). sourceNot checked yet

  Not checked in the free run.

Classified as probably not a substantial claim.

Age, gender, and APOE ε4 status were controlled for by partial correlation in the BioFINDER connectivity analyses.

“Age, gender, and APOE ε4 status was controlled for by partial correlation.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

One explanation for Aβ aggregation within the DMN is that deposition of Aβ fibrils could be caused by high neuronal activity within the DMN, supported by animal studies showing Aβ secretion and deposition is enhanced by neuronal activity.

“One explanation is that the deposition of Aβ fibrils could be caused by the high neuronal activity within the DMN, which is supported by animal studies showing that Aβ secretion and deposition is enhanced by neuronal activity27–29.”

• cites [27] Cirrito, J. R. et al. Endocytosis is required for synaptic activity-dependent release of amyloid-beta in vivo. Neuron 58, 42–51 (2008). sourceNot checked yet

  Not checked in the free run.

• cites [28] Kamenetz, F. et al. APP processing and synaptic function. Neuron 37, 925–937 (2003). sourceNot checked yet

  Not checked in the free run.

• cites [29] Li, X. et al. Neuronal activity and secreted amyloid beta lead to altered amyloid beta precursor protein and presenilin 1 interactions. Neurobiol. Dis. 50, 127–134 (2013). sourceNot checked yet

  Not checked in the free run.

May combine two claims.

We cannot pinpoint the exact Aβ forms within the early Aβ regions, nor can we say if Aβ aggregates not detected by PET are present in other areas of the brain at this early stage.

“We can therefore not pinpoint the exact Aβ forms within the early Aβ regions, neither can we say if Aβ aggregates not detected by PET are present in other areas of the brain at this early stage.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

In neuropathological studies, one study reported that the presumably first Aβ phase had Aβ deposits throughout the neocortex, while Braak & Braak showed an early pattern of Aβ deposits in the basal parts of the medial and anterior regions of the prefrontal cortex, and the basal anterior temporal lobe.

“One study reported that the presumably first Aβ phase had Aβ deposits throughout the neocortex5, while a prior publication by Braak & Braak19 showed an early pattern of Aβ deposits in the basal parts of the medial and anterior regions of the prefrontal cortex, and the basal anterior temporal lobe.”

• cites [5] Thal, D. R., Rub, U., Orantes, M. & Braak, H. Phases of A beta-deposition in the human brain and its relevance for the development of AD. Neurology 58, 1791–1800 (2002). sourceNot checked yet

  Not checked in the free run.

• cites Braak & Braak19Not checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

The differences between neuropathological studies are probably partly explained by different staining methods and their affinity to different Aβ forms.

“The differences are probably partly explained by the different staining methods and their affinity to different Aβ forms”

Classified as probably not a substantial claim. May combine two claims.

Mixture modeling provides an unbiased threshold for abnormality and is a well-established method for defining Aβ PET cut-offs.

“Mixture modeling statistics provide an unbiased threshold for abnormality (i.e., the diagnosis or status is not used in analysis) and it is a well-established method for defining Aβ PET cut-offs12, 17, 60, 61.”

• cites [12] Palmqvist, S., Mattsson, N., Hansson, O. & Alzheimer’s Disease Neuroimaging Initiative Cerebrospinal fluid analysis detects cerebral amyloid-beta accumulation earlier than positron emission tomography. Brain 139, 1226–1236 (2016). sourceNot checked yet

  Not checked in the free run.

• cites [17] Villeneuve, S. et al. Existing Pittsburgh Compound-B positron emission tomography thresholds are too high: statistical and pathological evaluation. Brain 138, 2020–2033 (2015). sourceNot checked yet

  Not checked in the free run.

• cites [60] Palmqvist, S. et al. Accuracy of brain amyloid detection in clinical practice using cerebrospinal fluid beta-amyloid 42: a cross-validation study against amyloid positron emission tomography. JAMA Neurol. 71, 1282–1289 (2014). sourceNot checked yet

  Not checked in the free run.

• cites [61] Toledo, J. B. et al. Nonlinear association between cerebrospinal fluid and florbetapir F-18 beta-amyloid measures across the spectrum of Alzheimer disease. JAMA Neurol. 72, 571–581 (2015). sourceNot checked yet

  Not checked in the free run.

Classified as probably not a substantial claim. May combine two claims.

All results were adjusted for gender and age and, in the longitudinal analyses, time between Aβ PET examinations.

“All results were adjusted for gender and age and, in the longitudinal analyses, time between Aβ PET examinations.”

Classified as probably not a substantial claim. May combine two claims.

Partial volume error correction was performed for florbetapir SUVRs with the geometric transfer matrix method using Freesurfer segmented regions, and all florbetapir results shown in tables and figures are from PVE corrected data.

“Partial volume error (PVE) correction was performed for florbetapir SUVRs with the geometric transfer matrix (GTM) method51 using Freesurfer segmented regions52 (all florbetapir results shown in the tables and figures are from PVE corrected data).”

• cites [51] Rousset, O. G., Ma, Y. & Evans, A. C. Correction for partial volume effects in PET: principle and validation. J. Nucl. Med. 39, 904–911 (1998).Not checked yet

  Not checked in the free run.

• cites [52] Han, X. & Fischl, B. Atlas renormalization for improved brain MR image segmentation across scanner platforms. IEEE Trans. Med. Imaging 26, 479–486 (2007). sourceNot checked yet

  Not checked in the free run.

Classified as probably not a substantial claim.

Outliers in whole-brain voxel-to-voxel BOLD-signal correlations were removed to control for motion-induced global signal confound.

“As an extra precautionary step, the voxel-to-voxel BOLD-signal correlations across the whole brain (including GM, WM, and CSF) was calculated and summed. Outliers in this measure likely originate in a motion-induced global signal confound capable of eluding conventional motion estimation70 and were removed.”

• cites [70] He, H. & Liu, T. T. A geometric view of global signal confounds in resting-state functional MRI. NeuroImage 59, 2339–2348 (2012). sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

The variance of the SUVRs were similar in each group.

“The variance of the SUVRs were similar in each group.”

Probably not a substantial claim: may not pass S3 (load-bearing).

Original p values are presented for ROI-based analyses but are only reported as significant if they are significant after FDR correction.

“Original p values are presented for the ROI-based analyses but are only reported as significant if they are significant after the FDR correction.”

Classified as probably not a substantial claim. May combine two claims.

The resulting t-maps were thresholded to present results with p < 0.001 height, uncorrected for family-wise error, and k > 100 voxels cluster extent.

“The resulting t-maps were thresholded to present results with a p < 0.001 height, uncorrected for family-wise error, and a k > 100 voxels cluster extent.”

Classified as probably not a substantial claim.

Age, gender and APOE ε4 status were controlled for by partial correlation in the network component analysis.

“Age, gender and APOE ε4 status was controlled for by partial correlation.”

Classified as probably not a substantial claim.

To control for multiple testing in ROI-based analyses, the Benjamini-Hochberg procedure with a conservative false discovery rate (FDR) of 0.05 was used.

“To control for multiple testing in the ROI-based analyses we used the Benjamini–Hochberg procedure with a conservative false discovery rate (FDR) of 0.05 (not to be confused with a p value of 0.05)74.”

• cites [74] Benjamini, Y. & Hochberg, J. Controlling the false discovery rate: a practical and powerful approach to multiple testing. J. R. Stat. Soc. 57, 289–300 (1995). sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing).

The models were adjusted for clinical status (MCI/healthy control) in subanalyses.

“To account for this inclusion the models were adjusted for clinical status (MCI/healthy control) in subanalyses.”

Classified as probably not a substantial claim.

The component size was compared to a permutation-generated null distribution, controlling for family-wise error rate at α = 0.05.

“The component size was compared to a permutation-generated null distribution of sizes, thus controlling for the family-wise error rate in the weak sense at α = 0.05”

Probably not a substantial claim: may not pass S3 (load-bearing).

Additional analyses adjusted for changes in cortical thickness over 2 years in each ROI and clinical status (healthy control/MCI).

“We also performed additional analyses adjusting for changes in cortical thickness over 2 years in each ROI and clinical status (healthy control/MCI) in addition to the above covariates.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

The study subjects gave written informed consent and the study was approved by each participating site's Institutional Review Board.

“Study subjects gave written informed consent and the study was approved by each participating site’s Institutional Review Board.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Voxelwise two-sample t-test and multiple regressions used age, gender, and ICV as covariates.

“We employed voxelwise two-sample t-test and multiple regressions using age, gender, and ICV (for analyses involving VBM data) as covariates.”

Classified as probably not a substantial claim.

Abnormal CSF Aβ42 values were defined using the previously established cut-off of <192 ng/L.

“Abnormal CSF Aβ42 values were defined using the previously established cut-off of <192 ng/L57–59.”

• cites [57] Shaw, L. M. et al. Cerebrospinal fluid biomarker signature in Alzheimer’s disease neuroimaging initiative subjects. Ann. Neurol. 65, 403–413 (2009). sourceNot checked yet

  Not checked in the free run.

• cites [58] De Meyer, G. et al. Diagnosis-independent Alzheimer disease biomarker signature in cognitively normal elderly people. Arch. Neurol. 67, 949–956 (2010). sourceNot checked yet

  Not checked in the free run.

• cites [59] Weigand, S. D. et al. Transforming cerebrospinal fluid Abeta42 measures into calculated Pittsburgh Compound B units of brain Abeta amyloid. Alzheimers Dement. 7, 133–141 (2011). sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing).

A strength of the methodology is that similar early Aβ regions were detected in two different cohorts using two different types of PET ligands; 18F-florbetapir and 18F-flutemetamol.

“Nonetheless, a strength of the methodology is that we could detect similar early Aβ regions in two different cohorts using two different types of PET ligands; 18F-florbetapir (a stilbene compound) and 18F-flutemetamol (an 18F-labeled analog of 11C-Pittsburgh Compound B (PiB) derived from thioflavin T)40.”

• cites [40] Vandenberghe, R., Adamczuk, K., Dupont, P., Laere, K. V. & Chetelat, G. Amyloid PET in clinical practice: its place in the multidimensional space of Alzheimer’s disease. Neuroimage Clin. 2, 497–511 (2013). sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Our data indicated that Aβ starts accumulating before overt metabolic changes or atrophy, and that hypoconnectivity within the early Aβ-accumulating regions has already occurred when Aβ fibrils just starts to accumulate.

“Our data indicated that Aβ starts accumulating before overt metabolic changes or atrophy, and that hypoconnectivity within the early Aβ-accumulating regions has already occurred when Aβ fibrils just starts to accumulate.”

Classified as probably not a substantial claim.

Only Aβ PET negative subjects were used in the connectivity analysis.

“Only Aβ PET negative subjects were used in the connectivity analysis.”

Probably not a substantial claim: may not pass S3 (load-bearing).

Because of the limited number of subjects in the subanalysis of 'CSF converters' (n = 11), non-parametric statistics were primarily used for this subgroup.

“Because of the limited number of subjects in the subanalysis of “CSF converters” (n = 11), we primarily used non-parametric statistics for this subgroup (the Mann–Whitney U and Wilcoxon signed rank test).”

Classified as probably not a substantial claim.

For the resting-state correlation analysis, a component was assigned a p value as a whole based on component size relative a permutation-generated null distribution, correcting for family-wise error in the weak sense.

“For the resting-state correlation analysis, a component (consisting a connected set of links correlating with CSF biomarker levels above a p = 0.001 threshold) was assigned a p value as a whole based on the component size relative a permutation-generated null distribution, thus correcting for family-wise cerror in the weak sense”

Probably not a substantial claim: may not pass S3 (load-bearing).

For florbetapir, the reference region consisted of the whole cerebellum, the pons/brainstem region, and eroded cortical white matter as this composite region has produced more reliable results in longitudinal analyses.

“For florbetapir, the reference region consisted of the whole cerebellum, the pons/brainstem region, and eroded cortical white matter as this composite region has produced more reliable results in longitudinal analyses49.”

• cites [49] Landau, S. M. et al. Measurement of longitudinal beta-amyloid change with 18F-florbetapir PET and standardized uptake value ratios. J. Nucl. Med. 56, 567–574 (2015). sourceNot checked yet

  Not checked in the free run.

Classified as probably not a substantial claim.

Subjects with a mean/maximum frame-wise displacement exceeding 0.6/3.0 mm were excluded.

“Subjects with a mean/maximum frame-wise displacement29, 69 exceeding 0.6/3.0 mm were excluded.”

• cites [29] Li, X. et al. Neuronal activity and secreted amyloid beta lead to altered amyloid beta precursor protein and presenilin 1 interactions. Neurobiol. Dis. 50, 127–134 (2013). sourceNot checked yet

  Not checked in the free run.

• cites [69] Friston, K. J., Williams, S., Howard, R., Frackowiak, R. S. & Turner, R. Movement-related effects in fMRI time-series. Magn. Reson. Med. 35, 346–355 (1996). sourceNot checked yet

  Not checked in the free run.