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Cellular, synaptic, and biochemical features of resilient cognition in Alzheimer’s disease
Open accessAbstract
While neuritic plaques and neurofibrillary tangles in older adults are correlated with cognitive impairment and severity of dementia, it has long been recognized that the relationship is imperfect as some people exhibit normal cognition despite high levels of AD pathology. We compared the cellular, synaptic and biochemical composition of midfrontal cortices in female subjects from the Religious Orders Study who were stratified into three subgroups: 1) pathological AD with normal cognition (“AD-Resilient”), 2) pathological AD with AD-typical dementia (“AD-Dementia)” and 3) pathologically normal with normal cognition (“Normal Comparison”). The AD-Resilient group exhibited preserved densities of synaptophysin-labeled presynaptic terminals and synaptopodin-labeled dendritic spines compared to the AD-Dementia group, and increased densities of GFAP astrocytes compared to both the AD-Dementia and Normal Comparison group. Further, in a discovery antibody microarray protein analysis we identified a number of candidate protein abnormalities that were associated with diagnostic group. These data characterize cellular and synaptic features and identify novel biochemical targets that may be associated with resilient cognitive brain aging in the setting of pathological AD.
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“GFAP astrocyte densities differed among groups with post-hoc tests demonstrating increased density in the AD-Resilient group compared to both the AD-Dementia and NC groups.”
- Also stated in: § Abstract · plain
“increased densities of GFAP astrocytes compared to both the AD-Dementia and Normal Comparison group.”
§ Cellular, synaptic and biochemical features of resilient cognition in Alzheimer’s disease > 3. Results > 3.2 Cellular and Synaptic Features
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“negatively correlated with synaptopodin spines (ρ=−0.45, p=0.01)”
§ Cellular, synaptic and biochemical features of resilient cognition in Alzheimer’s disease > 3. Results > 3.3 Relation of Neuropathologic Indices to Cellular and Synaptic Features
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“Using one-way ANOVA, we then identified 57 proteins that distinguished the groups (Table 3), and visualized the proteins in a heat map (Figure 2b).”
§ Cellular, synaptic and biochemical features of resilient cognition in Alzheimer’s disease > 3. Results > 3.4 Antibody Microarray Protein Expression Profiling
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“In accord with their expected relationship, pre- and postsynaptic measures were highly correlated (Spearman’s r = 0.58, p = 0.0009).”
§ Cellular, synaptic and biochemical features of resilient cognition in Alzheimer’s disease > 3. Results > 3.2 Cellular and Synaptic Features
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“negatively correlated with synaptopodin spines (ρ=−0.44, p=0.02)”
§ Cellular, synaptic and biochemical features of resilient cognition in Alzheimer’s disease > 3. Results > 3.3 Relation of Neuropathologic Indices to Cellular and Synaptic Features
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“With PCA we observed tight clustering of NC cases while AD-Dementia and AD-Resilient cases were more dispersed (Figure 2a).”
§ Cellular, synaptic and biochemical features of resilient cognition in Alzheimer’s disease > 3. Results > 3.4 Antibody Microarray Protein Expression Profiling
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“The AD-Dementia group exhibited lower measures compared to both AD-Resilient and NC groups.”
- Also stated in: § Abstract · plain
“The AD-Resilient group exhibited preserved densities of synaptophysin-labeled presynaptic terminals and synaptopodin-labeled dendritic spines compared to the AD-Dementia group”
§ Cellular, synaptic and biochemical features of resilient cognition in Alzheimer’s disease > 3. Results > 3.2 Cellular and Synaptic Features
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“Post-hoc comparisons identified 16 proteins that significantly differentiated AD-Resilient and AD-Dementia groups (Table 3).”
§ Cellular, synaptic and biochemical features of resilient cognition in Alzheimer’s disease > 3. Results > 3.4 Antibody Microarray Protein Expression Profiling
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“They negatively correlated with NeuN neurons (ρ=−0.39, p=0.03)”
§ Cellular, synaptic and biochemical features of resilient cognition in Alzheimer’s disease > 3. Results > 3.3 Relation of Neuropathologic Indices to Cellular and Synaptic Features
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“positively correlated with GFAP astrocytes (ρ=0.49, p=0.008)”
§ Cellular, synaptic and biochemical features of resilient cognition in Alzheimer’s disease > 3. Results > 3.3 Relation of Neuropathologic Indices to Cellular and Synaptic Features
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“Both synaptopodin spines and synaptophysin immunoexpression were preserved in AD-Resilient group, with levels comparable to those in the NC group.”
§ Cellular, synaptic and biochemical features of resilient cognition in Alzheimer’s disease > 3. Results > 3.2 Cellular and Synaptic Features
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“Whjle not statistically significant, PHFtau tangles negatively correlated with NeuN neurons (ρ=−0.31, p=0.10)”
§ Cellular, synaptic and biochemical features of resilient cognition in Alzheimer’s disease > 3. Results > 3.3 Relation of Neuropathologic Indices to Cellular and Synaptic Features
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“The NC group was especially distinct from AD-Dementia and AD-Resilient groups, but we did observe some differentiation in the expression pattern between AD-Dementia and AD-Resilient groups.”
§ Cellular, synaptic and biochemical features of resilient cognition in Alzheimer’s disease > 3. Results > 3.4 Antibody Microarray Protein Expression Profiling
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“and synaptophysin (ρ=−0.27, p=0.16).”
§ Cellular, synaptic and biochemical features of resilient cognition in Alzheimer’s disease > 3. Results > 3.3 Relation of Neuropathologic Indices to Cellular and Synaptic Features
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“Brain weights were less in the AD-Dementia group compared to the AD-Resilient and NC groups but differences were not statistically significant (Table 1 and Supplement Figure).”
§ Cellular, synaptic and biochemical features of resilient cognition in Alzheimer’s disease > 3. Results > 3.1 Clinical and Neuropathological Features
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“Immunohistochemically labeled amyloid-β plaque % areas and PHFtau neurofibrillary tangle densities in midfrontal cortex were comparable in the AD-Resilient and AD-Dementia groups and both were significantly greater in these groups than the NC group.”
§ Cellular, synaptic and biochemical features of resilient cognition in Alzheimer’s disease > 3. Results > 3.1 Clinical and Neuropathological Features
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“As expected, significant differences were found in frequency of apolipoprotein E ε4 allele, mini-mental state examination score, and CERAD and Braak scores.”
§ Cellular, synaptic and biochemical features of resilient cognition in Alzheimer’s disease > 3. Results > 3.1 Clinical and Neuropathological Features
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“NeuN neuron density was slightly lower in the NC group compared to both the AD-Resilient and AD-Dementia groups, but differences were not significant.”
§ Cellular, synaptic and biochemical features of resilient cognition in Alzheimer’s disease > 3. Results > 3.2 Cellular and Synaptic Features
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“normal synaptophysin expression in midfrontal cortex in the AD-Resilient group indicates preserved connectivity while the reduced synaptophysin expression in the AD-Dementia group suggests decreased connectivity.”
§ Cellular, synaptic and biochemical features of resilient cognition in Alzheimer’s disease > 4. Discussion
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“It is noteworthy that PCA found tight clustering of component scores of the NC cases while the cases with pathological AD, both AD-Dementia and AD-Resilient, were more variable in their distributions.”
§ Cellular, synaptic and biochemical features of resilient cognition in Alzheimer’s disease > 4. Discussion
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“serine/threonine-protein phosphatase (“PP2A”, an important phosphatase for tau (Iqbal, et al., 2009))”
§ Cellular, synaptic and biochemical features of resilient cognition in Alzheimer’s disease > 4. Discussion
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesThe quote only partly states this claim.
- Rests on an assumption: The differentially expressed proteins identified by the antibody microarray are not false positives arising from multiple comparisons.
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In the paper
“We found synaptopodin-labeled spine puncta density to be reduced in AD-Dementia as well, but densities were equivalent to normal in the AD-Resilient group.”
§ Cellular, synaptic and biochemical features of resilient cognition in Alzheimer’s disease > 4. Discussion
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In the paper
“lymphocyte-specific protein tyrosine kinase (which phosphorylates tyrosine residues in tau, has been reported to be decreased in AD and genetically associated with AD (Scales, et al., 2011))”
§ Cellular, synaptic and biochemical features of resilient cognition in Alzheimer’s disease > 4. Discussion
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- Rests on an assumption: The differentially expressed proteins identified by the antibody microarray are not false positives arising from multiple comparisons.
In the paper
“Amyloid-β plaques and hyperphosphorylated tau neurofibrillary tangles are common age-related lesions that are presumed to play primary pathophysiological roles in the dementia of Alzheimer’s disease (AD)(Jellinger, 2009).”
§ Cellular, synaptic and biochemical features of resilient cognition in Alzheimer’s disease > 1. Introduction
What the sources say
- Not checked yetcites Jellinger, 2009 source
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“For example, the Nun Study has shown discordance of cognition with pathology as well as the important effects of education, diet, linguistic ability, and childhood positive emotion on cognitive function in late life (Iacono, et al., 2009,Tyas, et al., 2007).”
§ Cellular, synaptic and biochemical features of resilient cognition in Alzheimer’s disease > 1. Introduction
What the sources say
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In the paper
“We then filtered 10 cases from each group that were most closely matched for age and postmortem interval.”
§ Cellular, synaptic and biochemical features of resilient cognition in Alzheimer’s disease > 2. Methods > 2.1 Case Materials
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In the paper
“We excluded any cases with clinical or pathological diagnoses other than normal, MCI or AD that potentially contributed to cognitive impairment (e.g., abundant Lewy body pathology, infarcts, hippocampal sclerosis, etc.).”
§ Cellular, synaptic and biochemical features of resilient cognition in Alzheimer’s disease > 2. Methods > 2.1 Case Materials
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In the paper
“Independent publications report very high validity of differential protein expression, verified with Western blotting, and our preliminary study findings were consistent with this.”
§ Cellular, synaptic and biochemical features of resilient cognition in Alzheimer’s disease > 2. Methods > 2.4 Antibody Microarray
What the sources say
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In the paper
“Neuropathologic diagnoses of AD were established by a board-certified neuropathologist blinded to age and all clinical data according to NIA-Reagan (Hyman and Trojanowski, 1997), Braak (Braak and Braak, 1995), and CERAD (Mirra, et al., 1991) classifications.”
§ Cellular, synaptic and biochemical features of resilient cognition in Alzheimer’s disease > 2. Methods > 2.1 Case Materials
What the sources say
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“The midfrontal gyrus cortex (corresponding predominantly to Brodmann area 46) was chosen for semi-quantitative image analyses of AD pathology, cellular and synaptic markers because of its important role in complex cognition and its common neuropathological involvement in the spectrum of AD (Arnold, et al., 1991).”
§ Cellular, synaptic and biochemical features of resilient cognition in Alzheimer’s disease > 2. Methods > 2.2 Immunohistochemistry of AD Lesions, Neurons, Glia, Synapses and Spines
What the sources say
- Not checked yetcites Arnold, et al., 1991 source
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In the paper
“Finally, we inspected the selected cases for other clinical data that might skew the relationship between pathology and cognition, i.e., unusual medical or psychiatric conditions, medicines, or causes of death, and substituted alternative cases as necessary.”
§ Cellular, synaptic and biochemical features of resilient cognition in Alzheimer’s disease > 2. Methods > 2.1 Case Materials
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“Annual evaluations included a uniform structured interview and examination consisting of medical history, neurological examination and cognitive testing by trained personnel who are blind to previous evaluations, as previously described (Bennett, et al., 2002).”
- Also stated in: § 2.1 Case Materials · plain
“Follow-up evaluations, identical in all essential details, were performed annually by examiners blinded to previously collected data.”
§ Cellular, synaptic and biochemical features of resilient cognition in Alzheimer’s disease > 2. Methods > 2.1 Case Materials
What the sources say
- Not checked yetcites Bennett, et al., 2002 source
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- Also stated in: § 2.1 Case Materials · plain
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In the paper
“All image acquisition and analyses were conducted masked to case information.”
§ Cellular, synaptic and biochemical features of resilient cognition in Alzheimer’s disease > 2. Methods > 2.3 Image Acquisition and Analysis
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In the paper
“Data was collected in single sections that were all stained in single runs with uniform development times.”
§ Cellular, synaptic and biochemical features of resilient cognition in Alzheimer’s disease > 2. Methods > 2.2 Immunohistochemistry of AD Lesions, Neurons, Glia, Synapses and Spines
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In the paper
“The hemisphere used for diagnostic and frozen blocks alternated randomly between cases.”
§ Cellular, synaptic and biochemical features of resilient cognition in Alzheimer’s disease > 2. Methods > 2.1 Case Materials
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In the paper
“The Clontech antibody array has been used in a variety of settings since 2003 (Anderson, et al., 2003,Hatjiharissi, et al., 2007).”
§ Cellular, synaptic and biochemical features of resilient cognition in Alzheimer’s disease > 2. Methods > 2.4 Antibody Microarray
What the sources say
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In the paper
“We first limited our selection to female participants in the ROS cohort, thus minimizing sex and major lifestyle differences (given relatively similar lifestyles activities, diet, habits and healthcare of Catholic female clergy).”
§ Cellular, synaptic and biochemical features of resilient cognition in Alzheimer’s disease > 2. Methods > 2.1 Case Materials
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In the paper
“Statistical analyses further showed no significant differences among groups for education, use of hormone replacement therapy (only 1 normal comparison case had ever been on this), postmortem interval, brain weight, and presence or absence of macroscopic or microscopic infarcts, which if present, were in regions other than mid-frontal cortex.”
§ Cellular, synaptic and biochemical features of resilient cognition in Alzheimer’s disease > 3. Results > 3.1 Clinical and Neuropathological Features
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In the paper
“This suggests that the protein expression profile of healthy brain tissues is distinct from those with abundant AD pathology and that AD pathology disrupts protein expression in non-cohesive ways.”
§ Cellular, synaptic and biochemical features of resilient cognition in Alzheimer’s disease > 3. Results > 3.4 Antibody Microarray Protein Expression Profiling
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In the paper
“Preliminary experiments with the microarray were conducted to examine the inter-experiment reliability of the platform. Aliquots of pooled tissue homogenates from two groups were run in four separate experiments and coefficient of variations (CV) were calculated for each of the protein measurements on the array. Average CV was 0.14 (SD=0.27, range 0.01 to 2.0)”
§ Cellular, synaptic and biochemical features of resilient cognition in Alzheimer’s disease > 2. Methods > 2.4 Antibody Microarray
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In the paper
“Synaptic loss is frequently cited as the best neuropathological correlate of dementia severity in AD (Terry, et al., 1991) and has been linked to the accumulation of both amyloid-β and tau pathology (Arendt, 2009).”
§ Cellular, synaptic and biochemical features of resilient cognition in Alzheimer’s disease > 4. Discussion
What the sources say
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In the paper
“Cortical astrocytes maintain brain health through structural and biochemical support to neurons and endothelial cells, maintain extracellular ion balance, provide nutrients to neurons, regulate cortical blood flow, transmitter uptake and release, modulate synaptic neurotransmission and provide trophic and detoxifying support in response to injury (Sofroniew and Vinters, 2010).”
§ Cellular, synaptic and biochemical features of resilient cognition in Alzheimer’s disease > 4. Discussion
What the sources say
- Not checked yetcites Sofroniew and Vinters, 2010 source
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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
“These data characterize cellular and synaptic features and identify novel biochemical targets that may be associated with resilient cognitive brain aging in the setting of pathological AD.”
§ Cellular, synaptic and biochemical features of resilient cognition in Alzheimer’s disease > Abstract
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- Rests on an assumption: The 507 proteins measured by the Clontech antibody microarray include proteins relevant to resilient cognition in Alzheimer’s disease.
In the paper
“Supporting this notion, Price et al. reported no measureable cognitive impairment per se in such preclinical AD cases, but degraded cognitive function in the presence of plaques and tangles (Price, et al., 2009).”
§ Cellular, synaptic and biochemical features of resilient cognition in Alzheimer’s disease > 4. Discussion
What the sources say
- Not checked yetcites Price, et al., 2009 source
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt 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
“An antibody microarray served as an unbiased measure of the relative expression levels of over 500 proteins that span a broad range of functional groups.”
§ Cellular, synaptic and biochemical features of resilient cognition in Alzheimer’s disease > 4. Discussion
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In the paper
“However, they may introduce systematic inaccuracies that might be obviated with reference volume-based stereological approaches.”
§ Cellular, synaptic and biochemical features of resilient cognition in Alzheimer’s disease > 4. Discussion
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In the paper
“but the challenge of multiple comparisons remains, especially in relatively small sample sizes.”
§ Cellular, synaptic and biochemical features of resilient cognition in Alzheimer’s disease > 4. Discussion
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In the paper
“while postmortem neuropathology remains the best approach to investigate the neurobiology of uniquely human brain diseases, it only allows a snapshot of the brain as it was near the time of death, it can suggest, but not establish, causal relationships between clinical and brain data, and confounds such as agonal state and postmortem changes can alter the brains’ cellular and molecular integrity.”
§ Cellular, synaptic and biochemical features of resilient cognition in Alzheimer’s disease > 4. Discussion
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In the paper
“Our use of a pooled tissue standard as a reference in all experiments, dye swapping and calculated INR attenuated many potential pitfalls”
§ Cellular, synaptic and biochemical features of resilient cognition in Alzheimer’s disease > 4. Discussion
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably 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
“These minimize operator bias, lend themselves well to larger scale, high-throughput studies, and they successfully found between group differences.”
§ Cellular, synaptic and biochemical features of resilient cognition in Alzheimer’s disease > 4. Discussion
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
The paper relies on this without support.
There has been little postmortem investigation of neurobiological factors that might confer or be associated with resilient brain aging.
“Aside from noting such discordance in clinicopathological studies, there has been little pursuant postmortem investigation of neurobiological factors that might confer or be associated with resilient brain aging.”
The paper relies on this without support.
The correlation between Alzheimer’s disease neuropathological lesions and cognition is modest and accounts for limited variance among older adults.
“However, it is also recognized that the correlation between these neuropathological lesions and cognition is modest and accounts for a limited amount of the variance of cognition among older adults.”
The paper relies on this without support.
The 507 proteins measured by the Clontech antibody microarray include proteins relevant to resilient cognition in Alzheimer’s disease.
“The Clontech. Antibody Microarray 500 (Clontech, Mountainview, CA) was used to profile relative expression levels of 507 proteins.”
The paper relies on this without support.
Composite cognition scores from the last assessment before death accurately reflect the participants’ cognitive status relevant to group classification.
“We next stratified according to composite cognition scores from the last assessment before death and global pathology (average plaque and tangle burdens in diagnostic blocks).”
The paper relies on this without support.
The observed cellular and biochemical differences between the AD-Resilient group and the other groups are not attributable to confounds such as agonal state or postmortem changes.
“confounds such as agonal state and postmortem changes can alter the brains’ cellular and molecular integrity.”
The paper relies on this without support.
The differentially expressed proteins identified by the antibody microarray are not false positives arising from multiple comparisons.
“the challenge of multiple comparisons remains, especially in relatively small sample sizes.”
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?
In the citing paper
“Some studies have reported preserved neuronal numbers and synaptic densities in the hippocampus in “preclinical/resilient AD” compared with normal and clinical AD cases [62], [108], [109].”
From Repair of Oxidative DNA Damage, Cell-Cycle Regulation and Neuronal Death May Influence the Clinical Manifestation of Alzheimer’s Disease (2014) · cites this paper as [62]
Citations
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1 of the 66 references couldn’t be matched to a known paper.
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Items 101–123 of 123
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Metadata
- Authors
- Arnold, S. E., Louneva, N., Cao, K., Wang, L.-S., Han, L.-Y., Wolk, D. A., Negash, S., Leurgans, S. E., Schneider, J. A., Buchman, A. S., Wilson, R. S., & Bennett, D. A.
- Affiliations
- University of Pennsylvania (US)
- Rush University (US)
- ORCID
- Venue
- Neurobiology of Aging
- Publisher
- Elsevier BV
- Published
- 2013-01
- Volume
- 34
- Issue
- 1
- Pages
- 157-168
- ISSN
- 0197-4580 (ISSN-L)
- PMC
- PMC3478410
- OpenAlex
- W2046582067
- Semantic Scholar
- 35b7b967d421550d0fbfcd374180037594e42757
- Cited by
- 123
- References
- 66
- Citations by year
- 2026: 7 · 2025: 18 · 2024: 5 · 2023: 10 · 2022: 17 · 2021: 7 · 2020: 7 · 2019: 10 · 2018: 5 · 2017: 9 · 2016: 6 · 2015: 3 · 2014: 9 · 2013: 9
- FWCI
- 4.72
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Neurobiology of Aging (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute on Aging (R01AG039478, R01AG15819, P30AG10161, P30AG10124)
- Marian S. Ware Alzheimer's Program/National Philanthropic Trust
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- Alzheimer's disease, cognitive resilience, synaptophysin, synaptopodin, presynaptic terminals, dendritic spines, astrocytes, glial fibrillary acidic protein, antibody microarrays, protein biomarkers, dementia, Religious Orders Study, brain aging
- MeSH terms
- Aged, Aged, 80 and over, Alzheimer Disease, Brain, Cognition Disorders, Female, Glial Fibrillary Acidic Protein, Humans, Male, Nerve Tissue Proteins, Neurons, Phosphopyruvate Hydratase, Synapses, tau Proteins, Protein Array Analysis, Microscopy, Electron, Transmission
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
A language model drew the claims from the paper on 2026-10-05, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-10-05 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
Statistics and arithmetic are recomputed, not judged.
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