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Neurofibrillary tangles mediate the association of amyloid load with clinical Alzheimer disease and level of cognitive function
Bennett DA, Schneider JA, Wilson RS, Bienias JL, Arnold SE.. Archives of neurology, 2004-03-01
Topic: Amyloid, tau and blood-test diagnosis
Objective To test the hypothesis that the association of amyloid load with clinical Alzheimer disease (AD) and cognitive impairment is mediated through neurofibrillary tangles. Design Longitudinal clinicopathologic cohort study. Participants and setting Forty-four individuals with clinically diagnosed AD and 53 without dementia who participated in the Religious Orders Study underwent a uniform structured clinical evaluation for AD and cognitive testing about 8 months prior to death, and brain autopsy at death. Methods The percent area occupied by amyloid-beta and the density of neurofibrillary tangles were quantified from 6 brain regions and averaged to yield summary measures of amyloid load and neurofibrillary tangles. Multivariate regression analyses were used to simultaneously examine the effects of amyloid load and neurofibrillary tangles on clinically diagnosed AD and level of cognition. Main outcome measures Clinically diagnosed AD and level of global cognitive function proximate to death. Results In separate logistic regression analyses, each 1% increase in amyloid load was associated with about a 50% increase in the odds of clinical AD (P =.002), and each neurofibrillary tangle was associated with a greater than 20% increase in the odds of clinical AD (P Conclusion These findings are consistent with a sequence of pathologic events whereby the effect of amyloid deposition on clinical disease is mediated by neurofibrillary tangles.
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APA 7th
Bennett, D. A., Schneider, J. A., Wilson, R. S., Bienias, J. L., & Arnold, S. E. (2004). Neurofibrillary tangles mediate the association of amyloid load with clinical Alzheimer disease and level of cognitive function. Archives of neurology. https://doi.org/10.1001/archneur.61.3.378
Vancouver
Bennett DA, Schneider JA, Wilson RS, Bienias JL, Arnold SE. Neurofibrillary tangles mediate the association of amyloid load with clinical Alzheimer disease and level of cognitive function. Archives of neurology. 2004. doi:10.1001/archneur.61.3.378. PMID: 15023815.
BibTeX
@article{bennett2004-15023815,
author = {Bennett, D. A. and Schneider, J. A. and Wilson, R. S. and Bienias, J. L. and Arnold, S. E.},
title = {{Neurofibrillary tangles mediate the association of amyloid load with clinical Alzheimer disease and level of cognitive function}},
journal = {Archives of neurology},
year = {2004},
doi = {10.1001/archneur.61.3.378},
pmid = {15023815},
url = {https://doi.org/10.1001/archneur.61.3.378}
}
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Key findings
- Results In separate logistic regression analyses, each 1% increase in amyloid load was associated with about a 50% increase in the odds of clinical AD (P =.002), and each neurofibrillary tangle was associated with a greater than 20% increase in the odds of clinical AD (P<.001).
Why it matters
At autopsy, 97 members of the Religious Orders Study (44 with clinically diagnosed Alzheimer's, 53 without dementia) who had been tested about 8 months before death showed that each 1% increase in amyloid load was linked to about 50% higher odds of clinical Alzheimer's, and each additional tangle to more than 20% higher odds, in separate analyses. The authors conclude this is "consistent with a sequence" in which amyloid's effect on clinical disease works through tangles. The study is an observational autopsy comparison that does not show cause and effect or test any treatment.
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Study details
- Study designcohort study
- Evidence strengthModerate
How this study scored 57/100
Published in a peer-reviewed journal, and it is a cohort study following people over time. Scored zero for sample size, effect reported, studied in people and randomized / blinded because the record does not state it.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (Archives of neurology) |
| Journal's citation record | 3 / 4 | Archives of Neurology: journal h-index 353 (OpenAlex, 2026-10-29) |
| Study design | 7 / 12 | A cohort study following people over time |
| Strength of evidence | 3 / 5 | Rated “moderate” in our summary |
| Peer-review validation | 10 / 10 | Peer-reviewed. Published as an article in a named peer-reviewed journal. |
| How recent | 1 / 5 | 2004 — older than 20 years, still counted |
| Sample size | 0 / 4 | Participant count not stated — scores zero (not stated in the record — scored 0) |
| Effect reported | 0 / 3 | No effect size reported — scores zero (not stated in the record — scored 0) |
| Studied in people | 0 / 3 | Not stated whether this was studied in people — scores zero (not stated in the record — scored 0) |
| Randomized / blinded | 0 / 2 | No randomization or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | 6 / 7 | Cited 531 times (OpenAlex, 2026-10-10) |
| Citations per year | 4 / 5 | 22.1 citations a year over 24 year(s) since 2004 |
| Impact for its field and year | 3 / 6 | Cited 7.6× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 4 / 6 | Cited by 49 other studies in this library |
| Still being cited | 3 / 4 | Cited 67 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 4 / 4 | Last-listed author Steven Edward Arnold: h-index 125 (OpenAlex, whole career) |
| Institution's track record | 0 / 3 | Rush University Medical Center: institution h-index 670 (OpenAlex) |
| Multicenter collaboration | 0 / 3 | OpenAlex lists 1 institution(s) in 1 country — scores zero (affiliation lists can be incomplete) |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 15023815) |
| Free to read | 0 / 2 | Behind a paywall — scores zero |
| Total | 57 / 100 | — |
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