Abstract
Introduction: Amyloid beta (Aβ), tau, and neurodegeneration jointly with the Alzheimer's disease (AD) risk factors affect the severity of clinical symptoms and disease progression. Methods: Within 248 Aβ-positive elderly with and without cognitive impairment and dementia, partial least squares structural equation pathway modeling was used to assess the direct and indirect effects of imaging biomarkers (global Aβ-positron emission tomography [PET] uptake, regional tau-PET uptake, and regional magnetic resonance imaging–based atrophy) and risk-factors (age, sex, education, apolipoprotein E [APOE], and white-matter lesions) on cross-sectional cognitive impairment and longitudinal cognitive decline. Results: Sixteen percent of variance in cross-sectional cognitive impairment was accounted for by Aβ, 46% to 47% by tau, and 25% to 29% by atrophy, although 53% to 58% of total variance in cognitive impairment was explained by incorporating mediated and direct effects of AD risk factors. The Aβ–tau–atrophy pathway accounted for 50% to 56% of variance in longitudinal cognitive decline while Aβ, tau, and atrophy independently explained 16%, 46% to 47%, and 25% to 29% of the variance, respectively. Discussion: These findings emphasize that treatments that remove Aβ and completely stop downstream effects on tau and neurodegeneration would only be partially effective in slowing of cognitive decline or reversing cognitive impairment.
Original language | English (US) |
---|---|
Pages (from-to) | 1370-1382 |
Number of pages | 13 |
Journal | Alzheimer's and Dementia |
Volume | 18 |
Issue number | 7 |
DOIs | |
State | Published - Jul 2022 |
Keywords
- Alzheimer's Disease Assessment Scale–Cognitive Subscale
- Preclinical Alzheimer Cognitive Composite
- amyloid beta
- atrophy
- cognition
- magnetic resonance imaging
- positron emission tomography
- tau
- white matter lesions
ASJC Scopus subject areas
- Epidemiology
- Health Policy
- Developmental Neuroscience
- Clinical Neurology
- Geriatrics and Gerontology
- Cellular and Molecular Neuroscience
- Psychiatry and Mental health
Access to Document
Other files and links
Fingerprint
Dive into the research topics of 'Contribution of Alzheimer's biomarkers and risk factors to cognitive impairment and decline across the Alzheimer's disease continuum'. Together they form a unique fingerprint.Cite this
- APA
- Standard
- Harvard
- Vancouver
- Author
- BIBTEX
- RIS
Contribution of Alzheimer's biomarkers and risk factors to cognitive impairment and decline across the Alzheimer's disease continuum. / for the Alzheimer's Disease Neuroimaging Initiative.
In: Alzheimer's and Dementia, Vol. 18, No. 7, 07.2022, p. 1370-1382.Research output: Contribution to journal › Article › peer-review
}
TY - JOUR
T1 - Contribution of Alzheimer's biomarkers and risk factors to cognitive impairment and decline across the Alzheimer's disease continuum
AU - for the Alzheimer's Disease Neuroimaging Initiative
AU - Tosun, Duygu
AU - Demir, Zeynep
AU - Veitch, Dallas P.
AU - Weintraub, Daniel
AU - Aisen, Paul
AU - Jack, Clifford R.
AU - Jagust, William J.
AU - Petersen, Ronald C.
AU - Saykin, Andrew J.
AU - Shaw, Leslie M.
AU - Trojanowski, John Q.
AU - Weiner, Michael W.
N1 - Funding Information: This work is funded by the National Institutes of Health Grants U01 AG024904, P30 AG062677, U01 AG006786, P30 AG010133, R01 AG019771, and U19 AG062418. Funding Information: Data collection and sharing for this project was funded by the Alzheimer's Disease Neuroimaging Initiative (ADNI) (National Institutes of Health Grant U01 AG024904). ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: AbbVie; Alzheimer's Association; Alzheimer's Drug Discovery Foundation; Araclon Biotech; BioClinica, Inc.; Biogen; Bristol-Myers Squibb Company; CereSpir, Inc.; Cogstate; Eisai Inc.; Elan Pharmaceuticals, Inc.; Eli Lilly and Company; EuroImmun; F. Hoffmann-La Roche Ltd and its affiliated company Genentech, Inc.; Fujirebio; GE Healthcare; IXICO Ltd.; Janssen Alzheimer Immunotherapy Research & Development, LLC; Johnson & Johnson Pharmaceutical Research & Development LLC; Lumosity; Lundbeck; Merck & Co., Inc.; Meso Scale Diagnostics, LLC; NeuroRx Research; Neurotrack Technologies; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Piramal Imaging; Servier; Takeda Pharmaceutical Company; and Transition Therapeutics. The Canadian Institutes of Health Research is providing funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health (www.fnih.org). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer's Therapeutic Research Institute at the University of Southern California. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of Southern California. Data used in preparation of this article were obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database (adni.loni.usc.edu). As such, the investigators within the ADNI contributed to the design and implementation of ADNI and/or provided data but did not participate in analysis or writing of this report. A complete listing of ADNI investigators can be found at: http://adni.loni.usc.edu/wp-content/uploads/how_to_apply/ADNI_Acknowledgement_List.pdf This work is funded by the National Institutes of Health Grants U01 AG024904, P30 AG062677, U01 AG006786, P30 AG010133, R01 AG019771, and U19 AG062418. Funding Information: Data collection and sharing for this project was funded by the Alzheimer's Disease Neuroimaging Initiative (ADNI) (National Institutes of Health Grant U01 AG024904). ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: AbbVie; Alzheimer's Association; Alzheimer's Drug Discovery Foundation; Araclon Biotech; BioClinica, Inc.; Biogen; Bristol‐Myers Squibb Company; CereSpir, Inc.; Cogstate; Eisai Inc.; Elan Pharmaceuticals, Inc.; Eli Lilly and Company; EuroImmun; F. Hoffmann‐La Roche Ltd and its affiliated company Genentech, Inc.; Fujirebio; GE Healthcare; IXICO Ltd.; Janssen Alzheimer Immunotherapy Research & Development, LLC; Johnson & Johnson Pharmaceutical Research & Development LLC; Lumosity; Lundbeck; Merck & Co., Inc.; Meso Scale Diagnostics, LLC; NeuroRx Research; Neurotrack Technologies; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Piramal Imaging; Servier; Takeda Pharmaceutical Company; and Transition Therapeutics. The Canadian Institutes of Health Research is providing funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health ( www.fnih.org ). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer's Therapeutic Research Institute at the University of Southern California. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of Southern California. Funding Information: Dr. Weintraub reports grants from NIA, Department of Veterans Affairs, Fox Foundation, Acadia Pharmaceuticals, and IPMDS. All payments made to U. Pennsylvania, compensation for licensing of QUIP, QUIP‐RS, and PDAQ‐15 through the University of Pennsylvania. He received personal consulting compensation from Acadia, Aptinyx, CHDI Foundation, Clintrex LLC (Otsuka), Eisai, Great Lake Neurotechnologies, Janssen, Sage, Scion, Signant Health, Sunovion, and Vanda. He serves as Chair DSMB for ATRI and ADCS. Dr. Aisen has received support over the last 36 months from payments to his institution from NIA, FNIH, Alzheimer's Association, Janssen, Lilly, Merck, and Eisai. He has served on the advisory boards of Biogen, Merck, Roche, Abbvie, Rainbow Medical, ImmunoBrain Checkpoint, Shionogi, and has no other support or conflicts of interest to declare. Dr. Jack was supported in the current work by NIH funding. Over the last 36 months, he has received support from NIH grants and the Alexander Family Alzheimer's Disease Research Professorship of the Mayo Clinic to his institution and has served on the advisory boards of iDMC and Roche with no payments made. He serves on an independent data monitoring board for Roche, has consulted for and served as a speaker for Eisai, and consulted for Biogen, but he receives no personal compensation from any commercial entity. He has no other support or conflicts of interest to declare. Dr. Jagust has received support over the last 36 months from grants to his institution (NIH grants R01 AG034570 [Dr. Jagust], R01AG062542 [Dr. Jagust], U24 AG067418 [Dr. Jagust], P01AG019724 [Dr. Bruce Miller], R01 AG031164 [Dr. Matthew Walker], RF1 AG054019 [Dr. Matthew Walker], U01 AG024904 [Dr. Weiner], RF1 AG054106‐01A1 [Dr. Matthew Walker], R44AG046025‐03 [Dr. Daojing Wang], R01 AG061303 [Dr. Lexin Li], MH112775 [Dr. Ming Hsu], 1R01AG062689‐01 [Dr. Landau], AG062624 [Dr. José Luchsinger], and R01AG069090), direct consulting fees (Biogen, Bioclinica, Genentech/Roche, CuraSen, Grifols), and has served on the advisory board of the Alzheimer's Prevention Initiative. He has no other support or conflicts of interest to declare. Dr. Petersen over the past 36 months received grants through his institution (P30 AG062677, U01 AG006786); licenses or royalties from Oxford University Press and UpToDate; and consulting fees from Roche, Merck, Biogen, Genentech, and Eisai. He served on the advisory board of Genentech and has no other support or conflicts of interest to declare. Dr. Saykin was supported in this work by grants from NIH and Department of Defense (NIH grants U01 AG024904, P30 AG010133, R01 AG019771, R01 LM013463, R01 LM011360 and DoD grants W81XWH‐13‐1‐0259 and W81XWH‐12‐2‐0012), and over the past 36 months received support from grants to his institution (as detailed above). He served on the Bayer Oncology Advisory Board and received PET tracer precursor from Eli Lilly/Avid Radiopharmaceuticals. He reports personal fees from Arkley BioTek and Springer Nature, outside the submitted work. He has no other support or conflicts of interest to declare. Dr. Shaw has received over the past 36 months grants through his institution (NIH grants U01 AG024904 (ADNI3), UPenn ADRC NIA grant for Biomarker Core; Michael J. Fox Foundation for Parkinson's Research for AD biomarker studies; Roche IIS for AD biomarker studies), fees for the Biogen Teaching program on AD Biomarkers, and travel funds from NIA ADNI3 Biomarker Core. He has served on the Roche Advisory Board, LEADS Advisory Board, and Fujirebio Advisory Board. He received in kind support from Roche (immunoassay reagents and equipment) for ADNI3. He has no other support or conflicts of interest to declare. Dr. Trojanowski has received over the past 36 months grants through his institution (AG10124). He has no other support or conflicts of interest to declare. Dr. Weiner is the Principal Investigator of NIH funded grants. Over the past 36 months he received funding administered through his institutions (NIH grants: 1RF1AG059009‐01 and 1R01AG058676‐01A1; CA Dept. of Health grant: 19‐10616; NIH Subaward from Dr. Richard Gershon: 1U2CA060426‐01), consulting fees (Cerecin/Accera, Inc., BioClinica, Nestle/Nestec, Roche, Genentech, NIH, The Buck Institute for Research on Aging, FUJIFILM‐Toyama Chemical [Japan], Garfield Weston, Baird Equity Capital, University of Southern California [USC], Cytox, and Japanese Organization for Medical Device Development, Inc. [JOMDD] and T3D Therapeutics), and payment for lecturing (The Buck Institute for Research on Aging). He holds stock options in Anven, Alzheon, and Aleca. He receives other grant support for his work (NIH: 5U19AG024904‐14; 1R01AG053798‐01A1; R01 MH098062; U24 AG057437‐01; 1U2CA060426‐01; 1R01AG058676‐01A1; and 1RF1AG059009‐01, DOD: W81XWH‐15‐2‐0070; 0W81XWH‐12‐2‐0012; W81XWH‐14‐1‐0462; W81XWH‐13‐1‐0259, PCORI: PPRN‐1501‐26817, California Dept. of Public Health: 16‐10054, U. Michigan: 18‐PAF01312, Siemens: 444951‐54249, Biogen: 174552, Hillblom Foundation: 2015‐A‐011‐NET, Alzheimer's Association: BHR‐16‐459161; The State of California: 18‐109929). He also receives support from Johnson & Johnson, Kevin and Connie Shanahan, GE, VUmc, Australian Catholic University (HBI‐BHR), The Stroke Foundation, and the Veterans Administration. He has served on advisory boards for Eli Lilly, Cerecin/Accera, Roche, Alzheon, Inc., Merck Sharp & Dohme Corp., Nestle/Nestec, PCORI/PPRN, Dolby Family Ventures, National Institute on Aging (NIA), Brain Health Registry, and ADNI. He has no other support or conflicts of interest to declare. Publisher Copyright: © 2021 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.
PY - 2022/7
Y1 - 2022/7
N2 - Introduction: Amyloid beta (Aβ), tau, and neurodegeneration jointly with the Alzheimer's disease (AD) risk factors affect the severity of clinical symptoms and disease progression. Methods: Within 248 Aβ-positive elderly with and without cognitive impairment and dementia, partial least squares structural equation pathway modeling was used to assess the direct and indirect effects of imaging biomarkers (global Aβ-positron emission tomography [PET] uptake, regional tau-PET uptake, and regional magnetic resonance imaging–based atrophy) and risk-factors (age, sex, education, apolipoprotein E [APOE], and white-matter lesions) on cross-sectional cognitive impairment and longitudinal cognitive decline. Results: Sixteen percent of variance in cross-sectional cognitive impairment was accounted for by Aβ, 46% to 47% by tau, and 25% to 29% by atrophy, although 53% to 58% of total variance in cognitive impairment was explained by incorporating mediated and direct effects of AD risk factors. The Aβ–tau–atrophy pathway accounted for 50% to 56% of variance in longitudinal cognitive decline while Aβ, tau, and atrophy independently explained 16%, 46% to 47%, and 25% to 29% of the variance, respectively. Discussion: These findings emphasize that treatments that remove Aβ and completely stop downstream effects on tau and neurodegeneration would only be partially effective in slowing of cognitive decline or reversing cognitive impairment.
AB - Introduction: Amyloid beta (Aβ), tau, and neurodegeneration jointly with the Alzheimer's disease (AD) risk factors affect the severity of clinical symptoms and disease progression. Methods: Within 248 Aβ-positive elderly with and without cognitive impairment and dementia, partial least squares structural equation pathway modeling was used to assess the direct and indirect effects of imaging biomarkers (global Aβ-positron emission tomography [PET] uptake, regional tau-PET uptake, and regional magnetic resonance imaging–based atrophy) and risk-factors (age, sex, education, apolipoprotein E [APOE], and white-matter lesions) on cross-sectional cognitive impairment and longitudinal cognitive decline. Results: Sixteen percent of variance in cross-sectional cognitive impairment was accounted for by Aβ, 46% to 47% by tau, and 25% to 29% by atrophy, although 53% to 58% of total variance in cognitive impairment was explained by incorporating mediated and direct effects of AD risk factors. The Aβ–tau–atrophy pathway accounted for 50% to 56% of variance in longitudinal cognitive decline while Aβ, tau, and atrophy independently explained 16%, 46% to 47%, and 25% to 29% of the variance, respectively. Discussion: These findings emphasize that treatments that remove Aβ and completely stop downstream effects on tau and neurodegeneration would only be partially effective in slowing of cognitive decline or reversing cognitive impairment.
KW - Alzheimer's Disease Assessment Scale–Cognitive Subscale
KW - Preclinical Alzheimer Cognitive Composite
KW - amyloid beta
KW - atrophy
KW - cognition
KW - magnetic resonance imaging
KW - positron emission tomography
KW - tau
KW - white matter lesions
UR - http://www.scopus.com/inward/record.url?scp=85117103137&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85117103137&partnerID=8YFLogxK
U2 - 10.1002/alz.12480
DO - 10.1002/alz.12480
M3 - Article
C2 - 34647694
AN - SCOPUS:85117103137
VL - 18
SP - 1370
EP - 1382
JO - Alzheimer's and Dementia
JF - Alzheimer's and Dementia
SN - 1552-5260
IS - 7
ER -