Metabolic profiling distinguishes three subtypes of Alzheimer's disease
Open accessAbstract
The cause of Alzheimer's disease is incompletely defined, and no truly effective therapy exists. However, multiple studies have implicated metabolic abnormalities such as insulin resistance, hormonal deficiencies, and hyperhomocysteinemia. Optimizing metabolic parameters in a comprehensive way has yielded cognitive improvement, both in symptomatic and asymptomatic individuals. Therefore, expanding the standard laboratory evaluation in patients with dementia may be revealing. Here I report that metabolic profiling reveals three Alzheimer's disease subtypes. The first is inflammatory, in which markers such as hs-CRP and globulin:albumin ratio are increased. The second type is non-inflammatory, in which these markers are not increased, but other metabolic abnormalities are present. The third type is a very distinctive clinical entity that affects relatively young individuals, extends beyond the typical Alzheimer's disease initial distribution to affect the cortex widely, is characterized by early non-amnestic features such as dyscalculia and aphasia, is often misdiagnosed or labeled atypical Alzheimer's disease, typically affects ApoE4-negative individuals, and is associated with striking zinc deficiency. Given the involvement of zinc in multiple Alzheimer's-related metabolic processes, such as insulin resistance, chronic inflammation, ADAM10 proteolytic activity, and hormonal signaling, this syndrome of Alzheimer's-plus with low zinc (APLZ) warrants further metabolic, genetic, and epigenetic characterization.
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Patients with LOAD often branch into distinct groups including slow versus rapid cognitive decliners, amnestic versus nonamnestic AD, executive versus cortical visual defect versus dysphasia-predominant AD, psychosis and depression-associated AD, and metabolic dysfunction-associated AD.
“For instance, patients with LOAD often branch into distinct groups including (i) slow versus rapid cognitive decliners (7), (ii) amnestic versus nonamnestic AD (8), (iii) executive versus cortical visual defect versus dysphasia-predominant AD (9), (iv) psychosis and depression-associated AD (10–12), and (v) metabolic dysfunction–associated AD modulated by abnormalities in insulin resistance, Hormo”
From Molecular subtyping of Alzheimer’s disease using RNA sequencing data reveals novel mechanisms and targets (2021) · cites this paper as [8]
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Meta-Analysis of 74,046 Individuals Identifies 11 New Susceptibility Loci for Alzheimer’s Disease
(EADI), E. A. D. I., Lambert, J.-C., (GERAD), G. A. E. R. I. A. D., Alzheimer's Disease Genetic Consortium (ADGC), (CHARGE), C. F. H. A. A. R. I. G. E., Ibrahim-Verbaas, C. A., Harold, D., Naj, A. C., Sims, R., Bellenguez, C., et al. (2013) · Nature Genetics · doi:10.1038/ng.2802 · Cited by 4,336 · see citing works
Ngandu, T., Lehtisalo, J., Solomon, A., Levälahti, E., Ahtiluoto, S., Antikainen, R., Bäckman, L., Hänninen, T., Jula, A., Laatikainen, T., et al. (2015) · The Lancet · doi:10.1016/s0140-6736(15)60461-5 · Cited by 3,689 · see citing works
Immune attack: the role of inflammation in Alzheimer disease
Heppner, F. L., Ransohoff, R. M., & Becher, B. (2015) · Nature Reviews Neuroscience · doi:10.1038/nrn3880 · Cited by 2,134 · see citing works
Wyss-Coray (2006) · doi:10.1038/nm1484 · Cited by 1,284 · see citing works
Function and Mechanism of Zinc Metalloenzymes
McCall, K. A., Huang, C.-C., & Fierke, C. A. (2000) · Journal of Nutrition · doi:10.1093/jn/130.5.1437s · Cited by 1,144 · see citing works
Kauppinen, A., Suuronen, T., Ojala, J. O., Kaarniranta, K., & Salminen, A. (2013) · Cellular Signalling · doi:10.1016/j.cellsig.2013.06.007 · Cited by 1,001 · see citing works
Focal cortical presentations of Alzheimer's disease
Alladi, S., Xuereb, J., Bak, T., Nestor, P., Knibb, J., Patterson, K., & Hodges, J. R. (2007) · Brain · doi:10.1093/brain/awm213 · Cited by 581 · cited 1× · see citing works
“Alzheimer’s disease presenting with non-amnestic features such as aphasia, partial Gerstmann’s syndrome, alexia, visual agnosia, or apraxias has been well described [16], but metabolic abnormalities distinguishing these atypical presentations have not been reported.”
BackgroundAltered lysosomal proteins in neural-derived plasma exosomes in preclinical Alzheimer disease
Goetzl, E. J., Boxer, A. L., Schwartz, J. B., Abner, E. L., Petersen, R. C., Miller, B. L., & Kapogiannis, D. (2015) · Neurology · doi:10.1212/wnl.0000000000001702 · Cited by 466 · see citing works
Contribution of Alzheimer disease to mortality in the United States
James, B. D., Leurgans, S. E., Hebert, L. E., Scherr, P. A., Yaffe, K. S., & Bennett, D. A. (2014) · Neurology · doi:10.1212/wnl.0000000000000240 · Cited by 364 · see citing works
Ineffective phagocytosis of amyloid-β by macrophages of Alzheimer's disease patients
Fiala, M., Lin, J., Ringman, J. M., Kermani-Arab, V., Tsao, G., Patel, A. J., Lossinsky, A. S., Graves, M. C., Gustavson, A. R., Sayre, J. W., et al. (2005) · Journal of Alzheimer s Disease · doi:10.3233/jad-2005-7304 · Cited by 328 · see citing works
Reversal of cognitive decline: A novel therapeutic program
Bredesen, D. E. (2014) · Aging · doi:10.18632/aging.100690 · Cited by 231 · see citing works
Self-citationHomocysteine induces tau phosphorylation by inactivating protein phosphatase 2A in rat hippocampus
Zhang, C.-E., Tian, Q., Wei, W., Peng, J.-H., Liu, G., Zhou, X., Wang, Q., Wang, D. W., & Wang, J. (2007) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2007.04.015 · Cited by 159 · see citing works
Homocysteine levels in schizophrenia and affective disorders—focus on cognition
Moustafa, A. A., Hewedi, D. H., Eissa, A. M., Frydecka, D., & Misiak, B. (2014) · Frontiers in Behavioral Neuroscience · doi:10.3389/fnbeh.2014.00343 · Cited by 149 · see citing works
Mizwicki, M. T., Liu, G., Fiala, M., Magpantay, L. I., Sayre, J. W., Siani, A., Mahanian, M., Weitzman, R. E., Hayden, E. Y., Rosenthal, M. J., et al. (2013) · Journal of Alzheimer s Disease · doi:10.3233/jad-121735 · Cited by 135 · see citing works
Chakrabarti, S., Kumar Khemka, V., Banerjee, A., Chatterjee, G., Ganguly, A., & Biswas, A. (2015) · Aging and disease · doi:10.14336/ad.2014.002 · Cited by 134 · see citing works
Neuroprotective Sirtuin ratio reversed by ApoE4
Theendakara, V., Patent, A., Peters Libeu, C. A., Philpot, B., Flores, S., Descamps, O., Poksay, K. S., Zhang, Q., Cailing, G., Hart, M., et al. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1314145110 · Cited by 101 · see citing works
Self-citationZinc Deficiency and Zinc Therapy Efficacy with Reduction of Serum Free Copper in Alzheimer’s Disease
Brewer, G. J., & Kaur, S. (2013) · International Journal of Alzheimer s Disease · doi:10.1155/2013/586365 · Cited by 34 · see citing works
Is there a link between gynecologic surgeries and Alzheimer disease?
Rocca, W. A., & Henderson, V. W. (2013) · Neurology · doi:10.1212/wnl.0000000000000043 · Cited by 23 · see citing works
Dynamic self-guiding analysis of Alzheimer's disease
Kurakin, A. V., & Bredesen, D. E. (2015) · Oncotarget · doi:10.18632/oncotarget.4221 · Cited by 7 · see citing works
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Neff, R. A., Wang, M., Vatansever, S., Guo, L., Ming, C., Wang, Q., Wang, E., Horgusluoglu-Moloch, E., Song, W.-M., Li, A., et al. (2021) · Science Advances · doi:10.1126/sciadv.abb5398 · Cited by 306 · see citing works
“For instance, patients with LOAD often branch into distinct groups including (i) slow versus rapid cognitive decliners (7), (ii) amnestic versus nonamnestic AD (8), (iii) executive versus cortical visual defect versus dysphasia-predominant AD (9), (iv) psychosis and depression-associated AD (10–12), and (v) metabolic…”
BackgroundAlzheimer’s Disease: Key Insights from Two Decades of Clinical Trial Failures
Kim, C. K., Lee, Y. R., Ong, L., Gold, M., Kalali, A., & Sarkar, J. (2022) · Journal of Alzheimer s Disease · doi:10.3233/jad-215699 · Cited by 241 · see citing works
Amen, D. G., Harris, W. S., Kidd, P. M., Meysami, S., & Raji, C. A. (2017) · Journal of Alzheimer s Disease · doi:10.3233/jad-170281 · Cited by 25 · see citing works
- Authors
- Bredesen, D. E.
- Affiliations
- Buck Institute for Research on Aging (US)
- Corresponding author
- Bredesen, Dale E.
- ORCID
- Bredesen, Dale E.
- Venue
- Aging
- Publisher
- Impact Journals, LLC
- Published
- 2015-08-31
- Volume
- 7
- Issue
- 8
- Pages
- 595-600
- ISSN
- 1945-4589 (ISSN-L)
- PMC
- PMC4586104
- OpenAlex
- W1798009377
- Cited by
- 76
- References
- 19
- Citations by year
- 2025: 8 · 2024: 8 · 2023: 11 · 2022: 5 · 2021: 8 · 2020: 7 · 2019: 5 · 2018: 5 · 2017: 11 · 2016: 8
- FWCI
- 6.50
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by
- Locations
- Aging (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- National Institute on Aging (P50AG016570, AG 16570, R21AG036975, AG036975, AG034427, R01AG034427)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Nursing › Nutrition and Dietetics › Trace Elements in Health
- Keywords
- Alzheimer's disease subtypes, metabolite profiling, zinc deficiency, insulin resistance, hyperhomocysteinemia, C-reactive protein, chronic inflammation, dyscalculia, aphasia, hormone signaling, atypical Alzheimer's disease, early-onset dementia
- MeSH terms
- Aged, Alzheimer Disease, Female, Humans, Male, Middle Aged, Zinc, Metabolome
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