The DOI matches its Crossref record; 215 of the 215 references it cites were found in a registry or an index.
Heterogeneity in Alzheimer’s Disease Diagnosis and Progression Rates: Implications for Therapeutic Trials
Open accessAbstract
The clinical presentation and the pathological processes underlying Alzheimer's disease (AD) can be very heterogeneous in severity, location, and composition including the amount and distribution of AB deposition and spread of neurofibrillary tangles in different brain regions resulting in atypical clinical patterns and the existence of distinct AD variants. Heterogeneity in AD may be related to demographic factors (such as age, sex, educational and socioeconomic level) and genetic factors, which influence underlying pathology, the cognitive and behavioral phenotype, rate of progression, the occurrence of neuropsychiatric features, and the presence of comorbidities (e.g., vascular disease, neuroinflammation). Heterogeneity is also manifest in the individual resilience to the development of neuropathology (brain reserve) and the ability to compensate for its cognitive and functional impact (cognitive and functional reserve). The variability in specific cognitive profiles and types of functional impairment may be associated with different progression rates, and standard measures assessing progression may not be equivalent for individual cognitive and functional profiles. Other factors, which may govern the presence, rate, and type of progression of AD, include the individuals' general medical health, the presence of specific systemic conditions, and lifestyle factors, including physical exercise, cognitive and social stimulation, amount of leisure activities, environmental stressors, such as toxins and pollution, and the effects of medications used to treat medical and behavioral conditions. These factors that affect progression are important to consider while designing a clinical trial to ensure, as far as possible, well-balanced treatment and control groups.
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“These differences result from a combination of intrinsic factors, such as genetic background, sex, and immune system variability, as well as extrinsic influences including dietary patterns, comorbid conditions, and environmental exposures418,419.”
From Artificial intelligence-driven multi-omics approaches in Alzheimer's disease: Progress, challenges, and future directions (2025) · cites this paper as [418]
Experimental — accuracy not yet measuredIn the citing paper
“More and more research is recognizing the etiological and clinical heterogeneity of AD as a hallmark of AD and related diseases (ADRDs), which makes it more difficult to diagnose, treat, and develop and test new medications for AD.”
From Recent Advances in Therapeutics for the Treatment of Alzheimer’s Disease (2024) · cites this paper as [190]
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“Cognitive, neurological, psychological, and functional deficits are complicated and different as a result of these interactions with environmental factors.”
From Recent Advances in Therapeutics for the Treatment of Alzheimer’s Disease (2024) · cites this paper as [190]
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“The interplay between phenotypes and genotypes is part of the heterogeneity of AD.”
From Recent Advances in Therapeutics for the Treatment of Alzheimer’s Disease (2024) · cites this paper as [190]
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Cites
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“In contrast to older trials, which used McKhann criteria [157] for AD dementia, more recent trials have required a clinical diagnosis of MCI or mild dementia due to AD, consistent with the NIA-AA Working Group Criteria [158, 159].”
ResultMild cognitive impairment as a diagnostic entity
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Research works printed but not linked: 1
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Cited by
Sorted by citations
Ren, F., Wei, J., Chen, Q., Hu, M., Yu, L., Mi, J., Zhou, X., Qin, D., Wu, J., & Wu, A. (2025) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2025.07.030 · Cited by 97
Nagori, K., Nakhate, K. T., Yadav, K., Ajazuddin, & Pradhan, M. (2023) · Future Pharmacology · doi:10.3390/futurepharmacol3040053 · Cited by 61
Recent Advances in Therapeutics for the Treatment of Alzheimer’s Disease
Thawabteh, A. M., Ghanem, A. W., AbuMadi, S., Thaher, D., Jaghama, W., Karaman, D., & Karaman, R. (2024) · Molecules · doi:10.3390/molecules29215131 · Cited by 56
“More work has to be conducted to take this variability into account in order to improve the results of AD clinical trials [190–192].”
BackgroundIdentification of metabolism-related subtypes and feature genes in Alzheimer’s disease
Lian, P., Cai, X., Wang, C., Liu, K., Yang, X., Wu, Y., Zhang, Z., Ma, Z., Cao, X., & Xu, Y. (2023) · Journal of Translational Medicine · doi:10.1186/s12967-023-04324-y · Cited by 29
Natural Products from Plants and Algae for Treatment of Alzheimer’s Disease: A Review
Klose, J., Griehl, C., Roßner, S., & Schilling, S. (2022) · Biomolecules · doi:10.3390/biom12050694 · Cited by 23
A review of neuroimaging-based data-driven approach for Alzheimer’s disease heterogeneity analysis
Liu, L., Sun, S., Kang, W., Wu, S., & Lin, L. (2024) · Reviews in the Neurosciences · doi:10.1515/revneuro-2023-0033 · Cited by 16
Zhou, M., Tang, A. S., Zhang, H., Xu, Z., Ke, A. M. C., Su, C., Huang, Y., Mantyh, W. G., Jaffee, M. S., Rankin, K. P., et al. (2025) · Journal of Biomedical Informatics · doi:10.1016/j.jbi.2025.104820 · Cited by 9
Wei, H., Wu, C., Yuan, Y., & Lai, L. (2023) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2023.1249682 · Cited by 3
Generating MRI ‐Derived CSF Proxy‐Markers to Predict and Visualize Alzheimer's Disease Progression
Abrol, A., Calhoun, V. D., & Initiative, T. A. D. N. (2025) · Human Brain Mapping · doi:10.1002/hbm.70391 · Cited by 3
Metadata
- Authors
- Duara, R., & Barker, W.
- Affiliations
- Florida International University (US)
- Mount Sinai Medical Center (US)
- Corresponding author
- Barker, Warren
- Venue
- Neurotherapeutics
- Publisher
- Elsevier BV
- Published
- 2022-01
- Volume
- 19
- Issue
- 1
- Pages
- 8-25
- ISSN
- 1878-7479 (ISSN-L)
- PMC
- PMC9130395
- OpenAlex
- W4210391623
- Cited by
- 187
- References
- 215
- Citations by year
- 2026: 59 · 2025: 64 · 2024: 46 · 2023: 12 · 2022: 5
- FWCI
- 5.51
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Neurotherapeutics (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute on Aging (1P30AG066506-01)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Clinical Neurology › Amyotrophic Lateral Sclerosis Research
- Keywords
- Alzheimer's disease, disease heterogeneity, disease progression rate, amyloid-beta deposition, neurofibrillary tangles, atypical presentation, brain reserve, cognitive reserve, functional reserve, neuropsychiatric symptoms, comorbidities, vascular disease, neuroinflammation, genetic factors, demographic factors, lifestyle factors, clinical trial design
- MeSH terms
- Alzheimer Disease, Brain, Humans, Disease Progression
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