The Evolution of Preclinical Alzheimer’s Disease: Implications for Prevention Trials
Open accessAbstract
As the field begins to test the concept of a "preclinical" stage of neurodegenerative disease, when the pathophysiological process has begun in the brain, but clinical symptoms are not yet manifest, a number of intriguing questions have already arisen. In particular, in preclinical Alzheimer's disease (AD), the temporal relationship of amyloid markers to markers of neurodegeneration and their relative utility in the prediction of cognitive decline among clinically normal older individuals remains to be fully elucidated. Secondary prevention trials in AD have already begun in both genetic at-risk and amyloid at-risk cohorts, with several more trials in the planning stages, and should provide critical answers about whether intervention at this very early stage of disease can truly bend the curve of clinical progression. This review will highlight recent progress in cognitive, imaging, and biomarker outcomes in the field of preclinical AD, and the remaining gaps in knowledge.
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Successful translation from neurodegenerative animal models to human clinical trials is far from adequate.
“successful translation from neurodegenerative animal models to human clinical trials is far from adequate”
From Cross-Species Single-Cell Analysis Reveals Divergence of the Primate Microglia Program (2019) · cites this paper as Sperling et al., 2014
The Introduction reports a failure to develop successful disease-modifying therapies for neurodegenerative disease and notes that most interventions were tested in people with clinically manifest illness. It does not attribute that failure to inadequate translation from animal models to human clinical trials; the animal-to-human comparison in the claim is unsupported. (LLM, conf=0.82)
Experimental — accuracy not yet measuredCerebral deposition of amyloid-beta fibrils can occur decades before an individual shows clinical symptoms.
“Previous studies have shown that the cerebral deposition of Aβ fibrils can occur decades before an individual shows clinical symptoms [18].”
From Clinical trials of new drugs for Alzheimer disease (2020) · cites this paper as [18]
In early detection of neurodegenerative disorders such as Alzheimer's disease, key indices of preclinical stages are cognitive, motor and sensory changes that occur 10 or 15 years prior to effective diagnosis.
“early detection of neurodegenerative disorders such as Alzheimer’s disease (AD), in which key indices of preclinical stages are cognitive, motor and sensory changes that occur 10 or 15 years prior to its effective diagnosis43,44.”
From Sex and gender differences and biases in artificial intelligence for biomedicine and healthcare (2020) · cites this paper as [43]
Cerebral deposition of Aβ fibrils can occur for decades before an individual with AD reaches the dementia stage.
“Previous studies have shown that cerebral deposition of Aβ fibrils can occur for decades before an individual with AD reaches the dementia stage2.”
From Earliest accumulation of β-amyloid occurs within the default-mode network and concurrently affects brain connectivity (2017) · cites this paper as [2]
Cerebral Aβ fibril deposition may occur decades before the onset of clinical symptoms.
“Cerebral Aβ fibril deposition may occur decades before the onset of clinical symptoms [8].”
From Clinical trials of new drugs for Alzheimer disease: a 2020–2023 update (2023) · cites this paper as [8]
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- Authors
- Sperling, R., Mormino, E., & Johnson, K.
- Affiliations
- Brigham and Women's Hospital (US)
- Harvard University (US)
- Corresponding author
- Sperling, Reisa
- Venue
- Neuron
- Publisher
- Elsevier BV
- Published
- 2014-11
- Volume
- 84
- Issue
- 3
- Pages
- 608-622
- ISSN
- 0896-6273 (ISSN-L)
- PMC
- PMC4285623
- OpenAlex
- W2011195206
- Cited by
- 725
- References
- 170
- Citations by year
- 2026: 30 · 2025: 59 · 2024: 38 · 2023: 61 · 2022: 70 · 2021: 84 · 2020: 85 · 2019: 78 · 2018: 78 · 2017: 63 · 2016: 38 · 2015: 41
- FWCI
- 6.47
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Neuron (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute on Aging (K24AG035007, R01AG046396, R01AG027435, F32AG044054, P01AG036694)
- 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 › Medicine › Pulmonary and Respiratory Medicine › Cancer-related cognitive impairment studies
- Keywords
- preclinical Alzheimer's disease, amyloid biomarkers, neurodegeneration biomarkers, cognitive decline prediction, disease progression, neuroimaging biomarkers, cognitive biomarkers
- MeSH terms
- Alzheimer Disease, Animals, Cognition Disorders, Drug Evaluation, Preclinical, Humans, Antipsychotic Agents, Biomedical Research, Neuroimaging
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