Resolving controversies on the path to Alzheimer's therapeutics
Abstract
Alzheimer's disease constitutes a personal and societal tragedy of immense proportions. Since 1960, research in laboratories and clinics worldwide has elucidated many features of this insidious and ultimately fatal syndrome, and this progress has led to initial human trials of potentially disease-modifying agents. However, some of these agents have already failed. Gnawing controversies and important gaps in our knowledge seem to cast additional doubt on the ability of the field to move forward effectively. Here I discuss some of these looming concerns and offer possible explanations for the major trial failures that suggest they are not predictive of the future. Rigorous preclinical validation of mechanism-based therapeutic agents followed by meticulously designed trials that focus on the cardinal cognitive symptoms and their associated biomarkers in the mild or presymptomatic phases of Alzheimer's disease are likely to lead to success, perhaps in the not-too-distant future.
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Accumulation of β-amyloid (Aβ) in the brain is essential to Alzheimer's disease pathogenesis.
“Accumulation of β-amyloid (Aβ) in the brain is essential to Alzheimer’s disease (AD) pathogenesis.”
From Blocking the apoE/Aβ interaction ameliorates Aβ-related pathology in APOE ε2 and ε4 targeted replacement Alzheimer model mice (2014) · cites this paper as [2]
Disturbance of Aβ homeostasis leading to progressive accumulation in the brain is a driving mechanism of Alzheimer's disease pathogenesis.
“Converging lines of evidence derived from genetic, neuropathological, biomarker, and transgenic animal studies implicate disturbance of Aβ homeostasis leading to its progressive accumulation in the brain as a driving mechanism of AD pathogenesis (reviewed in [1,2]).”
From Blocking the apoE/Aβ interaction ameliorates Aβ-related pathology in APOE ε2 and ε4 targeted replacement Alzheimer model mice (2014) · cites this paper as [2]
The accumulation of Aβ in the brain is considered to be a prime target of disease-modifying therapies for AD.
“The accumulation of Aβ in the brain is considered to be a prime target of disease-modifying therapies for AD [2].”
From Blocking the apoE/Aβ interaction ameliorates Aβ-related pathology in APOE ε2 and ε4 targeted replacement Alzheimer model mice (2014) · cites this paper as [2]
Autopsy series and PET imaging studies of fibrillar Aβ plaque load in AD patients have shown an ε4>>ε3>ε2 allele gradation effect on Aβ deposition.
“Autopsy series and more recently positron emission tomography (PET) imaging studies of fibrillar Aβ plaque load in AD patients have shown ε4> > ε3 > ε2 allele gradation effect on Aβ deposition [1–3].”
From APOE Genotype Differentially Modulates Effects of Anti-Aβ, Passive Immunization in APP Transgenic Mice (2017) · cites this paper as [2]
APOE genotype influences the load of Aβ parenchymal plaques and vascular Aβ (VAβ) deposits.
“Susceptibility to sporadic AD is foremost modulated by APOE genotype, which also influences the load of Aβ parenchymal plaques and vascular Aβ (VAβ) deposits.”
From APOE Genotype Differentially Modulates Effects of Anti-Aβ, Passive Immunization in APP Transgenic Mice (2017) · cites this paper as [2]
Previous studies of our group have identified molecular differences between SAD and FAD in addition to divergences in clinical manifestations.
“Previous studies of our group have identified molecular differences between SAD and FAD [55, 56, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79] in addition to divergences in the clinical manifestations [55, 56].”
From Gliovascular alterations in sporadic and familial Alzheimer's disease: <scp><i>APOE3</i></scp> Christchurch homozygote glioprotection (2023) · cites this paper as [70]
Genetic, pathological, and biochemical evidence suggests that elevation of Aβ levels is a causal event in AD pathogenesis that lies upstream of tau-induced neurodegeneration.
“Genetic, pathological, and biochemical evidence suggests that elevation of Aβ levels is a causal event in AD pathogenesis [2–8] that lies upstream of tau-induced neurodegeneration [3, 5, 9, 10].”
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Self-citation
- Authors
- Selkoe, D. J.
- Affiliations
- Brigham and Women's Hospital (US)
- Corresponding author
- Selkoe, Dennis J
- ORCID
- Selkoe, Dennis J
- Venue
- Nature Medicine
- Published
- 2011-09
- Volume
- 17
- Issue
- 9
- Pages
- 1060-1065
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- OpenAlex
- W2084121214
- Cited by
- 494
- References
- 9
- Citations by year
- 2026: 4 · 2025: 10 · 2024: 15 · 2023: 13 · 2022: 22 · 2021: 28 · 2020: 28 · 2019: 30 · 2018: 21 · 2017: 37 · 2016: 34 · 2015: 44 · 2014: 59 · 2013: 65 · 2012: 73
- FWCI
- 45.36
- Type
- journal article
- Language
- en
- Update notices
- Open access
- closed
- Locations
- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Pharmacology › Cholinesterase and Neurodegenerative Diseases
- Keywords
- Alzheimer's disease, disease-modifying therapy, clinical trial failure, preclinical validation, biomarkers, preclinical Alzheimer's disease, cognitive symptoms, therapeutic target
- MeSH terms
- Alzheimer Disease, Clinical Trials as Topic, Drug Evaluation, Preclinical, Humans, Research Design, Amyloid beta-Peptides, Plaque, Amyloid
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