Cited by 581Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroinflammation and Neurodegeneration Mechanisms

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Amyloid-β-independent regulators of tau pathology in Alzheimer disease

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van der Kant, Rik, Goldstein, Lawrence S. B., Ossenkoppele, Rik·2020·Nature reviews. Neuroscience

DOI 10.1038/s41583-019-0240-3

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Abstract

The global epidemic of Alzheimer disease (AD) is worsening, and no approved treatment can revert or arrest progression of this disease. AD pathology is characterized by the accumulation of amyloid-β (Aβ) plaques and tau neurofibrillary tangles in the brain. Genetic data, as well as autopsy and neuroimaging studies in patients with AD, indicate that Aβ plaque deposition precedes cortical tau pathology. Because Aβ accumulation has been considered the initial insult that drives both the accumulation of tau pathology and tau-mediated neurodegeneration in AD, the development of AD therapeutics has focused mostly on removing Aβ from the brain. However, striking preclinical evidence from AD mouse models and patient-derived human induced pluripotent stem cell models indicates that tau pathology can progress independently of Aβ accumulation and arises downstream of genetic risk factors for AD and aberrant metabolic pathways. This Review outlines novel insights from preclinical research that implicate apolipoprotein E, the endocytic system, cholesterol metabolism and microglial activation as Aβ-independent regulators of tau pathology. These factors are discussed in the context of emerging findings from clinical pathology, functional neuroimaging and other approaches in humans. Finally, we discuss the implications of these new insights for current Aβ-targeted strategies and highlight the emergence of novel therapeutic strategies that target processes upstream of both Aβ and tau.

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Authors: van der Kant, R., Goldstein, L. S. B., & Ossenkoppele, R.
Affiliations: University of California San Diego (US)
Lund University (SE)
ORCID: van der Kant, Rik
Goldstein, Lawrence S. B.
Ossenkoppele, Rik
Venue: Nature reviews. Neuroscience
Publisher: Springer Science and Business Media LLC
Published: 2019-11-28
Volume: 21
Issue: 1
Pages: 21-35
ISSN: 1471-003X (ISSN-L)
1471-0048
DOI: 10.1038/s41583-019-0240-3
OpenAlex: W2989855650
Cited by: 580
References: 216
Citations by year: 2026: 57 · 2025: 89 · 2024: 93 · 2023: 89 · 2022: 95 · 2021: 95 · 2020: 61
FWCI: 7.39
Type: journal article
Language: en
Open access: green
research.vu.nl
Licence: other-oa
www.springer.com/tdm (tdm)
www.springer.com/tdm (vor)
Locations: Nature reviews. Neuroscience (publishedVersion)
PubMed (publishedVersion)
VU Research Portal (publishedVersion, other-oa)
Lund University Publications (Lund University) (submittedVersion)
Amsterdam UMC (VU Amsterdam) - Institutional Repository (submittedVersion)
Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
Data Archiving and Networked Services (DANS) (submittedVersion)
Funders: National Institute on Aging (RF1AG048083)
Topics: Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords: Alzheimer's disease, tau pathology, amyloid-beta, apolipoprotein E, cholesterol metabolism, microglial activation, induced pluripotent stem cell models, mouse model
MeSH terms: Alzheimer Disease, Animals, Apolipoproteins E, Cholesterol, Endocytosis, Humans, Amyloid beta-Peptides, tau Proteins, Microglia, Plaque, Amyloid

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Amyloid-β-independent regulators of tau pathology in Alzheimer disease

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