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

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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Fig. 1: The amyloid-cascade hypothesis and the dual-cascade hypothesis of AD.
Fig. 2: Progression of Aβ and tau pathology in AD.
Fig. 3: Sporadic AD-associated pathways that act as upstream regulators of both Aβ and tau pathology.
Fig. 4: Testing the amyloid-cascade hypothesis in patients with AD.

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Acknowledgements

The authors thank P. Scheltens, J. Young and P. van Bokhoven for discussion and critical reading of the manuscript, and D. Berron for assistance with figure preparation. R.v.d.K. is supported by an Alzheimer Netherlands Pilot Grant (WE.-3-2017-09) and by a Weston Brain Institute Rapid Response Netherlands Grant (NR170059). L.S.B.G. is supported by National Institute on Ageing (NIA) grant 1RF1AG048083-01 and by California Institute for Regenerative Medicine (CIRM) RB5-07011 grants.

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R.v.d.K. and R.O. researched data for the article. All authors contributed substantially to discussions of the article content and to the writing, review and/or editing of the manuscript before submission.

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Correspondence to Rik van der Kant.

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Glossary

Neurofibrillary tangles

(NFTs). Intraneuronal aggregates of hyperphosphorylated tau abnormally folded into paired helical filaments. Tau pathology develops late in the progression of Alzheimer disease, and its severity correlates well with cognitive impairment and local neurodegeneration.

Mild cognitive impairment

(MCI). A clinical state characterized by objective cognitive impairment that does not interfere with daily functioning and is insufficient for the diagnosis of dementia. Patients with amyloid-β (positron emission tomography or cerebrospinal fluid) biomarker positivity are considered to have MCI due to Alzheimer disease.

Aβ immunoclearance

Pharmaceutical intervention aimed at clearing amyloid-β plaques and/or oligomerized peptides from the brains of patients with Alzheimer disease. Has been the major focus for the development of treatments for Alzheimer disease.

Positron emission tomography

(PET). Functional imaging technique that measures gamma rays emitted by radioactively labelled tracers and is used to track biological processes in vivo. Several PET tracers for amyloid-β and tau have been developed that can measure Alzheimer disease pathology in living individuals.

Aβ plaques

Aggregates of amyloid-β (Aβ) protein that accumulate extracellularly in individuals with Alzheimer disease. Aβ plaques (also known as neuritic or senile plaques) develop early in the course of Alzheimer disease but do not correlate well with cognitive decline or local neurodegeneration.

Primary age-related tauopathy

(PART). A neuropathological condition characterized by neurofibrillary tangles, restricted mostly to the temporal lobe in the absence of amyloid-β; evident in the brains of approximately 20% of cognitively normal elderly individuals.

β-secretase C-terminal fragment of APP

(βCTF). Direct precursor of amyloid-β (Aβ) that is generated by β-secretase cleavage of full-length amyloid precursor protein, prior to its γ-secretase cleavage to Aβ. Aβ and βCTF are therefore generated at equimolar concentration. βCTF drives the accumulation of phosphorylated tau in neurons from patients with familial Alzheimer disease.

Polymorphisms

Genetic variants that occur in at least 1% of the population; rare variants occur at frequencies below 1%.

Proteasomal degradation

The process by which cells recycle unneeded or damaged cytosolic proteins. Such proteins are first ubiquitylated, which targets them for degradation by the proteasome (a proteolytic multisubunit protein complex).

Endocytic system

An interconnected network of membranous vesicles that internalize molecules from the plasma membrane and transport them through the cell. Depending on the specific route of transport, molecules can be degraded in lysosomes or recycled back to the surface.

Retromer

A multiprotein sorting complex on early endosomes that redirects cargo molecules (such as amyloid precursor protein) from the endosome to the trans-Golgi network or the plasma membrane, which prevents their trafficking into the late endocytic system where they can be degraded.

Disease-associated microglia

A subset of activated microglia found at sites of neurodegeneration.

Adeno-associated virus

(AAV). A small virus that infects humans without causing disease and that can be engineered to deliver target genes into humans (gene therapy).

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van der Kant, R., Goldstein, L.S.B. & Ossenkoppele, R. Amyloid-β-independent regulators of tau pathology in Alzheimer disease. Nat Rev Neurosci 21, 21–35 (2020). https://doi.org/10.1038/s41583-019-0240-3

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