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Genetic forms of tauopathies: inherited causes and implications of Alzheimer's disease-like TAU pathology in primary and secondary tauopathies

  • Tauopathies are a heterogeneous group of neurologic diseases characterized by pathological axodendritic distribution, ectopic expression, and/or phosphorylation and aggregation of the microtubule-associated protein TAU, encoded by the gene MAPT. Neuronal dysfunction, dementia, and neurodegeneration are common features of these often detrimental diseases. A neurodegenerative disease is considered a primary tauopathy when MAPT mutations/haplotypes are its primary cause and/or TAU is the main pathological feature. In case TAU pathology is observed but superimposed by another pathological hallmark, the condition is classified as a secondary tauopathy. In some tauopathies (e.g. MAPT-associated frontotemporal dementia (FTD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and Alzheimer's disease (AD)) TAU is recognized as a significant pathogenic driver of the disease. In many secondary tauopathies, including Parkinson's disease (PD) and Huntington's disease (HD), TAU is suggested to contribute to the development of dementia, but in others (e.g. Niemann-Pick disease (NPC)) TAU may only be a bystander. The genetic and pathological mechanisms underlying TAU pathology are often not fully understood. In this review, the genetic predispositions and variants associated with both primary and secondary tauopathies are examined in detail, assessing evidence for the role of TAU in these conditions. We highlight less common genetic forms of tauopathies to increase awareness for these disorders and the involvement of TAU in their pathology. This approach not only contributes to a deeper understanding of these conditions but may also lay the groundwork for potential TAU-based therapeutic interventions for various tauopathies.

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Document Type:Article
Author:Felix Langerscheidt, Tamara Wied, Mohamed Aghyad Al Kabbani, Thilo van Eimeren, Gilbert Wunderlich, Hans Zempel
Parent Title (English):Journal of Neurology
Number of pages:27
First Page:2992
Last Page:3018
Publishing Institution:Hochschule Bonn-Rhein-Sieg
Date of first publication:2024/03/30
Copyright:© The Author(s) 2024. This article is licensed under a Creative Commons Attribution 4.0 International License.
Funding:This work was supported by the Koeln Fortune Program/Faculty of Medicine, University of Cologne, and the Alzheimer Forschungs Initiative e.V.
Keyword:Alzheimer Disease/genetics/pathology; Alzheimer’s disease; Genetic tauopathy; Humans; MAPT; Primary tauopathy; Secondary tauopathy; TAU; Tauopathies/genetics/pathology; tau Proteins/genetics/metabolism
Departments, institutes and facilities:Fachbereich Angewandte Naturwissenschaften
Dewey Decimal Classification (DDC):5 Naturwissenschaften und Mathematik / 57 Biowissenschaften; Biologie / 576 Genetik und Evolution
Entry in this database:2024/06/05
Licence (German):License LogoCreative Commons - CC BY - Namensnennung 4.0 International