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Suche nach Risikogenen bei der Alzheimer-Erkrankung

Search for risk genes in Alzheimer’s disease

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Zusammenfassung

Die Alzheimer-Erkrankung („Alzheimer’s disease“, AD) ist die häufigste Form der neurodegenerativen Demenz. Die Suszeptibilität für die AD wird durch eine komplexe Interaktion zwischen genetischen, epigenetischen und Umweltfaktoren bestimmt. Generell beträgt das Risiko, welches genetischen Faktoren zugeordnet werden kann, ca. 80 %. Obwohl die meisten AD-Fälle sporadisch sind, gibt es jedoch auch Familien mit seltenen voll penetranten Mutationen in APP, PSEN1 und PSEN2. Diese sind jedoch sehr selten und kaum mit sporadischen Fällen assoziiert. Über 20 Jahre lang war das APOE-ε4-Allel der einzige bekannte genetische Risikofaktor der sporadischen AD, der die Suszeptibilität zur AD in etwa dreifach erhöht. Durch die Entwicklung der genomweiten Assoziationsstudien wurde die Suche nach zusätzlichen genetischen Faktoren vorangetrieben und führte zur Identifizierung 26 neuer Risikovarianten. Bei genauerer Betrachtung lassen sich diese Gene in verschiedene Gruppen einordnen, die maßgeblich in bestimmten biologischen Signalwegen zusammengefasst werden können, wie Cholesterol- und Lipidmetabolismus, Immunantwort sowie endozytotische Transportvorgänge; u. a. mithilfe neuer Sequenziermethoden wurden zudem neue Impulse in der Risikogensuche gesetzt. Durch die Exomsequenzierung wurden Assoziationen zwischen der AD und seltenen kodierenden Varianten bei TREM2, SORL1 und ABCA1 aufgedeckt (geringere Allelfrequenz <1 %). Somit hat der Fortschritt der genetischen Forschung maßgeblich zum Verständnis der Krankheitsmechanismen beigetragen. Doch obwohl unser Wissen über die Genetik der AD deutlich vorangeschritten ist, ist es noch weit davon entfernt, vollständig zu sein. Um jedoch die genaue Architektur der AD zu vervollständigen, muss weitere intensive Forschung betrieben werden.

Abstract

Alzheimer’s disease (AD) is the most common form of neurodegenerative dementia. The susceptibility to AD is determined by a complex interaction between genetic, epigenetic, and environmental factors. Herein, the risk that can be attributed to genetic factors is high (up to 80%). While most AD patients are sporadic, in rare families Mendelian mode of inheritance can be observed. In these rare familial cases, full penetrant mutations have been identified in APP, PSEN1, and PSEN2. Mutations in these three genes are however rarely found in sporadic AD. For over 20 years, the only known genetic risk factor in sporadic AD cases was the APOE-ε4 allele, which increases susceptibility to AD by approximately threefold. Unfortunately, none of these genes explain the frequency of AD. Identification of additional genetic factors was propelled by the advent of genomic approaches such as genome-wide association studies, which has already led to the characterization of 26 novel genetic risk factors. Interestingly, several of these genetic signals cluster in biological pathways including cholesterol, lipid metabolism, immune response, and endocytic trafficking. An additional impulse in genetic research came from the development of novel sequencing technologies. For example, the whole exome sequencing approach has identified an association between the risk of AD and rare coding variants (minor allele frequency <1%) located in genes such as TREM2, SORL1, and ABCA7. Thus, progress from genetic research has significantly increased our understanding of the disease mechanisms operating in AD. However, even though our knowledge of the genetics of sporadic forms of AD has progressed markedly over the last years, it is still far from complete. Additional research is needed to complete the genetic architecture of AD.

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  1. Klinik und Poliklinik für Psychiatrie und Psychotherapie, Universitätsklinikum Bonn, 53127, Bonn, Deutschland

    I. Karaca, H. Wagner &  A. Ramirez

  2. Institut für Humangenetik, Universität Bonn, 53127, Bonn, Deutschland

    A. Ramirez

  3. Klinik und Poliklinik für Psychiatrie und Psychotherapie, Uniklinik Köln, Kerpener Straße 62, 50937, Köln, Deutschland

    A. Ramirez

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Karaca, I., Wagner, H. & Ramirez, A. Suche nach Risikogenen bei der Alzheimer-Erkrankung. Nervenarzt 88, 744–750 (2017). https://doi.org/10.1007/s00115-017-0354-7

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