Caroline Graff Group

Translational Genetics in Neurodegenerative disease

Research focus

We call ourselves Translational Genetics in Neurodegenerative disease and consist of three teams: Team Clinical Genetics, Team Molecular Genetics and Team Neuropathology and Functional Genetics.

We study the genetics and neuropathology of neurodegenerative diseases in particular Alzheimer disease (AD), Frontotemporal lobar degeneration (FTLD) and FTLD associated with amyotrophic lateral sclerosis (ALS). Our research is translational since team members are working both with genetic counselling as well as with research.

Our activities include:

  • studies of families with inherited dementia
  • association studies in case-control cohorts
  • neuropathological studies of human brain tissue
  • studies of mechanisms of neurodegeneration, spread of Aβ pathology and effect on intracellular functions such as mitochondria and autophagy in an in-house transgenic mouse model of AD (TgAPParc)
  • genetic counselling for families with inherited forms of dementia in the Memory clinic at Karolinska University hospital, Huddinge
  • screening patient samples from the clinic for mutations in known disease causing genes and apply our result in a clinical genetics setting

Research projects

Below follows a description of two of our research projects:

The Brain Bank at Karolinska Institutet

The Brain Bank at Karolinska Institutet is a new core-facility (from 2013) with the overall goal to build up and maintain the infrastructure of a brain bank for research on human brain and spinal cord tissue. We have established a brain donation program for informed consent and standardized collection of high quality nervous tissue which is available to anyone who wants to be a donor or wish to include brain/spinal cord donation in their research studies. Interested researchers are welcome to apply for brain tissue from the Brain Bank at KI. Tissue request forms are available at our home page.  All procedures will conform to the highest ethical, legal and scientific standards to meet the needs of tissue donors, the general community and researchers.  For more information see ki.se/brainbank or contact us at Brainbank@nvs.ki.se

Experimental and clinical studies of inherited forms of dementia

Of particular interest is to develop biomarkers for early diagnosis in AD and FTLD which we do by studying family members with 50% risk of inheriting a dominant disease causing mutation. During the course of the study the study subjects perform an extensive battery of clinical examinations as well as tissue sampling. Our hope is to better understand the natural history of AD and FTLD respectively, develop specific and sensitive biomarkers for early diagnosis and identify new drug targets. We also hope that our research will facilitate future clinical trials in this group of patients with early onset autosomal dominant disease.  Naturally being brought up in families with inherited forms of neurodegenerative disease has an effect on the family members on an existential and emotional level. Thus, we conduct quantitative (questionnaires) and qualitative (interviews) studies to get a better understanding of what it is like to live with the risk to develop early onset AD.

We are partners in several national and international collaborations such as: Swedish Brain Power, Strat Neuro, Brain Net Europe, IGAP (International Genomics of Alzheimer’s Project), ECEOD (European Consortium on Early Onset Dementia, EADC (European Alzheimer Disease Consortium), GENFI (Genetic FTD initiative) and FTD-GWAS. 

Selected publications

A unique gene expression signature discriminates familial Alzheimer's disease mutation carriers from their wild-type siblings.
Nagasaka Y, Dillner K, Ebise H, Teramoto R, Nakagawa H, Lilius L, et al
Proc. Natl. Acad. Sci. U.S.A. 2005 Oct;102(41):14854-9

Genome scan on Swedish Alzheimer's disease families.
Sillén A, Forsell C, Lilius L, Axelman K, Björk B, Onkamo P, et al
Mol. Psychiatry 2006 Feb;11(2):182-6

Positive association between risk for late-onset Alzheimer disease and genetic variation in IDE.
Björk B, Katzov H, Kehoe P, Fratiglioni L, Winblad B, Prince J, et al
Neurobiol. Aging 2007 Sep;28(9):1374-80

Progranulin mutation causes frontotemporal dementia in the Swedish Karolinska family.
Chiang H, Rosvall L, Brohede J, Axelman K, Björk B, Nennesmo I, et al
Alzheimers Dement 2008 Nov;4(6):414-20

The PSEN1 I143T mutation in a Swedish family with Alzheimer's disease: clinical report and quantification of Aβ in different brain regions.
Keller L, Welander H, Chiang H, Tjernberg L, Nennesmo I, Wallin A, et al
Eur. J. Hum. Genet. 2010 Nov;18(11):1202-8

The obesity related gene, FTO, interacts with APOE, and is associated with Alzheimer's disease risk: a prospective cohort study.
Keller L, Xu W, Wang H, Winblad B, Fratiglioni L, Graff C
J. Alzheimers Dis. 2011 ;23(3):461-9

Mutation screening of patients with Alzheimer disease identifies APP locus duplication in a Swedish patient.
Thonberg H, Fallström M, Björkström J, Schoumans J, Nennesmo I, Graff C
BMC Res Notes 2011 Nov;4():476

Amyloid neuropathology in the single Arctic APP transgenic model affects interconnected brain regions.
Rönnbäck A, Sagelius H, Bergstedt K, Näslund J, Westermark G, Winblad B, et al
Neurobiol. Aging 2012 Apr;33(4):831.e11-9

Low PiB PET retention in presence of pathologic CSF biomarkers in Arctic APP mutation carriers.
Schöll M, Wall A, Thordardottir S, Ferreira D, Bogdanovic N, Långström B, et al
Neurology 2012 Jul;79(3):229-36

A pan-European study of the C9orf72 repeat associated with FTLD: geographic prevalence, genomic instability, and intermediate repeats.
van der Zee J, Gijselinck I, Dillen L, Van Langenhove T, Theuns J, Engelborghs S, et al
Hum. Mutat. 2013 Feb;34(2):363-73

Dissertations

2008 Behnosh Fakhri Björk

Thesis title: Association studies on susceptibility genes in Alzheimer disease

2010 Lina Keller

Thesis title: Genetics in Dementia: Impact of sequence variations for families and populations

2012 Huei-Hsin Chiang

Thesis title: Genetic characterization of patients with frontotemporal dementia and amyotrophic lateral sclerosis in the Nordic countries

Group members

Research group leader, professor, MD, PhD

Caroline Graff

Phone: +46-(0)8-585 836 19
E-mail: Caroline.Graff@ki.se

Team Clinical Genetics:

 

Name

Position

Email address

Phone number

Anne Kinhult Ståhlbom

PhD, Genetic counsellor, Team leader

anne.kinhult-stahlbom@karolinska.se

08-585 837 87

Jenny Björkström

Genetic counsellor 

jenny.bjorkstrom@karolinska.se

08-585 864 71

Marie Fallström

Genetic counsellor, Coordinator of the Brain Bank at KI

marie.fallstrom@karolinska.se

08-585 836 67

Mette Bergman

Medical social worker, PhD Student

mette.bergman@ki.se

08-585 837 87

Steinunn Thordardottir

MD, PhD Student

steinunn.thordardottir@karolinska.se

08-585 837 87

Linn Öijerstedt

MD, PhD student

linn.oijerstedt@ki.se 

08-585 83787

Team Molecular Genetics:

 

Name

Position

Email address

Phone number

Håkan Thonberg

PhD, Molecular geneticist, Team leader

hakan.thonberg@karolinska.se

08-585 837 87

Lena Lilius

BMA

lena.lilius@ki.se

08-585 836 28

Lotta Forsell

BMA

lotta.forsell@ki.se

08-585 836 28

Huei-Hsin Chiang

PhD, Affiliated member

huei-hsin.chiang@ki.se

08-585 836 28

Team Neuropathology and Functional Genetics:

 

Name

Position

Email address

Phone number

Annica Rönnbäck

PhD, Team leader

annica.ronnback@ki.se

08-585 836 24

Anna-Karin Lindström

BMA at the Brain Bank at KI

anna-karin.lindstrom@ki.se

08-585 836 67

Antonio Piras

PhD, Hoffmann-La Roche Postdoctoral Fellow

antonio.piras@ki.se

08-585 836 28

GeneticsNeurobiologyPathology