Contact person
Prof. Dr. C.M. van Duijn
To contact via: B. van der Knaap
PA to Prof. Dr. C.M. van Duijn
Department of Epidemiology
Erasmus University Medical Centre
Office Ee21-73
P.O. Box 2040, 3000 CA
Rotterdam, The Netherlands
Tel: +31-10-704-3391
Fax: +31-10-704-4657
b.vanderknaap@erasmusmc.nl
www.erasmusmc.nl/epi

Gene discovery in Alzheimer's disease
Project leaders Erasmus MC: Prof. Dr. C.M. van Duijn and Prof. Dr. B.A. Oostra
Project leader VUMC: Prof. Dr. P. Heutink

Predicting Alzheimer's disease: diagnosis and prognosis
Project leader Erasmus MC: Prof. Dr. C.M. van Duijn
Project leaders LUMC: Prof. Dr. Ir. S.M. van der Maarel and Prof. Dr. M.A. van Buchem
Project leader UL: Dr. A. Alia

Within the elderly population, dementia is one of the major health problems. In Western society, Alzheimer's disease (AD) is the most common cause of dementia. AD causes impairment in intellectual functioning, which is manifested in a decline in memory, difficulty in learning, reduced ability to perform routine tasks, loss of language skills and impairment of judgment. After an insidious start, the disease shows a progressive course in which the patient's intellectual and cognitive functions gradually worsen. Patients suffering from AD often undergo personality changes and experience behavioural problems, leading to a very distressing situation for the patients, their families and caregivers. AD is strongly linked to age. Below age 70, less than 1% of the general population is affected by AD. But by age 90 years, a staggering 30% suffers from AD. As the average age of the Western population is rising, the impact of AD on society will grow further in the coming years.

Thanks to genetic research, remarkable progress has been made in unravelling the causes of AD. In particular, genetic studies in humans and subsequent biochemical research in animal models have identified four important proteins (amyloid precursor protein, presenilin 1 and 2 protein, and apolipoprotein E) as well as a key pathway (amyloid cascade) that are now targeted universally in scientific research and drug development.
However, in spite of these results, current knowledge leaves the disease unexplained in more than 82% of the patients. AD is typically divided into two categories; early onset (before age 65) and late onset. Early onset AD is an autosomal dominant hereditary disease, in which genetic factors play a crucial role. But this form is rare, accounting for less than 5% of AD patients. In the late onset form, a large number of genes are involved, most likely in interaction with each other and with environmental factors. Also vascular factors (atherosclerosis, hypertension) and inflammation are important risk factors for AD.
Research into AD has not yet produced an effective therapeutic strategy. Further dissection of the genetics is needed to increase our understanding of the disease and to reveal new genes, proteins and pathways involved. But so far, it has proven to be extremely difficult to find new genes.

Epidemiology:
Discovering new genes associated with AD starts with (genetic) epidemiological research. To this end, we employ a dual approach. In one approach, we search for genes in a genetically isolated population, as in such populations large kindreds can be reconstructed around the patients. This approach has been used successfully in Iceland as well as in the Netherlands. Of particular importance in this respect is the Genetic Research in Isolated Populations (GRIP) program, in which one of CMSB's key cohorts, the Erasmus Rucphen Family study (ERF) is based. The ERF study includes 2500 relatives from a genetically isolated population, that go back to 30 closely related founding couples, making the participants a unique single family.
The other approach involves the pursuit of candidate genes using large series of patients in unbiased population cohorts. In these studies, we pay particular attention to recent findings that indicate connectivity between AD and other conditions. One such finding is that inflammation plays a key role in the origination and progression of amyloid aggregation (formation of protein plaques) in the brain, which is characteristic of AD. There is also growing evidence that vascular factors, including atherosclerosis, hypertension and lipid levels, are involved in the pathogenesis of AD in up to 50% of the patients. Therefore, we include genes associated with inflammation and vascular diseases in our search as well.

In vitro studies:
As a valuable addition to our epidemiological studies, our technology and systems biology platforms enable in vitro studies of molecular interactions of the new genes identified. Not only will such studies support gene identification, they will also help determine whether newly identified genes are involved in the amyloid pathway or in other pathways that affect cerebral functioning. This work will be embedded in our technology and systems biology platforms. In this area, we will closely collaborate with Cyttron, a recently established platform focused on visualizing cellular processes down to atomic details.

Validation in model systems:
The roles of new genes will be validated in model systems harbouring the new mutations identified, in combination with known mutations. Model systems will also be a basis for further studies on processes underlying various forms of neuronal degeneration. Since neuronal degeneration in AD involves discrete and well-defined pathways (apoptosis, necrosis), animal model studies into the cellular and network events that trigger these cascades will be developed further.

The key objectives of the CMSB Alzheimer's disease program are to identify new genes involved in AD and related neurological and neurodegenerative diseases such as Parkinson's disease, Huntington's disease, atherosclerosis, depression and migraine, and to identify common determinants of AD, inflammation and vascular disease. Subsequently, we aim to unravel and validate pathways involved in these diseases. Thus, we aim to uncover new targets for treatment and to develop better and faster cellular and animal models for improved validation and readout in drug discovery.

1. Prokopenko I, Langenberg C, Florez JC, Saxena R, Soranzo N, Thorleifsson G, Loos RJ, Manning AK, Jackson AU, Aulchenko Y, Potter SC, Erdos MR, Sanna S, Hottenga JJ, Wheeler E, Kaakinen M, et al.: Variants in the melatonin receptor 1B gene (MTNR1B) influence fasting glucose levels, Nat Genet 2009, 41 (1): 77-81.
2. Aulchenko YS, Ripatti S, Lindqvist I, Boomsma D, Wichmann HE, Pramstaller PP, Penninx BWJH, Janssens ACJW, Wilson JF, Spector T, Martin NG, Pedersen NL, Ohm Kyvik C, Kaprio J, Hofman A, Freimer NB, Jarvelin MR, Gyllensten U, Campbell H, McCarthy MI, Duijn CM van, Peltonen L. For the ENGAGE consortium: Loci influencing lipid levels and coronary heart disease risk in 16 European population cohorts. Nat Genet 2009, 41 (1): 47-55.
3. Aulchenko YS, Hoppenbrouwers IA, Ramagopalan SV, Broer L, Jafar N, Hillert J, Link J, Lundström W, Greiner E, Sadovnick ED, Goossens D, Broeckhoven C van, Del-Favero J, Ebers GC, Oostra BA, Duijn CM van, Hintzen RQ: Genetic variation in the KIF1B locus determines susceptibility to multiple sclerosis. Nat Genet 2008, 40 (12): 1402-1403.
4. Liu F, Arias-Vasquez A, Sleegers K, Aulchenko YS, Kayser M, Sanchez-Juan P, Feng BJ, Bertoli-Avella AM, Swieten J van, Axenovich TI, Heutink P, Broeckhoven C van, Oostra BA, Duijn CM van: A genome wide screen for late-onset Alzheimer disease in a genetically isolated Dutch population. Am J Hum Genet 2007; 81: 17-31.
5. Bonifati V, Rizzu P, van Baren J, Schaap O, Breedveld GJ, Krieger E, Dekker MCJ, Squitieri F, Ibanez P, Joosse M, van Dongen JW, Vanacore N, van Swieten JC, Brice A, Meco G, van Duijn CM, Oostra BA, Heutink P. Mutations in the DJ-1 gene associated with autosomal rececessive early-onset parkinsonism. Science 2003; 299:256-259.
6. Chumakov I, Blumenfeld M, Guerassimenko O, Cavarec L, Palicio M, Abderrahim H, Bougueleret L, Barry C, Tanaka H, La Rosa P, Puech A, Tahri N, Cohen-Akenine A, Delabrosse S, Lissarrague S, Picard FP, et al.: Genetic and physiological data implicating the new human gene G72 and the gene for D-amino acid oxidase in schizophrenia. Proc Natl Acad Sci USA 2002; 99:13675-13680.
7. Van Duijn CM, Dekker MCJ, Bonifati V, Galjaard RJ, Houwing-Duistermaat JJ, Snijders PJLM, Testers L, Breedveld GJ, Horstink M, Sandkuijl LA, van Swieten JC, Oostra BA, Heutink P. PARK7, a novel locus for autosomal recessive early-onset parkinsonism on chromosome 1p36. Am J Hum Genet 2001; 69:629-634.

Erasmus Rucphen Family (ERF) study
The Erasmus Rucphen Family (ERF) study aims to identify genes involved in the pathogenesis of prognosis of complex genetic disorders. The ERF study includes 2,500 relatives from a genetically isolated population in the South Western part of the Netherlands, who constitute a unique single family. All participants are characterized for the presence of, and risk factors for, major chronic disorders, including cardiovascular disease, endocrine disorders, neuropsychiatric disorders, locomotor disease, and ophthalmologic disorders. Through a single genome screen we localize and identify genes involved in various traits.

Netherlands Twin Registry
The Netherlands Twin Registry (NTR) was founded in 1987 at the Vrije Universiteit in Amsterdam in order to perform scientific research into the contribution of genetic factors to personality and mood disorders, growth and development, brain function and cognition, and risk factors for cardiovascular disease. Currently, the NTR encompasses approximately 5,000 twin pairs aged 15 – 70 and their relatives (parents, siblings, spouses). In total, around 20,000 people have participated at least once in the longitudinal survey studies of the NTR.

Leiden 85+ Study
The Leiden 85+ Study was started in 1987 to examine the influence of genetic factors on aging and health. More than 1,500 inhabitants of Leiden aged 85 years and over have been included to generate data on cognitive status, cardiovascular disease, innate immunity, and causes of death. The Study also aims to determine why some people age in good health. For this reason, we test to which extent disease-associated genotypes are absent in old age by comparing people aged 85+ with two young control populations.

Alzheimer: ooit zeldzaam, nu volksziekte