Henne Holstege

DRS., (Principal Investigator)

20042019
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Personal profile

Research interests

Healthy aging

Alzheimer

Centenarians

resilience against cognitive decline

genetics

neurodegenerative disease

100-plus Study

Research interests

Research vision and research goals (August 2019)

Due to the advances in modern medicine in the past century, the majority of the Western population will reach ages beyond 75 years. This leads to an enormous increase in the prevalence of aging-related diseases, of which Alzheimer’s Disease may be considered the most devastating. The disease process involves the progressive loss of neuronal function and ultimately to neuronal cell death: cavities in the brain appear, where there were once that exerted their specific functions. The cells in every person’s brain are unique and irreplaceable: the information they held and their connections to other brain cells were the result of highly individual experiences and training which started from the earliest childhood. For this reason, the only effective cure against Alzheimer’s Disease is to prevent any damage and death. This means that we need to treat far before any clinical symptoms are noticeable. I envision that a cure for Alzheimer’s disease involves three steps: (1) we need to accurately predict who will develop the disease, (2) we need to predict which molecular pathways are predicted to underlie the decline per subject, (3) we have to develop personalized treatments that will selectively restore the function of these pathways.

Who to treat: The risk for developing Alzheimer’s Disease is ~80% heritable, therefore, each person’s risk for Alzheimer’s Disease can be accurately predicted based on their unique constellation of genetic factors. Since each individuals’ genome is available at birth, this will allow timely risk prediction and timely application of a personalized treatment strategy. I aim to identify genetic factors that modulate the risk for neurodegenerative diseases, with a focus on Alzheimer’s Disease (AD). For this, my lab leads the large international genetic sequencing studies of Alzheimer disease cases and control studies, currently encompassing the genetic information of ~25,000 individuals, I expect that this will scale up to >100,000 individuals in the next five years.

How to treat: The existence of individuals who reach ages >110 years without any signs of cognitive decline indicates that it is possible for the human brain to remain healthy until extreme ages, the question is: how? Moreover, longevity without cognitive decline is also highly heritable, such that the genetic profiles of those who escape cognitive decline until extreme ages hold precious information on maintaining cognitive health during the aging process. Therefore, next to the identification of factors that increase risk of AD, I set out to focus on factors that protect against AD. I have conceived and set up the unique 100-plus Study cohort of cognitively healthy centenarians (see www.100plus.nl). Indeed, we find that the genetic profiles of those who have escaped cognitive decline until extreme ages are enriched with protective genetic factors and depleted with risk factors. I study the downstream effects of these protective genetic factors on the composition on aged blood and brain tissues, which we collect from the centenarians. Here, I have a specific interest in the immune system and the mechanisms associated with neurodegenerative processes. Ultimately, I hope that we will be able to learn from the centenarians how to age without the burden of cognitive decline, and my hope is that the results from my experiments will contribute to a world with less, or preferably no Alzheimer’s Disease.

External positions

Technical University Delft

1 May 2013 → …

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Research Output 2004 2019

  • 33 Article
  • 1 Meeting Abstract
  • 1 Erratum
  • 1 Research VU University Amsterdam, graduation VU University Amsterdam

A nonsynonymous mutation in PLCG2 reduces the risk of Alzheimer’s disease, dementia with Lewy bodies and frontotemporal dementia, and increases the likelihood of longevity

van der Lee, S. J., Conway, O. J., Jansen, I., Carrasquillo, M. M., Kleineidam, L., van den Akker, E., Hernández, I., van Eijk, K. R., Stringa, N., Chen, J. A., Zettergren, A., Andlauer, T. F. M., Diez-Fairen, M., Simon-Sanchez, J., Lleó, A., Zetterberg, H., Nygaard, M., Blauwendraat, C., Savage, J. E., Mengel-From, J. & 37 othersMoreno-Grau, S., Wagner, M., Fortea, J., Keogh, M. J., Blennow, K., Skoog, I., Friese, M. A., Pletnikova, O., Zulaica, M., Lage, C., de Rojas, I., Riedel-Heller, S., Illán-Gala, I., Wei, W., Jeune, B., Hulsman, M., Beker, N., Tesi, N., Collij, L. E., van Berckel, B. N. M., Reinders, M. J. T., van Schoor, N. M., Lemstra, A. W., Pijnenburg, Y. A. L., Scheltens, P., Huisman, M. A., Heutink, P., Posthuma, D., van der Flier, W. M., Holstege, H., DESGESCO (Dementia Genetics Spanish Consortium), EADB (Alzheimer Disease European DNA biobank), EADB (Alzheimer Disease European DNA biobank), IFGC (International FTD-Genomics Consortium), IPDGC (The International Parkinson Disease Genomics Consortium), IPDGC (The International Parkinson Disease Genomics Consortium), RiMod-FTD (Risk and Modifying factors in Fronto-Temporal Dementia), Netherlands Brain Bank (NBB) & The GIFT (Genetic Investigation in Frontotemporal Dementia and Alzheimer’s Disease) Study Group, 1 Aug 2019, In : Acta Neuropathologica. 138, 2, p. 237-250

Research output: Contribution to journalArticleAcademicpeer-review

Open Access

Neuropathology and cognitive performance in self-reported cognitively healthy centenarians

Ganz, A. B., Beker, N., Hulsman, M., Sikkes, S., Netherlands Brain Bank, Scheltens, P., Smit, A. B., Rozemuller, A. J. M., Hoozemans, J. J. M. & Holstege, H., 2018, In : Acta Neuropathologica Communinications. 6, 1, p. 64

Research output: Contribution to journalArticleAcademicpeer-review

Open Access
Open Access

The 100-plus Study of cognitively healthy centenarians: rationale, design and cohort description

Holstege, H., Beker, N., Dijkstra, T., Pieterse, K., Wemmenhove, E., Schouten, K., Thiessens, L., Horsten, D., Rechtuijt, S., Sikkes, S., van Poppel, F. W. A., Meijers-Heijboer, H., Hulsman, M. & Scheltens, P., 25 Oct 2018, In : European Journal of Epidemiology.

Research output: Contribution to journalArticleAcademicpeer-review