Healthy aging

Alzheimer's Disease and Dementia

Centenarians

Resilience against cognitive decline

Resistance against cognitive decline

Genetics

Genetics of Neurodegenerative Disease

100-plus Study

For lab website see: www.holstegelab.eu

Reaching extreme ages with maintained cognitive function runs in families, suggesting that the genome is involved. To investigate the ‘protective genome’ and derivative cellular constellations, we have set upt the 100-plus Study (www.100plus.nl), a longitudinal cohort study of cognitively healthy centenarians. Currently the cohort includes >400 centenarians from whom we collect brain tissues, blood samples, DNA samples, and feces samples. This cohort has thus far provided a wealth of new insights into how these individuals maintained their cognitive health: we observed an enrichment of protective genetic elements, which may underlie the resistance or resilience against accumulation of specific neuropathological substrates we observed in their brains.

Genetic elements that protect against a specific phenotype commonly occur in genes that are also associated with increased risk of that phenotype. Therefore, my lab is taking a lead in the large international collaborative joint analysis of sequencing data thousands of Alzheimer Disease cases and cognitively healthy controls collected by European ADES and American ADSP consortia. We have processed the largest AD case/control exome dataset worldwide (~50,000 samples) at the Dutch Supercomputer facilities (SURF) in Amsterdam and we have identified novel genes associated with the increased or decreased risk of AD. 

We are particularly interested in the pathogenic genetic variants that occur in the SORL1 gene which are observed in an estimated ~2.75% of early onset Alzheimer Disease patients and ~1.5% of late onset AD cases. One of our major goals is, therefore, is to implement adequate clinical counseling strategies of SORL1 variants and rare variants in other genes to the carriers and their family members. Therefore, a part of the lab is embedded in the clinic, and involved in counseling genetically predisposed Alzheimer Disease patients. Futher, our interest lies in the function of the protective variant in the PLCG2 gene, and the effect of clonal hematopoiesis.

We are currently investing in the comparison of long-read sequencing of genomes from 300 centenarians and 300 AD patients, who represent the extremes on the cognitive spectrum. Structural genetic variants (SVs), such as larger deletions, insertions, duplications and inversions are associated with increased risk of neurodegenerative diseases. We have collected compelling preliminary evidence that  the expansions or contractions of specific subtype of structural genetic variants (SVs), ‘variable nucleotide tandem repeats’ VNTRs, is primarily associated with neurodegenerative diseases. Until recently it was not possible to systematically investigate the impact of SVs. Now, with the development of long-read sequencing technology, one of our major endeavours is to investigate the effect of VNTRs on AD risk.

(February 2022)