A remarkable accomplishment of human beings in recent centuries is the extension of their average lifespan, for example by improved living conditions. A downside of this achievement is that aging-related diseases, such as Alzheimer’s disease (AD), have risen, and as a consequence are impacting the lives of an increasing fraction of individuals. Although many conclude that aging is the main risk factor for AD, it might be better to say AD is one facet of aging. Indeed, the boundaries between brain aging and AD are largely fluent in the elderly. Nevertheless, dementia and AD are not inevitable. In fact, a small proportion of the population (<0.1%) reaches at least 100 years old while maintaining to have a healthy cognition. These rare but remarkable centenarians could shed light on how to escape age-related diseases.
This thesis studies cognitive healthy centenarians as extreme controls in the context of aging and AD. Based on a large cohort of data, this thesis indeed shows that some centenarians escaped the buildup of some neuropathologies, indicating resistance to these neuropathologies. Contrarily, this thesis also shows that average levels of AD-associated neuropathologies increase with age in non-demented individuals, whereas these neuropathologies decrease with age in AD cases. Most intriguingly, this thesis shows that some centenarians with the highest cognitive performance, did accumulate the highest levels of some neuropathologies, yet remained cognitive healthy. This thesis then speculates that these observations point towards a resilience to these neuropathologies by these centenarians.
To better understand the resilience and resistance mechanisms in centenarian brains, this thesis then continues with investigating brain proteomics in the context of the degree of AD pathology (Braak stages) as well as age. As a first characterization, clusters of Braak stage-related and age-related proteins are identified that separately are associated with specific biological processes. Some Braak stage-related proteins demonstrate a deviated abundance in centenarians compared to AD (at the Braak stage IV), indicating that these proteins may contribute to the resilient mechanisms of tau accumulation in centenarian brains. A remarkable finding regarding the age-related proteins is that centenarian brains are, in a median of, 18-years “younger" in their protein expression, when compared with non-demented controls, again hinting towards a resilience to age-related diseases.
To further explore the possible role of aging behind AD, this thesis studies the extend and locations of brain somatic mutations. We show that the number of excitatory neuron specific-somatic mutations increases with age, but there is no significant difference between AD and non-demented individuals. Interestingly, certain somatic mutations occurred more frequently in the brains of AD patients.
Concluding, this thesis demonstrates the value of cognitive healthy centenarians in studying brain aging and neurodegenerative diseases. In doing so, it reveals that the relationship between brain aging and neurodegeneration is extremely complex and deeply entangled. Nevertheless, basic processes that are altered during brain aging are identified, which brings targets to counteract the molecular disorder that leads to neurodegeneration, including AD, closer.

Motivation: Alzheimer’s disease (AD) is a highly prevalent disease whose genetic risk factors remain largely unknown. One potential genetic risk factor is tandem repeat expansions, which have been associated with over 40 diseases, most of which affect the nervous system. Detecting VNTRs from short-read data is a challenging task, leaving many VNTRs unidentified. To date only one variable number tandem repeat (VNTR) expansion (in the ABCA7 gene) has been linked to AD. We hypothesize there are many more VNTR expansions to be discovered that associate with an increased risk of AD.
Results: We created a pipeline with which we overcame the common limitations of VNTR detection (namely, the need for a predefined set of repeats and limited detectable VNTR sizes due to read length). We performed a genome-wide search for VNTRs with a motifsize ≥ 7 bp that show repeat size variations associated with AD. We detected 71 VNTR expansions and 1242 contractions, including expansions in genes ADAMTSL3, ARHGEF10, DIP2C, EVC2, GRM8, MPPED1, PID1 and an expansion in the SCIMP gene close to a well-known AD single nucleotide polymorphism (SNP). Our pipeline is, to our knowledge, one of the very few to detect VNTRs exceeding read length without a predefined set of repeats. It is able to detect both previously reported and novel VNTRs, resulting in a promising set of VNTRs showing an association with AD.