Background With the development of next‐generation sequencing technologies, it is possible to identify rare genetic variants that influence the risk of complex disorders. To date, whole exome sequencing (WES) strategies have shown that specific clusters of damaging rare variants in the TREM2, SORL1 and ABCA7 genes are associated with an increased risk of developing Alzheimer’s Disease (AD), reaching odds ratios comparable with the main AD genetic risk factor, the APOE‐ε4 allele. Here, we set out to identify additional AD‐associated genes by a genome‐wide investigation of the burden of rare damaging variants in the genomes of AD cases and cognitively healthy controls, the largest AD‐WES dataset available worldwide. Method We integrated the data from 25,982 cases and controls from the European ADES consortium and ADSP consortium from the USA on a single server. We developed a unique bioinformatic pipeline that applies new techniques to homogenize and analyze these data. Carriers of pathogenic variants in genes associated with Mendelian inheritance of AD were excluded. After quality control, we used 12,652 AD cases and 8,693 controls for analysis. Genes were analyzed using a burden analysis, using both non‐synonymous and loss‐of‐function rare variants. Variant impact was prioritized using REVEL. Result In our discovery phase, we confirmed and further substantiated that carriership of protein‐damaging genetic variants in TREM2, SORL1 or ABCA7 is a major AD‐risk factor. High‐impact variants in these genes are mostly extremely rare and they are enriched in AD patients with early ages at onset. Furthermore, we identified three additional genes that were significantly associated with AD, in which we identified a similar relationship between very rare, high‐impact variants and an enrichment in AD patients with early ages at onset. We are currently replicating these associations and several additional suggestive findings in independent datasets. The final results will be presented. Conclusion Development of new homogenization methods has enabled the combined analysis of the largest AD‐WES dataset worldwide. With this, we were able to validate and expand on previous findings and to identify new genetic determinants of AD. Together, these genes pinpoint the most relevant pathways in the pathophysiological processes leading to AD.

Parkinson’s disease is one of the most common age-related neurodegenerative disorders. Although predominantly a motor disorder, cognitive impairment and dementia are important features of Parkinson’s disease, particularly in the later stages of the disease. However, the rate of cognitive decline varies among Parkinson’s disease patients, and the genetic basis for this heterogeneity is incompletely understood. To explore the genetic factors associated with rate of progression to Parkinson’s disease dementia, we performed a genome-wide survival meta-analysis of 3,923 clinically diagnosed Parkinson’s disease cases of European ancestry from four longitudinal cohorts. In total, 6.7% of individuals with Parkinson’s disease developed dementia during study follow-up, on average 4.4 ± 2.4 years from disease diagnosis. We have identified the APOE ε4 allele as a major risk factor for the conversion to Parkinson’s disease dementia [hazards ratio = 2.41 (1.94–3.00), P = 2.32 × 10−15], as well as a new locus within the ApoE and APP receptor LRP1B gene [hazards ratio = 3.23 (2.17–4.81), P = 7.07 × 10−09]. In a candidate gene analysis, GBA variants were also identified to be associated with higher risk of progression to dementia [hazards ratio = 2.02 (1.21–3.32), P = 0.007]. CSF biomarker analysis also implicated the amyloid pathway in Parkinson’s disease dementia, with significantly reduced levels of amyloid β42 (P = 0.0012) in Parkinson’s disease dementia compared to Parkinson’s disease without dementia. These results identify a new candidate gene associated with faster conversion to dementia in Parkinson's disease and suggest that amyloid-targeting therapy may have a role in preventing Parkinson’s disease dementia.