Follow-up of loci from the International Genomics of Alzheimer's Disease Project identifies TRIP4 as a novel susceptibility gene

To follow-up loci discovered by the International Genomics of Alzheimer's Disease Project, we attempted independent replication of 19 single nucleotide polymorphisms (SNPs) in a large Spanish sample (Fundació ACE data set; 1808 patients and 2564 controls). Our results corroborate association with four SNPs located in the genes INPP5D, MEF2C, ZCWPW1 and FERMT2, respectively. Of these, ZCWPW1 was the only SNP to withstand correction for multiple testing (P=0.000655). Furthermore, we identify TRIP4 (rs74615166) as a novel genome-wide significant locus for Alzheimer's disease risk (odds ratio=1.31; confidence interval 95% (1.19-1.44); P=9.74 × 10 - 9)

New insights into the genetic etiology of Alzheimer's disease and related dementias

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele

Epidemiology of neurological diseases in elderly people: what did we learn from the Rotterdam Study?

The Rotterdam Study is a prospective cohort study that has been ongoing since 1990 in the city of Rotterdam, the Netherlands, among 7983 people aged 55 years or older. One part of the study targets neurological diseases, others deal with cardiovascular, ophthalmological, and endocrine diseases. The findings of the Rotterdam Study have been presented in some . Here we give the reasons for the study and its design, and present a summary of what has been learned about the frequencies and causes of neurological diseases. Perhaps the most important message from the Rotterdam Study is the great potential for prevention or postponement of neurological diseases in elderly people. The time for preventive nihilism is over.

Retinal vessel diameters and the role of inflammation in cerebrovascular disease

Retinal vessels may provide a way to study the cerebral microcirculation. In particular, larger retinal venular diameters have been associated with cerebrovascular disease. An inflammatory response may underlie this association. In a population-based cohort study among 5,279 participants aged 55 years or older with graded retinal vessel diameters, we observed that greater serum levels of C-reactive protein and fibrinogen and greater lipoprotein-associated phospholipase A(2) activity were strongly associated with larger venular diameters. Weaker associations were found with arteriolar diameters. Our findings support the hypothesis that larger retinal venular diameters reflect systemic inflammation and suggest that inflammation is involved in cerebrovascular disease.