Background and Aims:
Dementias are devastating neurodegenerative diseases with nearly 50 million people affected worldwide. There are no available curative treatments, and large parts of the underlying biology remain unknown. Clinically, Alzheimer’s disease often coexists with cerebral vascular diseases, and the major pathological hallmark of Alzheimer’s disease is accumulation of amyloid-β in the brain and in cerebral vessels. 
This study aims to test whether genetic variants in PICALM, BIN1, CD2AP, and RIN3 – suggested to be involved in blood-brain barrier amyloid-β transcytosis pathways – associate with Alzheimer's disease, vascular dementia, all-cause dementia, and stroke, and whether such associations are independent of the strong ε4 APOE risk allele.
Methods:
In a prospective cohort study of 74,754 individuals from the general population we genotyped PICALM (rs10792832), BIN1 (rs6733839), CD2AP (rs10948363), and RIN3 (rs10498633), and generated a weighted and a simple allele score.
Results
Multifactorially adjusted hazard ratios for the fourth quartile versus the first quartile of the weighted allele score were 1.42 (95% confidence interval 1.22-1.64) for Alzheimer’s disease, 1.71 (1.18-2.49) for vascular dementia, 1.33 (1.19-1.48) for all-cause dementia and 1.12 (1.04-1.22) for stroke. Hazard ratios for all endpoints were similar after APOE adjustment.
Conclusions:
Genetic variants in PICALM, BIN1, CD2AP, and RIN3 are associated with increased risk of Alzheimer's disease, vascular dementia and all-cause dementia independent of the strong APOE ε4 allele, but do not seem to associate with stroke. These findings may suggest that clathrin-mediated endocytosis in clearance of amyloid-β across the blood-brain barrier is important for the integrity of both brain tissue and cerebral vessels.

04 - BLOOD-BRAIN BARRIER TRANSCYTOSIS GENES, RISK OF DEMENTIA AND STROKE - A PROSPECTIVE COHORT STUDY IF 74,754 INDIVIDUALS