Cellular and Molecular Life Sciences

, Volume 75, Issue 14, pp 2577–2589 | Cite as

Impact of late-onset Alzheimer’s genetic risk factors on beta-amyloid endocytic production

  • Cláudia Guimas Almeida
  • Farzaneh Sadat Mirfakhar
  • Catarina Perdigão
  • Tatiana Burrinha


The increased production of the 42 aminoacids long beta-amyloid (Aβ42) peptide has been established as a causal mechanism of the familial early onset Alzheimer’s disease (AD). In contrast, the causal mechanisms of the late-onset AD (LOAD), that affects most AD patients, remain to be established. Indeed, Aβ42 accumulation has been detected more than 30 years before diagnosis. Thus, the mechanisms that control Aβ accumulation in LOAD likely go awry long before pathogenesis becomes detectable. Early on, APOE4 was identified as the biggest genetic risk factor for LOAD. However, since APOE4 is not present in all LOAD patients, genome-wide association studies of thousands of LOAD patients were undertaken to identify other genetic variants that could explain the development of LOAD. PICALM, BIN1, CD2AP, SORL1, and PLD3 are now with APOE4 among the identified genes at highest risk in LOAD that have been implicated in Aβ42 production. Recent evidence indicates that the regulation of the endocytic trafficking of the amyloid precursor protein (APP) and/or its secretases to and from sorting endosomes is determinant for Aβ42 production. Thus, here, we will review the described mechanisms, whereby these genetic risk factors can contribute to the enhanced endocytic production of Aβ42. Dissecting causal LOAD mechanisms of Aβ42 accumulation, underlying the contribution of each genetic risk factor, will be required to identify therapeutic targets for novel personalized preventive strategies.


Late-onset Alzheimer’s disease Trafficking Endocytosis APOE4 PICALM BIN1 CD2AP SORL1 PLD3 



We thank Inês Figueira for revising the manuscript. The Almeida lab has been supported by a Marie Curie Integration Grant (334366 TrafficInAD FP7-PEOPLE-2012-CIG; Marie Curie Actions, EC). iNOVA4Health—UID/Multi/04462/2013, a program financially supported by Fundação para a Ciência e Tecnologia (FCT)/Ministério da Educação e Ciência, through national funds and co-funded by FEDER under the PT2020 Partnership Agreement is acknowledged. CGA is funded by Investigator FCT (IF/00998/2012, FCT). FM has been the recipient of an FCT doctoral fellowship (PD/BD/128344/2017), CP has been the recipient of an FCT doctoral fellowship (SFRH/BD/128374/2017) and TB has been the recipient of an FCT doctoral fellowship (SFRH/BD/131513/2017).


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Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Neuronal Trafficking in Aging Lab, CEDOC, Chronic Diseases Research Centre, NOVA Medical School|Faculdade de Ciências MédicasUniversidade NOVA de LisboaLisbonPortugal

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