{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,26]],"date-time":"2026-10-26T17:22:58Z","timestamp":1793035378632,"version":"4.5.0"},"reference-count":58,"publisher":"Oxford University Press (OUP)","issue":"9","license":[{"start":{"date-parts":[[2018,8,16]],"date-time":"2018-08-16T00:00:00Z","timestamp":1534377600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/about_us\/legal\/notices"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2018,9,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Late-onset Alzheimer\u2019s disease is the most common dementia type, yet no treatment exists to stop the neurodegeneration. Evidence from monogenic lysosomal diseases, neuronal pathology and experimental models suggest that autophagic and endolysosomal dysfunction may contribute to neurodegeneration by disrupting the degradation of potentially neurotoxic molecules such as amyloid-\u03b2 and tau. However, it is uncertain how well the evidence from rare disorders and experimental models capture causal processes in common forms of dementia, including late-onset Alzheimer\u2019s disease. For this reason, we set out to investigate if autophagic and endolysosomal genes were enriched for genetic variants that convey increased risk of Alzheimer\u2019s disease; such a finding would provide population-based support for the endolysosomal hypothesis of neurodegeneration. We quantified the collective genetic associations between the endolysosomal system and Alzheimer\u2019s disease in three genome-wide associations studies (combined n = 62 415). We used the Mergeomics pathway enrichment algorithm that incorporates permutations of the full hierarchical cascade of SNP-gene-pathway to estimate enrichment. We used a previously published collection of 891 autophagic and endolysosomal genes (denoted as AphagEndoLyso, and derived from the Lysoplex sequencing platform) as a proxy for cellular processes related to autophagy, endocytosis and lysosomal function. We also investigated a subset of 142 genes of the 891 that have been implicated in Mendelian diseases (MenDisLyso). We found that both gene sets were enriched for genetic Alzheimer\u2019s associations: an enrichment score 3.67 standard deviations from the null model (P = 0.00012) was detected for AphagEndoLyso, and a score 3.36 standard deviations from the null model (P = 0.00039) was detected for MenDisLyso. The high enrichment score was specific to the AphagEndoLyso gene set (stronger than 99.7% of other tested pathways) and to Alzheimer\u2019s disease (stronger than all other tested diseases). The APOE locus explained most of the MenDisLyso signal (1.16 standard deviations after APOE removal, P = 0.12), but the AphagEndoLyso signal was less affected (3.35 standard deviations after APOE removal, P = 0.00040). Additional sensitivity analyses further indicated that the AphagEndoLyso Gene Set contained an aggregate genetic association that comprised a combination of subtle genetic signals in multiple genes. We also observed an enrichment of Parkinson\u2019s disease signals for MenDisLyso (3.25 standard deviations) and for AphagEndoLyso (3.95 standard deviations from the null model), and a brain-specific pattern of gene expression for AphagEndoLyso in the Gene Tissue Expression Project dataset. These results provide evidence that a diffuse aggregation of genetic perturbations to the autophagy and endolysosomal system may mediate late-onset Alzheimer\u2019s risk in human populations.<\/jats:p>","DOI":"10.1093\/brain\/awy197","type":"journal-article","created":{"date-parts":[[2018,7,2]],"date-time":"2018-07-02T06:58:43Z","timestamp":1530514723000},"page":"2711-2720","source":"Crossref","is-referenced-by-count":78,"title":["Genetic variation within endolysosomal system is associated with late-onset Alzheimer\u2019s disease"],"prefix":"10.1093","volume":"141","author":[{"given":"Song","family":"Gao","sequence":"first","affiliation":[{"name":"Heart Health Theme, South Australian Health and Medical Research Institute, Adelaide, South Australia"},{"name":"School of Biological Sciences, University of Adelaide, Adelaide, South Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aaron E","family":"Casey","sequence":"additional","affiliation":[{"name":"Heart Health Theme, South Australian Health and Medical Research Institute, Adelaide, South Australia"},{"name":"School of Biological Sciences, University of Adelaide, Adelaide, South Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tim J","family":"Sargeant","sequence":"additional","affiliation":[{"name":"Hopwood Centre for Neurobiology, Nutrition and Metabolism Theme, South Australian Health and Medical Research Institute, Adelaide, South Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ville-Petteri","family":"M\u00e4kinen","sequence":"additional","affiliation":[{"name":"Heart Health Theme, South Australian Health and Medical Research Institute, Adelaide, South Australia"},{"name":"School of Biological Sciences, University of Adelaide, Adelaide, South Australia"},{"name":"Computational Medicine, Faculty of Medicine, University of Oulu and Biocenter Oulu, Oulu, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2018,8,16]]},"reference":[{"key":"2019071816010150200_awy197-B1","doi-asserted-by":"crossref","first-page":"505","DOI":"10.1001\/jamaneurol.2013.5847","article-title":"Amyloid-\u03b2 and Tau: the trigger and bullet in alzheimer disease pathogenesis","volume":"71","author":"Bloom","year":"2014","journal-title":"JAMA Neurol"},{"key":"2019071816010150200_awy197-B2","doi-asserted-by":"crossref","first-page":"6926","DOI":"10.1523\/JNEUROSCI.0800-08.2008","article-title":"Autophagy induction and autophagosome clearance in neurons: relationship to autophagic pathology in Alzheimer\u2019s disease","volume":"28","author":"Boland","year":"2008","journal-title":"J Neurosci"},{"key":"2019071816010150200_awy197-B3","doi-asserted-by":"crossref","first-page":"6139","DOI":"10.1093\/hmg\/ddu334","article-title":"Genetic analysis implicates APOE, SNCA and suggests lysosomal dysfunction in 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