Neuronal Ceroid Lipofuscinosis (NCL) is one of the most prevalent neurodegenerative disorders of early-life, Parkinson's Disease (PD) the most common neurodegenerative disorder of mid-life, while Alzheimer's disease (AD) is the most common neurodegenerative disorders of late-life. While phenotypically distinct, recent studies suggest that they might share a common biological pathway—retromer-dependent endosomal trafficking. ‘Retromer’ is a multi-modular protein assembly critical for sorting and trafficking cargo out of the endosome. As a lysosomal storage disease, all 13 of NCL's causative genes affect endolysosomal function, and at least four have been directly linked to retromer. PD has several known causative genes, with one directly linked to retromer, and others causing endolysosomal dysfunction. AD has over twenty-five causative genes/risk factors with several of them linked to retromer or endosomal trafficking dysfunction. In this article, we summarize the emerging evidence on the association of genes causing NCL to retromer function and endosomal trafficking, review the recent evidence linking NCL genes to AD and discuss how NCL, AD and PD converge onto a shared molecular pathway. We will also discuss this pathway's role in microglia and neurons - cell populations critical to proper brain homeostasis, and dysfunction of which plays a key role in neurodegeneration.

Introduction Less than 10% of early-onset Alzheimer's disease (EOAD) is explained by known mutations. Methods We conducted genetic linkage analysis of 68 well-phenotyped Caribbean Hispanic families without clear inheritance patterns or mutations in APP , PSEN1 , and PSEN2 and with two or more individuals with EOAD. Results We identified 16 (logarithm of odds > 3.6) linked regions, including eight novel loci for EOAD (2p15, 5q14.1, 11p15.1, 13q21.22, 13q33.1, 16p12.1, 20p12.1, and 20q11.21) and eight regions previously associated with late-onset Alzheimer's disease. The strongest signal was observed at 16p12.1 (25 cM, 33 Mb; heterogeneity logarithm of odds = 5.3), ∼3 Mb upstream of the ceroid lipofuscinosis 3 ( CLN3 ) gene associated with juvenile neuronal ceroid lipofuscinosis (JNCL), which functions in retromer trafficking and has been reported to alter intracellular processing of the amyloid precursor protein. Discussion This study supports the notion that the genetic architectures of unexplained EOAD and late-onset AD overlap partially, but not fully.

BackgroundDepression (DEP) is a known risk factor for . However, DEP symptoms vary by race‐ethnicity (e.g. greater somatization among African Americans). The relationship between DEP and AD progression in underrepresented groups is not well‐understood. We hypothesize that certain DEP symptoms will be associated with earlier AAO, and that this relationship is moderated by race‐ethnicityMethodSelf‐declared Non‐Hispanic White (NWH), African American (AA), and Hispanic (HI) participants with AD and CDR data were identified from a larger genetic study. Our dataset consisted of 549 persons with a self‐completed GDS (mean CDR = 0.6; 15% NWH, 43% AA, 42% HI), 334 persons with informant completed CSDD (CDR = 1.7; 41% NWH, 20% AA, 39% HI), and 266 persons with self‐reported DEP and anxiety in a medical history exam (CDR = 0.7; 26% NWH, 23% AA, 51% HI). All measures were completed after the onset of AD. Univariate linear regressions examined the relationship between AAO and DEP (total scores and individual items), and race‐ethnicity x DEP interactions after controlling for sex, race‐ethnicity, disease duration, and APOE‐e4.ResultSelf‐reported (p = 0.04), informant‐reported anxiety (CSDD) (p = 0.02), and self‐reports of feeling empty (GDS) (p = 0.02) were associated with an earlier AAO across all groups. Informant‐reports of poor self‐esteem (CSDD) was associated with an earlier AAO overall (p < 0.01), but an interaction showed that this was not significant in HI (p = 0.). Unique items associated with an earlier AAO in NHW included higher GDS total scores (p = 0.01), feeling bored (GDS) (p < 0.01), and perceived problems with memory (GDS) (p < 0.01). In AA self‐reported DEP was associated with an earlier AAO (p = 0.02). No items were uniquely associated with AAO in HI.ConclusionSelf‐ and informant‐reported anxiety and self‐reported feelings of emptiness were associated with an earlier AAO in all groups. However, several DEP symptoms associated with earlier AAO differed as a function of race‐ethnicity. We believe our findings suggest that the occurrence of DEP may be culturally or ancestrally influenced, which in turn has a differential impact on AAO in underrepresented groups.

No abstract