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Recent large-scale genetic studies have allowed for the first glimpse of the effects of common genetic variability in dementia with Lewy bodies (DLB), identifying risk variants with appreciable effect sizes. However, it is currently well established that a substantial portion of the genetic heritable component of complex traits is not captured by genome-wide significant SNPs. To overcome this issue, we have estimated the proportion of phenotypic variance explained by genetic variability (SNP heritability) in DLB using a method that is unbiased by allele frequency or linkage disequilibrium properties of the underlying variants. This shows that the heritability of DLB is nearly twice as high as previous estimates based on common variants only (31% vs 59.9%). We also determine the amount of phenotypic variance in DLB that can be explained by recent polygenic risk scores from either Parkinson's disease (PD) or Alzheimer's disease (AD), and show that, despite being highly significant, they explain a low amount of variance. Additionally, to identify pleiotropic events that might improve our understanding of the disease, we performed genetic correlation analyses of DLB with over 200 diseases and biomedically relevant traits. Our data shows that DLB has a positive correlation with education phenotypes, which is opposite to what occurs in AD. Overall, our data suggests that novel genetic risk factors for DLB should be identified by larger GWAS and these are likely to be independent from known AD and PD risk variants.

Nicastrin is an integral member of PS-complexes that perform γ-secretase cleavage of numerous type I membrane proteins including amyloid precursor protein that underlies Alzheimer's disease; thus, diminishing γ-secretase activity by reducing levels of functional PS-complexes is suggested as a possible preventative/therapeutic avenue for the disease. One means of reducing PS-complex activity entails decreasing the levels of one or more of its components, such as nicastrin, which is fundamental to its assembly. Two previous studies detailing the effects of decreased nicastrin on γ-secretase cleavage of APP in nicastrin heterozygous mouse fibroblast, which express relatively low levels of endogenous nicastrin compared to neurons, were contradictory. One report documented a 50% reduction in γ-secretase cleavage of APP while the second showed markedly higher levels of this activity. Here we report that brains of heterozygous nicastrin mice show no difference in levels of APP γ-secretase cleavage, APP C-terminal fragments or β-amyloid peptides, compared to wild-type. This result is explained by the levels of nicastrin protein and functional presenilin complexes being similar between the heterozygous and wild-type brains, though nicastrin mRNA levels were diminished appropriately in the former. These in vivo results indicate that nicastrin mRNA and its immature protein are likely in overabundance in neurons and not limiting for assembly of PS-complexes, and that a 50% reduction of its mRNA or protein production would not affect APP processing, in contrast to fibroblast. Thus, partial reduction (maintaining a level above 50% of normal) of brain nicastrin would likely not be efficacious in reducing functional PS-complexes and γ-secretase activity as a therapeutic strategy for Alzheimer's disease.

Dietary or pharmacological manipulation of plasma lipids markedly influences amyloid deposition in animal models of Alzheimer’s Disease (AD). However, it is not known whether baseline plasma lipids in AD models differ from wild-type littermates throughout the natural history of disease. To address this question, we measured plasma total cholesterol and triglyceride levels over time in three transgenic AD mouse models in the absence of dietary or pharmacological treatments. Total cholesterol levels were not significantly different between transgenic and wild-type mice during the development of AD neuropathology in all models tested. In contrast, elevated very-low-density lipoprotein (VLDL) triglyceride levels preceded amyloid deposition in two AD models with abundant plasma Aβ. Elevated triglycerides were not accompanied by increased inflammatory markers nor decreased lipase activity, but were associated with a significant 30% increase in VLDL-triglyceride secretion rate. Our results suggest that the presence of Aβ in plasma may affect peripheral lipid metabolism early in AD pathogenesis.

Humans harboring missense mutations in the presenilin 1 (PS1) gene undergo progressive cerebral deposition of the 42-residue amyloid β-protein (Aβ42) at an early age and develop severe Alzheimer's disease. Aβ42is selectively elevated in the conditioned media of cells expressing mutant but not wild-type PS1, indicating that presenilin mutations alter APP processing. Here we analyze the effects of various PS1 mutant constructs on the cellular production of Aβ42. A construct expressing only the PS1 N-terminal endoproteolytic fragment with the mutation Y115H causes no significant increase in Aβ42, whereas a full-length PS1 construct with the same mutation does. This result suggests that the pathogenic effect of mutant presenilins is produced by the full-length molecule even though only a minor proportion of total PS1 occurs as holoprotein in tissues and cell lines. We demonstrate that the effects of two different PS1 mutations are additive when engineered into the same PS1 molecule. Therefore, two mutations alter γ-secretase processing of APP more than one and the PS1 mutations described to date do not cause the maximum possible PS1-mediated rise in Aβ42. When a PS1 mutation was expressed in cells carrying the APPV717Imutation, Aβ42rose dramatically to become the predominant secreted Aβ species, an observation of interest for transgenic modeling of AD. Our results are consistent with the hypothesis that presenilin is a major regulator of the proteolytic processing of APP by γ-secretases.

Humans inheriting missense mutations in thepresenilin(PS)1 and -2 genes undergo progressive cerebral deposition of the amyloid β-protein at an early age and develop a clinically and pathologically severe form of familial Alzheimer's disease (FAD). Because PS1 mutations cause the most aggressive known form of AD, it is important to elucidate the structure and function of this multitransmembrane protein in the brain. Using a panel of region-specific PS antibodies, we characterized the presenilin polypeptides in mammalian tissues, including brains of normal, AD, and PS1-linked FAD subjects, and in transfected and nontransfected cell lines. Very little full-length PS1 or -2 was detected in brain and untransfected cells; instead the protein occurred as a heterogeneous array of stable N- and C-terminal proteolytic fragments that differed subtly among cell types and mammalian tissues. Sequencing of the major C-terminal fragment from PS1-transfected human 293 cells showed that the principal endoproteolytic cleavage occurs at and near Met298in the proximal portion of the large hydrophilic loop. Full-length PS1 in these cells is quickly turned over (T1/2≈60 min), in part to the two major fragments. The sizes and amounts of the PS fragments were not significantly altered in four FAD brains with the Cys410Tyr PS1 missense mutation. Our results indicate that presenilins are rapidly processed to N- and C-terminal fragments in both neural and nonneural cells and that interference with this processing is not an obligatory feature of FAD-causing mutations.