Shade LM, Katsumata Y, Abner EL, Aung KZ, Claas SA, Qiao Q, Heberle BA, Brandon JA, Page ML, Hohman TJ, Mukherjee S, Mayeux RP, Farrer LA, Schellenberg GD, Haines JL, Kukull WA, Nho K, Saykin AJ, Bennett DA, Schneider JA, National Alzheimer’s Coordinating Center, Ebbert MT, Nelson PT, Fardo DW. GWAS of multiple neuropathology endophenotypes identifies new risk loci and provides insights into the genetic risk of dementia. Nat Genet. 2024 Nov;56(11):2407-2421. Epub 2024 Oct 8 PubMed.
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University of California, Irvine
This paper improves on previous AD GWAS by focusing on neuropathological endophenotypes (NPEs) rather than clinical diagnoses, providing a more concrete look at specific brain pathologies, such as amyloid plaques and cerebrovascular changes. It identifies four new genetic loci (COL4A1, PIK3R5, LZTS1, and APOC2) linked to distinct neuropathologies, refines the role of known loci like APOE, and uncovers pleiotropic effects through co-localization analysis, clarifying the genetic mechanisms contributing to AD.
Linking genes to NPEs provides insights into their mechanisms of action by associating specific loci with distinct neuropathologies, such as PIK3R5 with tau-related neurofibrillary tangles, LZTS1 with vascular arteriolosclerosis, and APOC2 with cerebral amyloid angiopathy (CAA). These associations clarify how genetic variants may influence processes like amyloid deposition, vascular pathology, and tau pathology, offering new avenues for understanding AD pathogenesis, particularly in relation to cerebrovascular and metabolic changes.
The study emphasizes that AD involves multiple overlapping neuropathologies, with individuals showing varying combinations of amyloid, tau, and cerebrovascular changes driven by distinct genetic risk factors. The identification of loci such as COL4A1 (atherosclerosis) and LZTS1 (arteriolosclerosis) highlights the critical role of vascular health in AD. By linking specific genetic variants to distinct pathologies, the paper offers a more detailed understanding of AD’s genetic complexity and opens avenues for targeted therapeutic interventions.
View all comments by Vivek SwarupCardiff University
Exploring relationships between biology and genetic susceptibility always provides valuable information to guide our understanding of disease mechanisms. Shade and colleagues present an interesting GWAS study of Alzheimer’s disease (AD), with neuropathology relevant to AD or indicative of other disorders, including vascular, Lewy body, and TDP-43 diseases. They report associations with four novel and four known susceptibility loci. However, it is important to unpack the specific questions addressed by each relationship tested.
Considering the AD-relevant measures (CERAD etc), one wonders if we are observing relationships with a cleaner, less noisy diagnosis, in that those with lower neuropath scores show less association. One could postulate that people with lower scores could go on to develop other disorders, thus increasing noise. In order to test the specific effects of particular genetic loci on the aspects of neuropathology, one might limit the sample to those at the same stage of disease and then explore relationships with specific neuropathology. This could be easily addressed and there is much to follow up in identifying disease mechanisms.
View all comments by Julie WilliamsUniversity of Eastern Finland
Shade et al. have set the focus on identifying Alzheimer’s disease and related dementias (ADRD)-associated gene loci by applying GWAS analysis of multiple neuropathology endophenotypes (NPE) retrieved from three data sources. Consequently, the authors discovered eight independently associated loci, of which four showed novel association—COL4A1, PIK3R5, LZTS1, and APOC. Importantly, detailed genetic co-localization analyses revealed pleiotropic and quantitative trait loci effects.
The protective association of PIK3R5 variant (rs72844606) with Braak NFT stage is particularly interesting because this gene is preferentially expressed in microglia and because previous studies have already discovered that the expression of PIK3R5 is upregulated in the aged individuals with Braak stages V-VI versus nondemented controls. PIK3R5 encodes the regulatory subunit for phosphoinositide 3-kinase (PI3K), and it plays a crucial role in the activation of the PI3K complex.
Apart from having a role in cell motility, growth, and survival, PI3K signaling is a central regulator of lipid metabolism and energy storage pathways. In microglia, PI3K activation promotes the uptake of fatty acids and the conversion of these fatty acids into triacylglycerols, which are stored in lipid droplets (LDs). Changes in the activity of PI3K due to the genetic variant(s) could therefore modulate also the accumulation of potentially damaging LDs in the microglia upon increased neurofibrillary pathology. This notion is also supported by the recent findings showing a reduction in the number of LDs in microglia after the inhibition of PI3K activity.
In conclusion, this article highlights the importance of using NPE-based genetic approaches when assessing the cellular mechanisms underlying the genetic risk of ADRD.
View all comments by Mikko HiltunenWashington University in St. Louis
The authors present a wonderful study that investigated, for the first time at this scale, genome-wide associations studies (GWAS) with various curated neuropathological traits. The findings are very relevant, strengthening insights into how known Alzheimer's disease risk variants/genes relate to core AD pathological features compared to comorbid features or other distinct biological mechanisms.
Along this line, GWAS don't typically consider the inherent heterogeneity in AD, as such they may associate both resistance genes—affecting levels of AD pathology—and resilience genes—affecting how one copes with AD pathology. Similarly, AD GWAS often include clinically diagnosed individuals, as well as health-registry or family-proxy defined cases and controls, but few pathologically verified individuals. This leaves the question of how "AD-specific" the associated variants and genes are.
These results from Shade et al. will help future studies disentangle AD resistance genes from AD resilience or general dementia genes, which in turn should improve genetic risk counseling, as well as genetically informed drug targeting.
View all comments by Michael BelloyMake a Comment
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