Geneticists are increasingly turning to endophenotypes, i.e., measurable disease traits, to help uncover genes that might be missed in heterogenous clinical cohorts. In the October 8 Nature Genetics, scientists led by David Fardo at the University of Kentucky, Lexington, described the largest GWAS yet to link genetic variants to neuropathological measures of dementia. The study of nearly 8,000 autopsied participants found four new risk loci: a microglial gene associated with tangles, two genes related to hardening of cerebral arteries, and an independent signal near the APOE locus that correlated with cerebral amyloid angiopathy. The study also tied 19 known Alzheimer’s genes to specific endophenotypes.

  • Neuropathology GWAS found four new genes linked to dementia endophenotypes.
  • Three associated with cerebrovascular disease, including a new locus near APOE.
  • The study also tied 19 known AD genes to specific pathologies.

Commenters praised the approach. “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,” Vivek Swarup at the University of California, Irvine, wrote to Alzforum. Michael Belloy at Washington University in St. Louis noted that the findings could help distinguish between genes that directly affect pathology, and those that instead help maintain cognition in the face of plaques and tangles. “The results 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,” he wrote.

Pathology Types. Ten of the 11 endophenotypes (x and y axes) cluster into three groups that define vascular, AD, and limbic-predominant age-related TDP-43 encephalopathy (LATE) neuropathologies. The outlier (red diamond) is Lewy body pathology. [Courtesy of Shade et al., Nature Genetics.]

Endophenotype GWAS are often limited by small sample sizes. First author Lincoln Shade overcame this by combining data from three different cohorts, comprising 5,940 participants from The National Alzheimer’s Coordinating Center, 1,183 participants in the Religious Orders Study and Rush Memory and Aging Project, and 681 from the Adult Changes in Thought study, an observational study in Seattle. Overall, 70 percent were clinically diagnosed with AD, 10 percent with other dementias, and 20 percent were cognitively unimpaired.

Shade correlated genetic and autopsy data for these 7,804 brains, focusing on 11 different endophenotypes (image above). These comprised three measures of Alzheimer’s pathology (total plaques, CERAD score, tangles), five of cerebrovascular disease (CAA, microinfarcts, large infarcts, atherosclerosis, arteriolosclerosis), and three of non-Alzheimer’s pathologies (Lewy bodies, TDP-43, hippocampal sclerosis).

The GWAS turned up eight dementia genes, four known and four new. First, the known genes: APOE, BIN1, TMEM106B, and GRN. APOE was associated with all three AD pathologies, as well as CAA and TDP-43, while the AD gene BIN1 associated with CERAD and tangles, but not total plaques. The CERAD score measures dense-core neuritic plaques that also incorporate tau fibrils, leading the authors to speculate that BIN1’s associations were driven by tau pathology. Meanwhile, TMEM106B and GRN, which are linked to frontotemporal dementia as well as AD, correlated with TDP-43 and hippocampal sclerosis, but not with specific AD pathologies.

The new genes? A locus in the broader APOE region but close to the microglial apolipoprotein gene APOC2 was related to CAA, and microglial kinase PIK3R5 to tangles. Endothelial gene LZTS1 associated with arteriolosclerosis, a hardening of the small arterioles of the brain. For the endothelial gene COL4A1, a component of collagen IV, atherosclerosis of large arteries provided the link. “The identification of loci such as COL4A1 and LZTS1 highlights the critical role of vascular health in AD,” Swarup noted.

A couple of previous studies had suggested the existence of a second risk locus near APOE, but the evidence had been inconclusive, the authors noted (Cervantes et al., 2011; Bellenguez et al., 2022). “The present study is the first to confirm that this association is independent of the known effects of APOE alleles,” the authors wrote. They could link the putative functional risk variant to hypomethylation of the APOC2 region, suggesting it would boost transcription.

In a separate analysis, the authors searched for associations between the 83 known AD genes and the 11 endophenotypes. This produced 15 more hits, with variants near ABCA7, CR1, FERMT2, INPP5D, PICALM, PTK2B, SNX1, SORL1, and ZCWPW1 associating with CERAD score, HLA-DQA1 and MME variants with tangles, PLCG2 and TPCN1 loci with microinfarcts, and IL34 and MAPT with hippocampal sclerosis. PICALM and TPCN1 were also correlated with CAA.

Julie Williams at Cardiff University, Wales, noted that tying genetic factors to neuropathology instead of clinical diagnosis could produce cleaner, less noisy relationships and offer clues to how each gene affects the brain. “There is much to follow up in identifying disease mechanisms,” she wrote.—Madolyn Bowman Rogers

Comments

  1. 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.

  2. 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.

  3. 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.

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References

Paper Citations

  1. . Genetic variation in APOE cluster region and Alzheimer's disease risk. Neurobiol Aging. 2011 Nov;32(11):2107.e7-17. PubMed.
  2. . New insights into the genetic etiology of Alzheimer's disease and related dementias. Nat Genet. 2022 Apr;54(4):412-436. Epub 2022 Apr 4 PubMed.

Further Reading

Primary Papers

  1. . GWAS of multiple neuropathology endophenotypes identifies new risk loci and provides insights into the genetic risk of dementia. Nat Genet. 2024 Oct 8; PubMed.