Benefits and Challenges of Rare Genetic Variation in Alzheimer’s Disease

Saad, Salha; Menzies, Georgina E.; Sims, Rebecca

doi:10.1007/s40142-019-0161-5

Cited by 9 publications

(7 citation statements)

References 117 publications

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“…While this is relatively straightforward when performing GWAS using data from genotyping arrays, it is more complex when merging data generated using different exome capture methods and with varying coverage [ 89 ]. Sequence capture uniformity and capture probe performance will determine how much raw sequence data for each sample will be available and, consequently, impact downstream analyses [ 90 ].…”

Section: The Challenges When Studying Rare Variantsmentioning

confidence: 99%

Challenge accepted: uncovering the role of rare genetic variants in Alzheimer’s disease

Khani

Gibbons

Brás

et al. 2022

Mol Neurodegeneration

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The search for rare variants in Alzheimer’s disease (AD) is usually deemed a high-risk - high-reward situation. The challenges associated with this endeavor are real. Still, the application of genome-wide technologies to large numbers of cases and controls or to small, well-characterized families has started to be fruitful.Rare variants associated with AD have been shown to increase risk or cause disease, but also to protect against the development of AD. All of these can potentially be targeted for the development of new drugs.Multiple independent studies have now shown associations of rare variants in NOTCH3, TREM2, SORL1, ABCA7, BIN1, CLU, NCK2, AKAP9, UNC5C, PLCG2, and ABI3 with AD and suggested that they may influence disease via multiple mechanisms. These genes have reported functions in the immune system, lipid metabolism, synaptic plasticity, and apoptosis. However, the main pathway emerging from the collective of genes harboring rare variants associated with AD is the Aβ pathway. Associations of rare variants in dozens of other genes have also been proposed, but have not yet been replicated in independent studies. Replication of this type of findings is one of the challenges associated with studying rare variants in complex diseases, such as AD. In this review, we discuss some of these primary challenges as well as possible solutions.Integrative approaches, the availability of large datasets and databases, and the development of new analytical methodologies will continue to produce new genes harboring rare variability impacting AD. In the future, more extensive and more diverse genetic studies, as well as studies of deeply characterized families, will enhance our understanding of disease pathogenesis and put us on the correct path for the development of successful drugs.

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Section: The Challenges When Studying Rare Variantsmentioning

confidence: 99%

Challenge accepted: uncovering the role of rare genetic variants in Alzheimer’s disease

Khani

Gibbons

Brás

et al. 2022

Mol Neurodegeneration

View full text Add to dashboard Cite

show abstract

“…Recent large scale studies of AD genetics, employing genome-wide association studies (GWAS), whole exome sequencing (WES), and whole genome sequencing (WGS), have defined additional genes whose variants contribute to increased risk [ 53 , 54 ]. These include Clusterin (CLU), Sortilin-related receptor-1 (SORL1), ATP-binding cassette subfamily A member 7 (ABCA7), Bridging integrator 1 (BIN1), phosphatidylinositol binding clathrin assembly protein (PICALM), CD2 associated protein (CD2AP), Complement component (3b/4b) receptor 1 (CR1), CD33, triggering receptor expressed on myeloid cells 2 (TREM2), and phospholipase D3 (PLD3) [ 55 , 56 , 57 ]. Intriguingly, more than 50% of validated gene variants are implicated in innate immune and microglial functions [ 58 , 59 , 60 ], including the top two AD risk genes, APOE and TREM2 [ 61 , 62 ].…”

Section: Introductionmentioning

confidence: 99%

Neuroinflammation in Alzheimer’s Disease

et al. 2021

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Alzheimer’s disease (AD) is a neurodegenerative disease associated with human aging. Ten percent of individuals over 65 years have AD and its prevalence continues to rise with increasing age. There are currently no effective disease modifying treatments for AD, resulting in increasingly large socioeconomic and personal costs. Increasing age is associated with an increase in low-grade chronic inflammation (inflammaging) that may contribute to the neurodegenerative process in AD. Although the exact mechanisms remain unclear, aberrant elevation of reactive oxygen and nitrogen species (RONS) levels from several endogenous and exogenous processes in the brain may not only affect cell signaling, but also trigger cellular senescence, inflammation, and pyroptosis. Moreover, a compromised immune privilege of the brain that allows the infiltration of peripheral immune cells and infectious agents may play a role. Additionally, meta-inflammation as well as gut microbiota dysbiosis may drive the neuroinflammatory process. Considering that inflammatory/immune pathways are dysregulated in parallel with cognitive dysfunction in AD, elucidating the relationship between the central nervous system and the immune system may facilitate the development of a safe and effective therapy for AD. We discuss some current ideas on processes in inflammaging that appear to drive the neurodegenerative process in AD and summarize details on a few immunomodulatory strategies being developed to selectively target the detrimental aspects of neuroinflammation without affecting defense mechanisms against pathogens and tissue damage.

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“…Several studies have also found a contribution of rare variants in genes such as TREM2 and ABCA7 toward AD [ 3 – 5 ]. A popular approach to discover AD relevant rare variants is the use of whole-exome/genome sequencing to assess rare-variants globally, and then to associate each variant with AD status [ 6 ]. However, the occurrence of AD is caused by a combination of pathways involving inflammation, cholesterol metabolism, tau pathology, endosome or ubiquitin-related functioning [ 7 ].…”

Section: Introductionmentioning

confidence: 99%

Rare variants in IFFO1, DTNB, NLRC3 and SLC22A10 associate with Alzheimer’s disease CSF profile of neuronal injury and inflammation

et al. 2022

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Alzheimer’s disease (AD) biomarkers represent several neurodegenerative processes, such as synaptic dysfunction, neuronal inflammation and injury, as well as amyloid pathology. We performed an exome-wide rare variant analysis of six AD biomarkers (β-amyloid, total/phosphorylated tau, NfL, YKL-40, and Neurogranin) to discover genes associated with these markers. Genetic and biomarker information was available for 480 participants from two studies: EMIF-AD and ADNI. We applied a principal component (PC) analysis to derive biomarkers combinations, which represent statistically independent biological processes. We then tested whether rare variants in 9576 protein-coding genes associate with these PCs using a Meta-SKAT test. We also tested whether the PCs are intermediary to gene effects on AD symptoms with a SMUT test. One PC loaded on NfL and YKL-40, indicators of neuronal injury and inflammation. Four genes were associated with this PC: IFFO1, DTNB, NLRC3, and SLC22A10. Mediation tests suggest, that these genes also affect dementia symptoms via inflammation/injury. We also observed an association between a PC loading on Neurogranin, a marker for synaptic functioning, with GABBR2 and CASZ1, but no mediation effects. The results suggest that rare variants in IFFO1, DTNB, NLRC3, and SLC22A10 heighten susceptibility to neuronal injury and inflammation, potentially by altering cytoskeleton structure and immune activity disinhibition, resulting in an elevated dementia risk. GABBR2 and CASZ1 were associated with synaptic functioning, but mediation analyses suggest that the effect of these two genes on synaptic functioning is not consequential for AD development.

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Benefits and Challenges of Rare Genetic Variation in Alzheimer’s Disease

Cited by 9 publications

References 117 publications

Challenge accepted: uncovering the role of rare genetic variants in Alzheimer’s disease

Challenge accepted: uncovering the role of rare genetic variants in Alzheimer’s disease

Neuroinflammation in Alzheimer’s Disease

Rare variants in IFFO1, DTNB, NLRC3 and SLC22A10 associate with Alzheimer’s disease CSF profile of neuronal injury and inflammation

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