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

AbstractThe 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.

Download Full-text

Rare Variants in PLD3 Increase Risk for Alzheimer’s Disease in Han Chinese

Journal of Alzheimer s Disease ◽

10.3233/jad-180205 ◽

2018 ◽

Vol 64 (1) ◽

pp. 55-59 ◽

Cited By ~ 6

Author(s):

Meng-Shan Tan ◽

Jun-Xia Zhu ◽

Xi-Peng Cao ◽

Jin-Tai Yu ◽

Lan Tan

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Rare Variants ◽

Han Chinese ◽

Increase Risk

Download Full-text

Rare Variants in APP, PSEN1 and PSEN2 Increase Risk for AD in Late-Onset Alzheimer's Disease Families

PLoS ONE ◽

10.1371/journal.pone.0031039 ◽

2012 ◽

Vol 7 (2) ◽

pp. e31039 ◽

Cited By ~ 158

Author(s):

Carlos Cruchaga ◽

Sumitra Chakraverty ◽

Kevin Mayo ◽

Francesco L. M. Vallania ◽

Robi D. Mitra ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Rare Variants ◽

Late Onset ◽

Increase Risk

Download Full-text

Weighted burden analysis of exome-sequenced late onset Alzheimer’s cases and controls provides further evidence for a role for PSEN1 and suggests involvement of the PI3K/Akt/GSK-3β and WNT signalling pathways

10.1101/596007 ◽

2019 ◽

Author(s):

David Curtis ◽

Kaushiki Bakaya ◽

Leona Sharma ◽

Sreejan Bandyopadhyay

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Rare Variants ◽

Late Onset ◽

Tyrosine Phosphatase ◽

Sequencing Project ◽

Functional Variants ◽

Increase Risk ◽

Gsk 3Β ◽

Additional Support

SummaryPrevious studies have implicated common and rare genetic variants as risk factors for late onset Alzheimer’s disease (AD, LOAD). Here, weighted burden analysis was applied to over 10,000 exome sequenced subjects from the Alzheimer’s Disease Sequencing Project. Analyses were carried out to investigate whether rare variants predicted to have a functional effect within a gene were more commonly seen in cases or in controls. Confirmatory results were obtained for TREM2, ABCA7 and SORL1. Additional support was provided for PSEN1 (p = 0.0002), which previously had been only weakly implicated in LOAD. There was suggestive evidence that functional variants in PIK3R1, WNT7A, C1R and EXOC5 might increase risk and that variants in TIAF1 and/or NDRG2 might have a protective effect. Overall, there was strong evidence (p = 5 × 10−6) that variants in tyrosine phosphatase genes reduce the risk of developing LOAD. Since PIK3R1 variants are expected to impair PI3K/Akt/GSK-3β signalling while variants in tyrosine phosphatase genes would enhance it, these findings are in line with those from animal models suggesting that this pathway is protective against AD.

Download Full-text

Probability of the Alzheimer’s disease based on common and rare genetic variants

10.21203/rs.3.rs-448021/v1 ◽

2021 ◽

Author(s):

Valentina Escott-Price ◽

Karl Michael Schmidt

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

High Risk ◽

Genetic Variants ◽

Rare Variants ◽

Disease Risk ◽

Age Groups ◽

Disease Prevalence ◽

Effect Sizes ◽

Rare Genetic Variants

Abstract Background: Alzheimer’s disease, among other neurodegenerative disorders, spans decades in individuals’ life and exhibits complex progression, symptoms and pathophysiology. Early diagnosis is essential for disease prevention and therapeutic intervention. Genetics may help identify individuals at high risk. As thousands of genetic variants may contribute to the genetic risk of Alzheimer’s disease, the polygenic risk score (PRS) approach has been shown to be useful for disease risk prediction. The APOE- ε4 allele is a known common variant associated with high risk to AD, but also associated with earlier onset. Rare variants usually have higher effect sizes than common ones; their impact may not be well captured by the PRS. Instead of standardised PRS, we propose to calculate the disease probability as a measure of disease risk that allows comparison between individuals. Methods: We estimate AD risk as a probability based on PRS and separately accounting for APOE, AD rare variants and the disease prevalence in age groups. The mathematical framework makes use of genetic variants effect sizes from summary statistics and AD disease prevalence in age groups. Results: The AD probability varies with respect to age, APOE status and presence of rare variants. In age group 65+ the probability of AD grows from 0.03 to 0.18 (without APOE), and 0.07 to 0.7 (APOE e4e4 carriers) as PRS increases. In 85+, these values are 0.08-0.6 and 0.3-0.85. Presence of rare mutations, e.g. in TREM2, may increase the probability (in 65+) from 0.02 at the negative tail of the PRS to 0.3.Conclusions: Our approach accounts for the varying disease prevalence in different genotype and age groups when modelling the APOE and rare genetic variants risk in addition to PRS. This approach can be directly implemented in a clinical setting and easily updated for novel rare variants and for other populations when appropriate ethnic GWASes appear.

Download Full-text

Correction: Rare Variants in APP, PSEN1 and PSEN2 Increase Risk for AD in Late-Onset Alzheimer's Disease Families

PLoS ONE ◽

10.1371/annotation/c92e16da-7733-421d-b063-1db19488daa6 ◽

2012 ◽

Vol 7 (5) ◽

Cited By ~ 18

Author(s):

Carlos Cruchaga ◽

Sumitra Chakraverty ◽

Kevin Mayo ◽

Francesco L. M. Vallania ◽

Robi D. Mitra ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Rare Variants ◽

Late Onset ◽

Increase Risk

Download Full-text

Probability of Alzheimer’s disease based on common and rare genetic variants

Alzheimer s Research & Therapy ◽

10.1186/s13195-021-00884-7 ◽

2021 ◽

Vol 13 (1) ◽

Author(s):

Valentina Escott-Price ◽

Karl Michael Schmidt

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

High Risk ◽

Genetic Variants ◽

Rare Variants ◽

Disease Risk ◽

Age Groups ◽

Disease Prevalence ◽

Effect Sizes ◽

Rare Genetic Variants

Abstract Background Alzheimer’s disease, among other neurodegenerative disorders, spans decades in individuals’ life and exhibits complex progression, symptoms and pathophysiology. Early diagnosis is essential for disease prevention and therapeutic intervention. Genetics may help identify individuals at high risk. As thousands of genetic variants may contribute to the genetic risk of Alzheimer’s disease, the polygenic risk score (PRS) approach has been shown to be useful for disease risk prediction. The APOE-ε4 allele is a known common variant associated with high risk to AD, but also associated with earlier onset. Rare variants usually have higher effect sizes than common ones; their impact may not be well captured by the PRS. Instead of standardised PRS, we propose to calculate the disease probability as a measure of disease risk that allows comparison between individuals. Methods We estimate AD risk as a probability based on PRS and separately accounting for APOE, AD rare variants and the disease prevalence in age groups. The mathematical framework makes use of genetic variants effect sizes from summary statistics and AD disease prevalence in age groups. Results The AD probability varies with respect to age, APOE status and presence of rare variants. In age group 65+, the probability of AD grows from 0.03 to 0.18 (without APOE) and 0.07 to 0.7 (APOE e4e4 carriers) as PRS increases. In 85+, these values are 0.08–0.6 and 0.3–0.85. Presence of rare mutations, e.g. in TREM2, may increase the probability (in 65+) from 0.02 at the negative tail of the PRS to 0.3. Conclusions Our approach accounts for the varying disease prevalence in different genotype and age groups when modelling the APOE and rare genetic variants risk in addition to PRS. This approach has potential for use in a clinical setting and can easily be updated for novel rare variants and for other populations or confounding factors when appropriate genome-wide association data become available.

Download Full-text

Natural Anti-inflammatory compounds as Drug candidates in Alzheimer’s disease

Current Medicinal Chemistry ◽

10.2174/0929867327666200730213215 ◽

2020 ◽

Vol 27 ◽

Author(s):

Reyaz Hassan Mir ◽

Abdul Jalil Shah ◽

Roohi Mohi-ud-din ◽

Faheem Hyder Potoo ◽

Mohd. Akbar Dar ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Natural Products ◽

Protective Action ◽

New Drugs ◽

Huperzine A ◽

Brain Disorder ◽

Anti Inflammatory

: Alzheimer's disease (AD) is a chronic neurodegenerative brain disorder characterized by memory impairment, dementia, oxidative stress in elderly people. Currently, only a few drugs are available in the market with various adverse effects. So to develop new drugs with protective action against the disease, research is turning to the identification of plant products as a remedy. Natural compounds with anti-inflammatory activity could be good candidates for developing effective therapeutic strategies. Phytochemicals including Curcumin, Resveratrol, Quercetin, Huperzine-A, Rosmarinic acid, genistein, obovatol, and Oxyresvertarol were reported molecules for the treatment of AD. Several alkaloids such as galantamine, oridonin, glaucocalyxin B, tetrandrine, berberine, anatabine have been shown anti-inflammatory effects in AD models in vitro as well as in-vivo. In conclusion, natural products from plants represent interesting candidates for the treatment of AD. This review highlights the potential of specific compounds from natural products along with their synthetic derivatives to counteract AD in the CNS.

Download Full-text

[18F]-florbetaben PET/CT Imaging in the Alzheimer’s Disease Mouse Model APPswe/PS1dE9

Current Alzheimer Research ◽

10.2174/1567205015666181022095904 ◽

2018 ◽

Vol 16 (1) ◽

pp. 49-55 ◽

Cited By ~ 1

Author(s):

J. Stenzel ◽

C. Rühlmann ◽

T. Lindner ◽

S. Polei ◽

S. Teipel ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Mouse Model ◽

New Drugs ◽

Imaging Data ◽

Wild Type ◽

Preclinical Research ◽

Standardized Uptake Values ◽

Pet Ct

Background: Positron-emission-tomography (PET) using 18F labeled florbetaben allows noninvasive in vivo-assessment of amyloid-beta (Aβ), a pathological hallmark of Alzheimer’s disease (AD). In preclinical research, [18F]-florbetaben-PET has already been used to test the amyloid-lowering potential of new drugs, both in humans and in transgenic models of cerebral amyloidosis. The aim of this study was to characterize the spatial pattern of cerebral uptake of [18F]-florbetaben in the APPswe/ PS1dE9 mouse model of AD in comparison to histologically determined number and size of cerebral Aβ plaques. Methods: Both, APPswe/PS1dE9 and wild type mice at an age of 12 months were investigated by smallanimal PET/CT after intravenous injection of [18F]-florbetaben. High-resolution magnetic resonance imaging data were used for quantification of the PET data by volume of interest analysis. The standardized uptake values (SUVs) of [18F]-florbetaben in vivo as well as post mortem cerebral Aβ plaque load in cortex, hippocampus and cerebellum were analyzed. Results: Visual inspection and SUVs revealed an increased cerebral uptake of [18F]-florbetaben in APPswe/ PS1dE9 mice compared with wild type mice especially in the cortex, the hippocampus and the cerebellum. However, SUV ratios (SUVRs) relative to cerebellum revealed only significant differences in the hippocampus between the APPswe/PS1dE9 and wild type mice but not in cortex; this differential effect may reflect the lower plaque area in the cortex than in the hippocampus as found in the histological analysis. Conclusion: The findings suggest that histopathological characteristics of Aβ plaque size and spatial distribution can be depicted in vivo using [18F]-florbetaben in the APPswe/PS1dE9 mouse model.

Download Full-text