@article {7598, title = {Hidden heterogeneity in Alzheimer{\textquoteright}s disease: Insights from genetic association studies and other analyses.}, journal = {Exp Gerontol}, year = {2017}, month = {2017 Oct 26}, abstract = {

Despite evident success in clarifying many important features of Alzheimer{\textquoteright}s disease (AD) the efficient methods of its prevention and treatment are not yet available. The reasons are likely to be the fact that AD is a multifactorial and heterogeneous health disorder with multiple alternative pathways of disease development and progression. The availability of genetic data on individuals participated in longitudinal studies of aging health and longevity, as well as on participants of cross-sectional case-control studies allow for investigating genetic and non-genetic connections with AD and to link the results of these analyses with research findings obtained in clinical, experimental, and molecular biological studies of this health disorder. The objective of this paper is to perform GWAS of AD in several study populations and investigate possible roles of detected genetic factors in developing AD hallmarks and in other health disorders. The data collected in the Framingham Heart Study (FHS), Cardiovascular Health Study (CHS), Health and Retirement Study (HRS) and Late Onset Alzheimer{\textquoteright}s Disease Family Study (LOADFS) were used in these analyses. The logistic regression and Cox{\textquoteright}s regression were used as statistical models in GWAS. The results of analyses confirmed strong associations of genetic variants from well-known genes APOE, TOMM40, PVRL2 (NECTIN2), and APOC1 with AD. Possible roles of these genes in pathological mechanisms resulting in development of hallmarks of AD are described. Many genes whose connection with AD was detected in other studies showed nominally significant associations with this health disorder in our study. The evidence on genetic connections between AD and vulnerability to infection, as well as between AD and other health disorders, such as cancer and type 2 diabetes, were investigated. The progress in uncovering hidden heterogeneity in AD would be substantially facilitated if common mechanisms involved in development of AD, its hallmarks, and AD related chronic conditions were investigated in their mutual connection.

}, issn = {1873-6815}, doi = {10.1016/j.exger.2017.10.020}, author = {Yashin, Anatoliy I and Fang, Fang and Kovtun, Mikhail and Wu, Deqing and Duan, Matt and Arbeev, Konstantin and Akushevich, Igor and Kulminski, Alexander and Culminskaya, Irina and Zhbannikov, Ilya and Yashkin, Arseniy and Stallard, Eric and Ukraintseva, Svetlana} } @article {8397, title = {Genetic and regulatory architecture of Alzheimer{\textquoteright}s disease in the region.}, journal = {Alzheimers Dement (Amst)}, volume = {12}, year = {2020}, month = {2020}, pages = {e12008}, abstract = {

Introduction: Apolipoprotein E () ε2 and ε4 alleles encoded by rs7412 and rs429358 polymorphisms, respectively, are landmark contra and pro "risk" factors for Alzheimer{\textquoteright}s disease (AD).

Methods: We examined differences in linkage disequilibrium (LD) structures between (1) AD-affected and unaffected subjects and (2) older AD-unaffected and younger subjects in the 19q13.3 region harboring rs7412 and rs429358.

Results: AD is associated with sex-nonspecific heterogeneous patterns of decreased and increased LD of rs7412 and rs429358, respectively, with other polymorphisms from five genes in this region in AD-affected subjects. The LD patterns in older AD-unaffected subjects resembled those in younger individuals. Polarization of the ε4- and ε2 allele-related heterogeneous LD clusters differentiated cell types and implicated specific tissues in AD pathogenesis.

Discussion: Protection and predisposition to AD is characterized by an interplay of rs7412 and rs429358, with multiple polymorphisms in the 19q13.3 region in a tissue-specific manner, which is not driven by common evolutionary forces.

}, issn = {2352-8729}, doi = {10.1002/dad2.12008}, author = {Kulminski, Alexander M and Shu, Leonardo and Loika, Yury and He, Liang and Nazarian, Alireza and Arbeev, Konstantin and Ukraintseva, Svetlana and Yashin, Anatoliy and Culminskaya, Irina} } @article {9509, title = {Vaccination Against Pneumonia May Provide Genotype-Specific Protection Against Alzheimer{\textquoteright}s Disease.}, journal = {J Alzheimers Dis}, year = {2023}, month = {2023 Oct 03}, abstract = {

Vaccine repurposing that considers individual genotype may aid personalized prevention of Alzheimer{\textquoteright}s disease (AD). In this retrospective cohort study, we used Cardiovascular Health Study data to estimate associations of pneumococcal polysaccharide vaccine and flu shots received between ages 65-75 with AD onset at age 75 or older, taking into account rs6859 polymorphism in NECTIN2 gene (AD risk factor). Pneumococcal vaccine, and total count of vaccinations against pneumonia and flu, were associated with lower odds of AD in carriers of rs6859 A allele, but not in non-carriers. We conclude that pneumococcal polysaccharide vaccine is a promising candidate for genotype-tailored AD prevention.

}, issn = {1875-8908}, doi = {10.3233/JAD-230088}, author = {Ukraintseva, Svetlana and Duan, Matt and Simanek, Amanda M and Holmes, Rachel and Bagley, Olivia and Rajendrakumar, Aravind L and Yashkin, Arseniy P and Akushevich, Igor and Tropsha, Alexander and Whitson, Heather and Yashin, Anatoliy and Arbeev, Konstantin} }