Journal of Alzheimer's Disease - Volume 70, issue 3

Authors: Nazarian, Alireza | Kulminski, Alexander M.

Article Type: Research Article

Abstract: Heritability analysis of complex traits/diseases is commonly performed to obtain illustrative information about the potential contribution of the genetic factors to their phenotypic variances. In this study, we investigated the narrow-sense heritability (h 2 ) of Alzheimer’s disease (AD) using genome-wide single-nucleotide polymorphisms (SNPs) data from three independent studies in the linear mixed models framework. Our meta-analyses demonstrated that the estimated h 2 values (and their standard errors) of AD in liability scale were 0.280 (0.091), 0.348 (0.113), and 0.389 (0.126) assuming AD prevalence rates of 10%, 20%, or 30% at ages of 65+, 75+, and 85+ years, respectively. …We also found that chromosomal regions containing two or more AD-associated SNPs at p  < 5E-08 could collectively explain 37% of the additive genetic variance of AD in our samples. AD-associated regions in which at least one SNP had attained p  < 5E-08 explained 56% of the additive genetic variance of AD. These regions harbored 3% and 11% of SNPs in our analyses. Also, the chromosomal regions containing two or more and one or more AD-associated SNPs at p  < 5E-06 accounted for 72% and 94% of the additive genetic variance of AD, respectively. These regions harbored 27% and 44% of SNPs in our analyses. Our findings showed that the overall contribution of the additive genetic effects to the AD liability was moderate and age-dependent. Also, they supported the importance of focusing on known AD-associated chromosomal regions to investigate the genetic basis of AD, e.g., through haplotype analysis, analysis of heterogeneity, and functional studies. Show more

Keywords: Aging, complex disorders, dementia, missing heritability, narrow-sense heritability, neurodegenerative disorders, polygenic inheritance

DOI: 10.3233/JAD-190168

Citation: Journal of Alzheimer's Disease, vol. 70, no. 3, pp. 907-915, 2019

Authors: Pandey, Janardan P. | Kothera, Ronald T. | Liu, Shufeng | Costa, Andrea Saul | Mancuso, Roberta | Agostini, Simone

Article Type: Research Article

Abstract: Although genome-wide association studies (GWAS) of late-onset Alzheimer’s disease (AD) have identified numerous genes that influence the risk for disease, the majority of the genetic variance of AD remains uncharacterized. Furthermore, current GWAS, despite their name, do not evaluate all genes in the human genome. One such gene complex is immunoglobulin GM (γ marker) genes on chromosome 14. GM genes are excellent candidate genes for AD because they influence immunity to herpes simplex virus type 1 (HSV1), which has been implicated in AD pathology by an increasing number of reports. The aim of this investigation was to determine if …particular GM genotypes were associated with AD and mild cognitive impairment (MCI), and whether they contributed to the interindividual differences in the level of anti-HSV1 IgG antibodies. A total of 141 HSV1 seropositive individuals—56 AD patients, 48 MCI individuals, and 37 sex- and age-matched healthy controls—were characterized for GM alleles 3, 17, and 23. The homozygosity for the GM 3 allele was significantly associated with MCI (p  = 0.025). GM 3/17 heterozygous AD patients had significantly higher levels of anti-HSV1 antibodies than the healthy controls expressing the same genotype (p  = 0.0004). Among MCI subjects, the GM 3/17 genotype was associated with significantly higher level of anti-HSV1 antibodies as compared to the GM 17/17 homozygous genotype (pc  = 0.040). Among AD patients, the GM 23+/–genotype was significantly associated with anti-HSV1 antibody responses (pc  = 0.025). These results suggest that GM genes could act as potential unifiers of the genetic and viral etiology of AD. Show more

Keywords: Antibody dependent cellular cytotoxicity, APOE4, Fcγ receptor, γ marker (GM) allotypes, HSV1, immunoevasion

DOI: 10.3233/JAD-190265

Citation: Journal of Alzheimer's Disease, vol. 70, no. 3, pp. 917-924, 2019

Authors: Yu, Qian | Dai, Chun-Ling | Zhang, Yongli | Chen, Yanxing | Wu, Zhe | Iqbal, Khalid | Liu, Fei | Gong, Cheng-Xin

Article Type: Research Article

Abstract: General anesthesia increases the risk for cognitive impairment and Alzheimer’s disease (AD) in vulnerable individuals such as the elderly. We previously reported that prior administration of insulin through intranasal delivery can prevent the anesthesia-induced cognitive impairment and biochemical changes in the brain. However, little is known about the underlying molecular mechanisms. Here, we report that general anesthesia resulted in downregulation of mammalian/mechanistic target of rapamycin (mTOR) and eukaryotic elongation factor 2 (eEF2) in the brain along with reduction of presynaptic proteins and brain-derived neurotrophic factor and cognitive impairment in aged mice. Prior administration of intranasal insulin prevented these anesthesia-induced changes. …These results suggest the involvement of the mTOR-eEF2 signaling pathway in the anesthesia-induced brain changes and cognitive impairment and in the prevention of these changes with insulin. Correlation analyses and the use of eEF2 kinase inhibitor further support our conclusions. These studies shed light on the molecular mechanism by which anesthesia and insulin could act on synaptic proteins and cognitive function. Show more

Keywords: Anesthesia, cognitive impairment, eEF2, insulin, intranasal delivery, mTOR, synaptic proteins

DOI: 10.3233/JAD-190280

Citation: Journal of Alzheimer's Disease, vol. 70, no. 3, pp. 925-936, 2019

Authors: Taniguchi, Kaori | Yamamoto, Fumiko | Arai, Takuya | Yang, Jinwei | Sakai, Yusuke | Itoh, Masayuki | Mamada, Naomi | Sekiguchi, Masayuki | Yamada, Daisuke | Saitoh, Akiyoshi | Kametani, Fuyuki | Tamaoka, Akira | Araki, Yumiko M. | Wada, Keiji | Mizusawa, Hidehiro | Araki, Wataru

Article Type: Research Article

Abstract: Soluble amyloid-β (Aβ) oligomers (AβOs), which elicit neurotoxicity and synaptotoxicity, are thought to play an initiating role in the pathology of Alzheimer’s disease (AD). Since AβOs are a key therapeutic target, we attempted to identify natural agents that reduce AβO neurotoxicity. Using an assay system in which primary cultured neurons are treated with AβOs, we found that Rhodiola rosea extracts and one of its main constituents, tyrosol, significantly inhibited AβO-induced caspase-3 activation. We then assessed the in vivo efficacy of tyrosol by oral administration of the compound into AD model (5XFAD) transgenic and non-transgenic mice from either 2 …or 4 to 7 months of age. In both paradigms, tyrosol treatment did not affect body weights of mice. Immunohistochemical analysis revealed that the immunoreactivity of spinophilin, a dendritic synaptic protein, was significantly reduced in three hippocampal subregions of vehicle-treated AD mice compared with non-transgenic mice, which was reversed in tyrosol-treated AD mice. Tyrosol treatment also prevented the enhancement of 4-hydroxy-2-nonenal immunoreactivity in the hippocampal CA3 region of AD mice. By contrast, tyrosol administration did not affect Aβ accumulation, as evaluated by immunohistochemical and biochemical analyses. Moreover, the Barnes maze test showed that tyrosol administration modestly mitigated spatial memory impairment in AD mice. These findings collectively indicate that the natural agent tyrosol protects neurons against AβO neurotoxicity in vitro and ameliorates synaptic disturbance, oxidative stress responses, and cognitive impairment in vivo . We thus suggest that tyrosol is potentially an effective, safe, and unique drug candidate for AD. Show more

Keywords: Alzheimer’s disease, amyloid-β, neuron, oligomer, oxidative stress, synapse

DOI: 10.3233/JAD-190098

Citation: Journal of Alzheimer's Disease, vol. 70, no. 3, pp. 937-952, 2019

Authors: Low, Audrey | Ng, Kok Pin | Chander, Russell Jude | Wong, Benjamin | Kandiah, Nagaendran

Article Type: Research Article

Abstract: Background: Asymmetrical patterns of cerebral damage have been widely observed in a range of neurodegenerative diseases, including Alzheimer’s disease (AD). Objective: To elucidate the clinical associations of asymmetrical white matter hyperintensities (WMH) in mild cognitive impairment (MCI) and AD. Methods: Regional WMH asymmetry of 340 participants (90 healthy controls, 132 MCI, 118 AD) was calculated as the difference in normalized hemispheric WMH volume (WMH/ICV) adjusted for structural brain asymmetry of respective lobar regions and total WMH. WMH asymmetry was analyzed in relation to disease classification, cognition, and APOE4 status using ANCOVA and multiple regression analysis, …controlling for gender, age, ethnicity, and correcting for multiple comparisons using Bonferroni correction. Moderation analysis examined interaction effects of APOE4 on associations between cognition and WMH asymmetry. Results: Greater left-dominant occipital WMH asymmetry was observed in AD, compared to healthy controls and MCI, and was associated with poorer global cognition, memory, language, and executive functions among cognitively impaired participants (MCI and AD). Cognitively impaired APOE4 carriers displayed greater left-dominant WMH asymmetry in the whole brain and frontal lobe, compared to non-carriers. Importantly, effects were independent of structural brain asymmetry, global cerebral atrophy, and overall WMH burden. Moderation analysis demonstrated associations between left-dominant WMH asymmetry and cognition in cognitively impaired APOE4 non-carriers, but not APOE4 carriers. Conclusion: Leftward asymmetry of WMH may be more pathological in nature, compared to symmetrical WMH. Furthermore, the detrimental effects of WMH asymmetry was more relevant in APOE4 -negative cognitive impairment, compared to APOE4 -positive which may be driven primarily by AD pathology. Show more

Keywords: Alzheimer’s disease, apolipoprotein E4, cerebral small vessel diseases, cognitive aging, leukoaraiosis, magnetic resonance imaging, mild cognitive impairment

DOI: 10.3233/JAD-190159

Citation: Journal of Alzheimer's Disease, vol. 70, no. 3, pp. 953-964, 2019