MTHFR and ACE gene polymorphisms and risk of vascular and degenerative dementias in the elderly

Focal lacunar infarctions due to cerebral small vessel atherosclerosis or single/multiple large cortical infarcts lead to vascular dementia, and different genes and environmental factors have been implicated in causation or aggravation of the disease. Previous reports suggest that some of the risk factors may be common to both vascular as well as degenerative dementia. Among genetic factors, role of angiotensin converting enzyme (ACE) and methylene-tetrahydrofolate reductase (MTHFR) genes as putative risk factors has been examined but the outcome of these studies remain inconclusive. Present study attempted to see the importance of ACE alu insertion/deletion and MTHFR C677T polymorphisms as genetic predisposers to dementia. The study comprised of 80 vascular dementia patients, 90 degenerative dementia patients and 170 age matched controls. All were genotyped for ACE, MTHFR and APOE polymorphisms using PCR-RFLP method. Frequency of ACE D allele was seemingly high in dementia cases (26.7%) when compared to controls (11.2%). However, after adjusting for age and APOE E4^*, none of the ACE alleles showed good correlation. MTHFR genotypes or alleles also did not show any correlation. Our study suggests no true correlation of ACE or MTHR genes with dementia in elderly.     

Association of polymorphisms in BDNF, MTHFR, and genes involved in the dopaminergic pathway with memory in a healthy Chinese population

The contribution of genetic factors to the memory is widely acknowledged. Research suggests that these factors include genes involved in the dopaminergic pathway, as well as the genes for brain-derived neurotrophic factor (BDNF) and methylenetetrahydrofolate reductase (MTHFR). The activity of the products of these genes is affected by single nucleotide polymorphisms (SNPs) within the genes. This study investigates the association between memory and SNPs in genes involved in the dopaminergic pathway, as well as in the BDNF and MTHFR genes, in a sample of healthy individuals. The sample includes 134 Taiwanese undergraduate volunteers of similar cognitive ability. The Chinese versions of the Wechsler Memory Scale (WMS-III) and Wechsler Adult Intelligence Scale (WAIS-III) were employed. Our findings indicate that the BDNF Met66Val polymorphism and dopamine receptor D3 (DRD3) Ser9Gly polymorphism are associated significantly with long-term auditory memory. Further analysis detects no significant associations in the other polymorphisms and indices. Future replicated studies with larger sample sizes, and studies that consider different ethnic groups, are encouraged.     

The relation between APOE status and neuropsychological memory test performance: an analysis of the Canadian Study of Health and Aging

This study examined the relationship between two risk factors for dementia, the apolipoprotein (APOE) epsilon4 allele and poor memory test performance. Participants were from the Canadian Study of Health and Aging, a 4-year longitudinal population-based study. Persons with no cognitive impairment who had an epsilon4 allele but whose memory was average or better were not at increased risk of developing dementia after five years. Risk was increased for those with below average memory and no epsilon4 allele, but was particularly increased for those with below average memory and an epsilon4 allele. While the APOE epsilon4 allele was associated with slightly lower memory test performance for persons without cognitive impairment at baseline, it only increased their risk of developing dementia if their memory was below average.     

Association between serotonin Cumulative Genetic Score and the Behavioral Approach System (BAS): Moderation by early life environment

The present study investigates if genetic variation in the serotonergic system interacts with early adversity to predict changes in the Behavioral Approach System (BAS), a system that taps into reward processing. In a sample of community adults (N = 236) the influence of single serotonergic candidate polymorphisms on BAS was analyzed, we also examined the aggregate contribution of these genetic variants by creating a Cumulative Genetic Score (CGS). A CGS quantifies an individual’s cumulative risk by aggregating the number of risk alleles across the candidate polymorphisms. After individual gene analysis, three candidate genes rs7305115 (TPH2), rs6311 (HTR2A), and rs6295 (HTR1A) were combined into the CGS. There were no significant interactions between individual candidate polymorphisms and childhood adversity, but the CGS interacted with childhood adversity to explain a significant amount of variance (11.6%) in the BAS. Findings suggest that genetic variations in the serotonergic system in combination with childhood adversity contribute to individual differences in reward sensitivity.     

Frontal lobe dementia and subcortical vascular dementia: a neuropsychological comparison

We compared the performance of 40 patients with frontal lobe dementia to that of 40 patients with subcortical vascular dementia (80 patients including, 46 men and 34 women) in a set of tasks assessing attentional, executive, and behavioural tasks. The frontal lobe dementia represents an important cause for degenerative disruption and is increasingly recognised as an important form (up to 25%) of degenerative dementia among individuals of late-middle-age. The main involvement is the frontal-subcortical pathway, which is the final target of impairment even in subcortical vascular dementia. A wider involvement of the cortical (decisional) layers in frontal dementia, in contrast with the prominent and widespread involvement of the subcortical pathways (refinement and corrections programs) creates the different profiles of the two groups. Frontal patients have more difficulties in abstract reasoning, focusing attention, and implementing strategies to solve problems. They exhibit more profound behavioural alterations in personality and social conduct and show only moderate depression, and a total lack of insight concerning their dinical condition. In contrast, the patients with subcortical vascular dementia have poor general cognitive functions, high insight, and important depression and apathy as the principal and most salient characteristic of their behavioral conduct.     

Apolipoprotein epsilon4 is associated with more rapid decline in odor identification than in odor threshold or Dementia Rating Scale scores

Individuals with the apolipoprotein E epsilon4 genetic risk factor for Alzheimer's disease (AD) show deficits in olfactory function. The purpose of the present study was to examine longitudinally odor identification (odor ID), odor threshold, picture identification, and global cognitive status in allele positive (epsilon4+) and negative (epsilon4-) persons. Participants were initially given the San Diego Odor Identification test, an odor threshold test, and the Dementia Rating Scale (DRS). Participants were re-tested approximately four years later. The results indicate: (1) odor ID declined more rapidly in epsilon4+ than in epsilon4- normal elderly adults; (2) neither group exhibited a significant decline in odor threshold, picture identification or DRS scores. These results suggest that declines in odor identification occur before declines in other measures of dementia in persons at risk for AD because of their APOE allele genetic status.     

MTHFR: Addressing Genetic Counseling Dilemmas Using Evidence-Based Literature

The 5, 10 methylenetetrahydrofolate reductase (MTHFR) enzyme is a catalyst in the folate metabolism pathway, the byproducts of which are involved in the remethylation of homocysteine to methionine. Methionine is a precursor for a major DNA methyl donor and is important for DNA methylation and gene regulation. Rare mutations in the MTHFR gene have been associated with autosomal recessive MTHFR deficiency leading to homocystinuria. In addition, two polymorphic variants in this gene (C677T and A1298C) have been implicated in a mild form of MTHFR deficiency associated with hyperhomocysteinemia. Mild to moderate hyperhomocysteinemia has been previously implicated as a risk factor for cardiovascular disease. Further, the presence of these variants, with and without mildly elevated levels of homocysteine, has been studied in relation to several multifactorial disorders including recurrent pregnancy loss, neural tube defects and congenital anomalies, cancer, and neurodevelopmental disorders. Given this wide spectrum of purported clinical implications and the prevalence of these polymorphisms, genetic counselors may encounter questions regarding the significance of MTHFR polymorphisms in a variety of settings. Here we present a brief background of the MTHFR polymorphisms, review of the literature regarding clinical considerations, and discussion of relevant genetic counseling aspects through case vignettes. Educational resources for patients and providers are also included.     

The heritability of cognitive functioning in very old adults: evidence from Danish twins aged 75 years and older

Heritable influences on cognitive functioning were investigated in a sample of 403 pairs of like-sex Danish twins aged 75 years and older. Twins completed the Mini-Mental State Examination and 3 other cognitive tests. Genetic factors accounted for 26-54% of the variance on these measures, with the balance being due to environmental factors that create differences rather than similarities among reared-together relatives. Deleting twins with severe cognitive impairment had little effect on the results, indicating that the heritability of cognitive functioning was not due entirely to genes affecting dementia. Neither age nor gender moderated twin similarity, and differential social contact could not account for correlation differences between monozygotic and dizygotic twins. These results replicate G. E. McClearn et al.'s (1997) study in indicating substantial genetic influences on late-life cognitive functioning.     

Risk- and protective factors for memory plasticity in aging

ABSTRACT

Risk and protective factors for cognitive function in aging may affect how much individuals benefit from their environment or life experiences by preserving or improving cognitive abilities. We investigated the relations between such factors and outcome from episodic-memory training in 136 healthy young and older adults. Tested risk factors included carrying the ?4 variant of the apolipoprotein E allele (APOE), age, body mass index, blood pressure, and cholesterol. Protective factors included higher levels of education, intelligence quotient (IQ), physical activity, fatty acids, and vitamin D. Average increases in memory performance were seen after training, with ample variation between individuals. Being young, female, and having higher IQ were positive predictors of memory improvement. No other relationships were observed. Similar benefit was observed across APOE allelic variation. This indicates that beyond IQ, age, and sex, known risk -and protective factors of cognitive function in aging were not significantly related to memory plasticity.     

Genetics, Dementia, and the Elderly

ABSTRACT— Whether or not an individual develops dementia is powerfully influenced by genes. For Alzheimer's disease, the most common type of dementia, one susceptibility gene with major effects has been identified, but progress finding other susceptibility genes has stalled. Twin studies have revealed that nongenetic risk also plays an important role, as there are many monozygotic twin pairs in which only one individual has dementia. Scientists have argued that gene-by-environment interactions will be key to understanding vulnerability to Alzheimer's disease; but to date, few substantial gene-by-environment interactions have been replicated. Often, too, the nongenetic or lifestyle factor appears to have a protective effect only for those individuals not carrying the risky version of the gene, not for those individuals who are at genetic risk.     

The role of cardiovascular risk factors in Alzheimer's disease

The distinction between Alzheimer's disease and vascular dementia, the two most common types of dementia, has been undermined by recent advances in epidemiologic, clinical, imaging, and neuropathological studies. Cardiovascular risk factors, traditionally regarded as distinguishing criteria between the two entities, have been shown to be associated with both AD and vascular dementia. In this article, we propose mechanisms of action of cardiovascular risk factors in AD, suggest possible explanations for the overlap with vascular dementia and discuss the implications this might have on future differential diagnosis, research, and treatment strategies.     

利手与语言功能偏侧化的遗传模型

利手与语言功能偏侧化现象不仅具有跨文化一致性和发生、发展上的关联性, 还具有明显的生态学优势, 从遗传角度探讨它们的成因是必要的。早期遗传模型认为, 存在一对等位基因分别决定左、右利手。当代单基因模型则将语言功能偏侧化也纳入进来, 认为等位基因不仅可以决定具有方向性的偏侧化, 而且可以使偏侧化有一定几率向左或向右。在这个框架下形成了方向-随机等位基因模型、X-连锁隐性基因模型和右侧位移理论, 它们对等位基因的位置和功能有不同表述, 对利手的划分标准、性别差异以及遗传和环境的关系也有不同阐释。今后需加强对语言偏侧化的数据验证, 进一步阐明语言感知、理解与利手的关系, 并注重基因怎样决定表型、基因多效性和多基因合作等问题的研究。     

The Burden of Dementia: A Medical and Research Perspective

Alzheimer's disease remains the most common form of dementia. Dementia symptoms vary depending on individual personality, life experience, and social and cultural influences. As dementia progresses, involvement of multi-disciplinary health care professionals is needed to manage the disease. Alzheimer research is progressing rapidly. While 5% of all Alzheimer's disease may be genetically determined, the majority is not. Susceptibility genes can reveal the risk of contracting Alzheimer's disease. Early life risk factors such as education, nutrition, and vascular disease may increase the likelihood of dementia in later life. In the United States, two acetylcholinesterase inhibitors have been approved as cognitive enhancers. Possible prevention and symptomatic treatment interventions have focused on estrogen replacement therapy, antioxidants, and anti-inflammatory medications. Research advances have improved the clinical management of dementia. Ethical implications to the patient, family, and society are multiple and remain challenging.     

5-HTTLPR,HTR1A,and HTR2A cumulative genetic score interacts with mood reactivity to predict mood-congruent gaze bias

Genetic variation within the serotonin system has been associated with biased attention for affective stimuli and, less consistently, with vulnerability for major depressive disorder. In particular, 5-HTTLPR, HTR1A (rs6295), and HTR2A (rs6311) polymorphisms have been linked with biased cognition. The present study developed a serotonergic cumulative genetic score (CGS) that quantified the number of risk alleles associated with these candidate polymorphisms to yield a single CGS. The CGS was then used to model genetic influence on the relationship between reactivity to a negative mood induction and negatively biased cognition. A passive-viewing eye-tracking task was administered to 170 healthy volunteers to assess sustained attention for positive, dysphoric, neutral, and threatening scenes. Participants were then induced into a sad mood and readministered the passive-viewing task. Change in gaze bias, as a function of reactivity to mood induction, was the primary measure of cognitive vulnerability. Results suggest that, although none of the individual genes interacted with mood reactivity to predict change in gaze bias, individuals with higher serotonin CGS were significantly more likely to look toward dysphoric images and away from positive images as mood reactivity increased. These findings suggest that a CGS approach may better capture genetic influences on cognitive vulnerability and reaffirm the need to examine multilocus approaches in genomic research.     

The Impact of Genetic Research on our Understanding of Normal Cognitive Ageing: 1995 to 2009

Identifying the risk factors for individual differences in age-related cognitive ability and decline is amongst the greatest challenges facing the healthcare of older people. Cognitive impairment caused by “normal ageing” is a major contributor towards overall cognitive deficit in the elderly and a process that exhibits substantial inter- and intra-individual differences. Both cognitive ability and its decline with age are influenced by genetic variation that may act independently or via epistasis/gene-environment interaction. Over the past fourteen years genetic research has aimed to identify the polymorphisms responsible for high cognitive functioning and successful cognitive ageing. Unfortunately, during this period a bewildering array of contrasting reports have appeared in the literature that have implicated over 50 genes with effect sizes ranging from 0.1 to 21%. This review will provide a comprehensive account of the studies performed on cognitively healthy individuals, from the first study conducted in 1995 to present. Based on current knowledge the strong and weak methodologies will be identified and suggestions for future study design will be presented.     

The question not asked: the challenge of pleiotropic genetic tests

Nearly all of the literature on the ethical, legal, or social issues surrounding genetic tests has proceeded on the assumption that any particular test for a gene mutation yields information about only one disease condition. Even though the phenomenon of pleiotropy, where a single gene has multiple, apparently unrelated phenotypic effects, is widely recognized in genetics, it has not had much significance for genetic testing until recently. In this article, I examine a moral dilemma created by one sort of pleiotropic testing, APOE genotyping, which can yield information about the risk of two different conditions -- coronary heart disease and Alzheimer's disease. A physician administering APOE testing for the beneficial purpose of assessing the risk of heart disease may discover medically useless and socially harmful information about the patient's risk of Alzheimer's disease. I explore how much providers should disclose to patients about pleiotropic test results and whether patients are obligated to know as much about their genetic condition as possible.     

Dramatic Increase in Heritability of Cognitive Development From Early to Middle Childhood: An 8-Year Longitudinal Study of 8,700 Pairs of Twins

ABSTRACT— The generalist genes hypothesis implies that general cognitive ability ( g ) is an essential target for understanding how genetic polymorphisms influence the development of the human brain. Using 8,791 twin pairs from the Twins Early Development Study, we examine genetic stability and change in the etiology of g assessed by diverse measures during the critical transition from early to middle childhood. The heritability of a latent g factor in early childhood is 23%, whereas shared environment accounts for 74% of the variance. In contrast, in middle childhood, heritability of a latent g factor is 62%, and shared environment accounts for 33%. Despite increasing importance of genetic influences and declining influence of shared environment, similar genetic and shared environmental factors affect g from early to middle childhood, as indicated by a cross-age genetic correlation of .57 and a shared environmental correlation of .65. These findings set constraints on how genetic and environmental variation affects the developing brain.     

Association between polymorphisms in the dopamine transporter gene and depression: evidence for a gene-environment interaction in a sample of juvenile detainees

Previous research has generated examples of how genetic and environmental factors can interact to create risk for psychopathology. Using a gene-by-environment (G x E) interaction design, we tested whether three polymorphisms in the dopamine transporter gene (DAT1, also referred to as SLC6A3, located at 5p15.33) interacted with maternal parenting style to predict first-onset episodes of depression. Participants were male adolescents (N= 176) recruited from a juvenile detention center in northern Russia. As hypothesized, one of the polymorphisms (rs40184) moderated the effect of perceived maternal rejection on the onset of major depressive disorder, as well as on suicidal ideation. Further, this G x E interaction was specific to depression; it did not predict clinically significant anxiety. These results highlight the need for further research investigating the moderating effects of dopaminergic genes on depression.