Different implication of NEDD9 genetic variant in early and late-onset Alzheimer's disease

Alzheimer's disease (AD) is a complex and multifactorial progressive neurodegenerative disease. Recently, two studies reported inconsistent results on a possible involvement of the NEDD9 (neural precursor cell expressed, developmentally down-regulated 9, 6p25-p24) as a candidate gene for the risk of developing AD and/or Parkinson's disease (PD). We analyzed the distribution of the rs760678 SNP polymorphism in 735 Italian subjects: 214 unrelated sporadic late-onset AD patients (LOAD, 64.5% females, mean age-at-onset 71.8 ± 5.2 years), 135 early-onset AD patients (EOAD, 57.3% females, mean age-at-onset 57.5 ± 5.5 years) and 386 healthy controls (68.9% females, mean age 83.4 ± 17.9 years; SD). We observed a statistically significant difference between LOAD patients and controls according to genotypes (P = 0.016) and allele frequency (P = 0.007); CC genotype was more frequent in LOAD cases (44.4%) than controls (36.0%). No difference after stratification of the data in terms of gender and status of the APOE ?4 allele was observed. In conclusion, our data do support an implication of the NEDD9 allelic variant in late-onset AD, with an independent effect of the apolipoprotein E (APOE) ?4 allele in the risk of developing AD.     

C9orf72 G4C2 repeat expansions in Alzheimer's disease and mild cognitive impairment

C9orf72 G₄C₂ repeat expansion is a major cause of amyotrophic lateral sclerosis and frontotemporal lobar degeneration. Its role in Alzheimer's disease (AD) is less clear. We assessed the prevalence of G₄C₂ pathogenic repeat expansions in Flanders-Belgian patients with clinical AD or mild cognitive impairment (MCI). In addition, we studied the effect of non-pathogenic G₄C₂ repeat length variability on susceptibility to AD, and on AD cerebrospinal fluid (CSF) biomarker levels. A pathogenic repeat expansion was identified in 5 of 1217 AD patients (frequency <1%). No pathogenic expansions were observed in patients with MCI (n = 200) or control individuals (n = 1119). Nonpathogenic repeat length variability was not associated with AD, risk of conversion to AD in MCI individuals, or CSF biomarker levels. We conclude that pathogenic C9orf72 G₄C₂ repeat expansions can be detected in clinical AD patients and could act as a contributor to AD pathogenesis. Non-pathogenic repeat length variability did not affect risk of AD or MCI, nor AD biomarker levels in CSF, indicating that C9orf72 is not a direct AD risk factor.     

Evaluation of late-onset Alzheimer disease genetic susceptibility risks in a Canadian population

We performed case-control studies using 2 Canadian cohorts to examine the role of 10 promising Alzheimer's disease (AD) loci identified in recent genomewide association studies. Patients age 65 years and older diagnosed with AD at baseline (prevalent cases) or who developed AD during follow-up assessments (incident cases) were compared with control subjects with no cognitive impairment. Our prevalent case study comparing prevalent AD cases (n = 428) with participants with no cognitive impairment (n = 524) revealed a significant association of rs6656401 and rs3818361 (CR1), rs2075650 (TOMM40), rs7561528 (BIN1), and rs3865444 (CD33) with late-onset AD that were robust to adjustment with age and apolipoprotein E ε4 genotype. The incident case study comparing patients who developed AD during longitudinal observation (n = 152) with participants with no cognitive impairment found that rs2075650 (TOMM40) and rs3865444 (CD33) influence the risk of developing AD in this population. In addition, pooled analysis of our AD patients confirmed that CR1, TOMM40, BIN1, and CD33 contribute to late-onset AD susceptibility, in addition to apolipoprotein E.     

Association between a variant of the sigma-1 receptor gene and Alzheimer's disease

Alzheimer's disease (AD) is a progressive neurodegenerative disorder with complex etiology and strong genetic predisposition. A number of investigations support the possible involvement of sigma non-opioid intracellular receptor 1 (SIGMAR1) in the pathophysiology of AD. We aimed to investigate the association between SIGMAR1 polymorphisms and late-onset AD, therefore we genotyped rs1799729 (GC-241-240TT) and rs1800866 (Q2P) in 322 Hungarian late-onset AD patients and 250 ethnically matched, elderly control individuals. The investigated polymorphisms were in nearly complete linkage disequilibrium resulting in the GC-Q and TT-P predominant haplotypes that were subjected to the statistical analyses. Our data demonstrates an association between the SIGMAR1 TT-P variant and the risk for developing AD (p=0.019), and a potential modest interaction effect (p=0.058) of the co-presence of the TT-P haplotype with apolipoprotein E4 allele on the risk for AD. Based on this mild significance, we could not fully support the hypothesis that TT-P haplotype in interaction with APOE E4 allele confers risk for developing AD.     

The androgen receptor CAG and GGN repeat polymorphisms and prostate cancer susceptibility in African-American men: results from the Flint Men’s Health Study

Repeat lengths of the CAG and GGN microsatellites in exon 1 of the androgen receptor (AR) gene have been hypothesized to be associated with prostate cancer risk. In vitro studies have showed an inverse association between AR CAG and GGN repeat length and activity levels of the AR product. It is known that men of African descent have a higher incidence of and greater mortality from prostate cancer than men of Caucasian or Asian descent and, on average, a smaller number of repeats at AR CAG and GGN. Consistent with these findings, studies have also found increased AR protein expression levels in benign prostatic hyperplasia and prostatic diseased tissues from men of African descent. Despite these findings, limited studies have been conducted to evaluate the association between repeat lengths at AR CAG and prostate cancer risk in African Americans. Our study is the first such study to examine whether repeat length of the AR GGN repeat is associated with prostate cancer risk in African Americans. We found no evidence for an association between AR CAG or GGN repeat lengths and prostate cancer risk in a population-based sample of African Americans.     

The genetic landscape of Alzheimer disease: clinical implications and perspectives

The search for the genetic factors contributing to Alzheimer disease (AD) has evolved tremendously throughout the years. It started from the discovery of fully penetrant mutations in Amyloid precursor protein, Presenilin 1, and Presenilin 2 as a cause of autosomal dominant AD, the identification of the ɛ4 allele of Apolipoprotein E as a strong genetic risk factor for both early-onset and late-onset AD, and evolved to the more recent detection of at least 21 additional genetic risk loci for the genetically complex form of AD emerging from genome-wide association studies and massive parallel resequencing efforts. These advances in AD genetics are positioned in light of the current endeavor directing toward translational research and personalized treatment of AD. We discuss the current state of the art of AD genetics and address the implications and relevance of AD genetics in clinical diagnosis and risk prediction, distinguishing between monogenic and multifactorial AD. Furthermore, the potential and current limitations of molecular reclassification of AD to streamline clinical trials in drug development and biomarker studies are addressed.     

SORL1 is genetically associated with Alzheimer disease in a Japanese population

A recent study reported that variants of the neuronal sortilin-related receptor gene (SORL1) increased the risk of late-onset Alzheimer disease (AD) in several populations. Here, we examined the risk effect in a large, well-characterized group of 437 late-onset AD patients and 451 control subjects in a Japanese population. Among eight single-nucleotide polymorphisms (SNPs) of the SORL1 gene for which association has been reported, we found a significant association for four of them, located between exon 24 and intron 37. This risk was evident in non-carriers of the apolipoprotein E-?4 allele, but not in its carriers. Our results support the evidence that genetic variants of SORL1 affect susceptibility to late-onset AD.     

Association between CAG repeat length in the PPP2R2B gene and Alzheimer disease in the Japanese population

We analyzed the association between PPP2R2B gene CAG repeat length and Alzheimer disease (AD) susceptibility in the Japanese population. Blood samples were collected from 218 late-onset AD patients and 86 controls. DNA fragments containing the target CAG repeat region were amplified using polymerase chain reaction (PCR). PCR products were sequenced using ABI PRISM 310 genetic analyzer. The mean CAG repeat length did not differ significantly between the control and AD groups. In contrast, the frequency of CAG repeats shorter than 15 was significantly higher in AD group, specifically in the AD with APOE4 subgroup, than in the control group. The results suggest that CAG repeat lengths in the PPP2R2B gene may be potential genetic markers for AD susceptibility in the Japanese population.     

Sequencing analysis of the spinal bulbar muscular atrophy CAG expansion reveals absence of repeat interruptions

Trinucleotide repeat disorders are a heterogeneous group of diseases caused by the expansion, beyond a pathogenic threshold, of unstable DNA tracts in different genes. Sequence interruptions in the repeats have been described in the majority of these disorders and may influence disease phenotype and heritability. Spinal bulbar muscular atrophy (SBMA) is a motor neuron disease caused by a CAG trinucleotide expansion in the androgen receptor (AR) gene. Diagnostic testing and previous research have relied on fragment analysis polymerase chain reaction to determine the AR CAG repeat size, and have therefore not been able to assess the presence of interruptions. We here report a sequencing study of the AR CAG repeat in a cohort of SBMA patients and control subjects in the United Kingdom. We found no repeat interruptions to be present, and we describe differences between sequencing and traditional sizing methods.     

The genetics of Alzheimer''s disease

Alzheimer's disease (AD) is the major cause of dementia in the U.K. The clinical diagnosis of the specific disease resulting in dementia is unreliable and thus a definitive diagnosis of AD is best made in conjunction with post-mortem findings of amyloid plaques and neurofibrillary tangles. Alzheimer's disease is neuropathologically indistinguishable in the young and old, but has been divided arbitrarily into early- and late-onset disease using age cut-offs of 60 or 65 years. Twin and family studies suggest that genetic factors play a major role in its aetiology. This review considers the three loci which have been shown to be associated with early-onset AD: amyloid precursor protein, presenilin (PS)-l and PS-2. Mutations in these genes seem to be associated with overproduction of the 42-amino acid form of β-bamyloid, suggesting that this may be a central pathological process in AD. The impact of the different apo E alleles on the risks for late- and early-onset AD is discussed and compared with other dementing conditions. Recent analyses suggest that there are likely to be other genes besides apo E which impact on late-onset AD risk. The possible roles in AD of the mitochondria) mutation at position 4336, the PS intron 8 polymorphism, and variants in the alpha I-antichymotrypsin and VLDL-receptor genes, are considered.     

Increased risk of non-insulin dependent diabetes mellitus, arterial hypertension and coronary artery disease in perimenopausal women with a history of the polycystic ovary syndrome

The aim of the study was to determine the prevalence of non-insulin dependent diabetes mellitus (NIDDM), arterial hypertension, coronary artery disease and the risk factors for these diseases in perimenopausal women with a history of polycystic ovary syndrome (PCOS) treatment. A group of 28 women was selected from a large group of patients who had undergone wedge ovarian resection. A total of 752 controls was selected by age (45-59 years) from a random female population sample. There was no difference between the two groups in body mass index, waist circumference or waist-hip ratio. Both groups were found to have identical family histories of NIDDM, hypertension, and coronary artery disease and identical smoking habits. We did not find a difference between the mean concentrations of lipids and fasting glucose. The two groups did not differ in the proportions of women with elevated lipid concentrations. The prevalence of NIDDM and coronary artery disease was significantly higher in PCOS women. In conclusion, women in the general population have the same level of risk factors at perimenopausal age as PCOS women. Patients with markedly expressed clinical symptoms of PCOS made up a subgroup in the general population at high risk for developing NIDDM and coronary artery disease.     

No association of toll-like receptor 2 polymorphisms with Alzheimer's disease in Han Chinese

Toll-like receptor 2 (TLR2) represents a reasonable functional and positional candidate gene for Alzheimer's disease (AD) as it is located under the linkage region of AD on chromosome 4q, and is functionally involved in the microglia-mediated inflammatory response and amyloid β (Aβ) clearance. In the current study, 7 single nucleotide polymorphisms (SNPs) that span the TLR2 were selected and their associations with late-onset AD (LOAD) risk were assessed in a case-control sample comprising 785 individuals in a Han Chinese population. No significant differences in the frequency of TLR2 alleles, genotypes, and haplotypes in the AD cases were detected compared with the controls. TLR2 gene might not play a major role in the genetic predisposition to late-onset Alzheimer's disease in this population.     

Analysis of alpha-1 antichymotrypsin,presenilin-1, angiotensin-converting enzyme,and methylenetetrahydrofolate reductase loci as candidates for dementia

The genetic factors which predispose individuals to dementia in old age have not been fully defined. Although the apolipoprotein E4 allele accounts for a proportion of the genetic risk for late-onset Alzheimer disease (AD), it is neither necessary nor sufficient to cause this disease. Recent suggestions that other loci are involved in dementia risk have been supported by findings of associations of genotypes at the alpha-1 antichymotrypsin (ACT) and presenilin-1 (PS-1) loci with AD. We investigated these loci in two community-based aged Cambridgeshire populations: the rural Ely population (cohort 1) comprised 60 pairs of demented and nondemented elderly individuals, with a mean age of 84.2 years; and the Cambridge city population (cohort 2) comprised 81 pairs all over age 84, with a mean age of 87.3 years. Since vascular risk factors are likely to impact on dementia risk, we also examined the angiotensin-converting enzyme (ACE) and methylenetetrahydrofolate reductase (MTHFR) genes as candidates. ACE, ACT, PS-1, and MTHFR genotype and allele frequencies were not significantly different in cases and matched controls. These data support the doubts which have been raised about the involvement of the PS-1 and ACT polymorphisms in late-onset dementia. Am. J. Med. Genet. 74:207–212, 1997. © 1997 Wiley-Liss, Inc.     

Midlife homocysteine and late-life dementia in women. A prospective population study

Elevated serum total homocysteine (tHcy) is an established risk factor for cardiovascular disease. Its role in dementia is still controversial, and no study has examined the role of midlife tHcy, or reports longer than 8 years of follow-up. We examined the relation between midlife tHcy and late-life dementia in women followed for 35 years.The Prospective Population Study of Women in Gothenburg began in 1968-1969, comprising a representative population of women aged 38-60 years. Four extensive follow-ups were conducted by 2003. Serum samples from 1968 to 1969 were analysed for tHcy in 1368 women. In total, 151 women developed dementia. The highest tHcy tertile was related to a hazard ratio of 1.7 (95% CI 1.1-2.6) for developing any dementia, 2.1 (95% CI 1.2-3.7, n = 100) for AD and 2.4 (95% CI 1.3-4.7, n = 68) for AD without cerebrovascular disease. Kaplan-Meier plots showed divergence with respect to dementia after 22 years of follow-up. In conclusion, high homocysteine in midlife is an independent risk factor for the development of late-life Alzheimer dementia in women.     

Female specific risk factors for the development of Alzheimer’s disease neuropathology and cognitive impairment: Call for a precision medicine approach

Alzheimer's disease (AD) includes a long asymptomatic stage, which precedes the formal diagnosis of dementia. AD biomarker models provide a framework for precision medicine approaches during this stage. However, such approaches have ignored the possible influence of sex on cognition and brain health, despite female sex noted as a major risk factor. Since AD-related changes may emerge in midlife, intervention efforts are being redirected around this period. Midlife coincides with several endocrinological changes, such as the menopausal transition experienced by women. In this narrative review, we discuss evidence for sex-differences in AD neuropathological burden and outline key endocrinological mechanisms for both sexes, focussing on hormonal events throughout the lifespan that may influence female susceptibility to AD neuropathology and dementia onset. We further consider common non-modifiable (genetic) and modifiable (lifestyle and health) risk factors, highlighting possible sex-dependent differential effects for the AD disease course. Finally, we evaluate the studies selected for this review demonstrating sex-differences in cognitive, pathological and health factors, summarising the state of sex differences in AD risk factors. We further provide recommendations for targeted research on female-specific risk factors, to inform personalised strategies for AD-prevention and the promotion of female brain health.     

Reproductive aging and risk for chronic disease: Insights from studies of nonhuman primates

Reproductive aging and ovarian senescence have considerable public health relevance because they are associated with increased risk for coronary heart disease (CHD), osteoporosis and other degenerative conditions including cognitive decline and potentially the metabolic syndrome. It has been suggested that the hormonal dysregulation that occurs during the perimenopausal transition may play a role in the initiation of pathobiological changes (e.g., adverse lipid profiles, atherosclerotic plaques) that will increase risk for chronic disease (e.g., CHD) during the postmenopausal years. Moreover, these early changes are suspected to establish a trajectory of disease progression that may be difficult to alter if interventions are not begun until after menopause. Even a slight increase in the rate of disease progression during the pre- or perimenopausal years could have substantial consequences for health and quality of life over the postmenopausal lifespan. Thus, the years leading up to menopause may offer a “critical window” for interventions aimed at reducing the postmenopausal disease burden. The relationship between perimenopausal hormonal dysregulation and the risk for chronic disease is poorly understood due, in large part, to the lack of appropriate animal models of the perimenopausal transition and natural menopause. In this review we assesses studies of nonhuman primates (NHPs) evaluated in various reproductive stages (naturally pre-, peri- and postmenopausal, surgically menopausal) and their contribution to our understanding about risk factors for chronic disease. Finally, because large numbers of naturally perimenopausal and menopausal NHPs are not available for research at present, experimental approaches that have the potential to hasten the onset of the perimenopausal transition will be described.     

Lack of association between the CYP46 gene polymorphism and Italian late-onset sporadic Alzheimer's disease

Recent studies have provided evidence toward the possible involvement of brain cholesterol homeostasis in late-onset Alzheimer's disease (LOAD). We analyzed an intronic T-->C substitution (rs 754203) of the cholesterol 24S-hydroxylase (CYP46) gene, encoding an enzyme acting on brain cholesterol turnover, which has been recently associated with an increased risk of AD, dependent or not on Apolipoprotein E (ApoE) genotype. No significant association was found for the CYP46 polymorphism in LOAD compared to the controls, even after stratification for the presence/absence of the ApoE*4 allele. Our data do not support a role of the CYP46 polymorphism as a possible susceptibility factor for developing AD.     

The complex interaction between APOE promoter and AD: an Italian case�Ccontrol study

The single nucleotide polymorphisms (SNPs) rs449647, rs769446 and rs405509 in the promoter region of the APOE gene have been variously suggested to be ɛ4-independent risk factors for Alzheimer''s disease (AD). A previous Italian study found that the rs449647 was significantly associated with late-onset AD. The aim of this study was to verify whether these APOE promoter SNPs are genetic risk factors for AD and to investigate their interaction with the common APOE polymorphism. A total of 169 clinically diagnosed AD patients and 99 cognitively intact age-matched controls were included in the study. Significant associations with AD independent from sex, age and APOE/ɛ4 status were found for rs449647 A/A and rs405509 G/G genotypes (positive), and rs449647 A/T and rs405509 T/T genotypes (negative). Haplotype frequency estimation at the APOE locus showed significant associations for the ATG4, ATT4 and ACG3 (positive) and ATT2, ATT3 and TCG3 (negative) haplotypes. Therefore this study confirms the role of the rs449647 A/A genotype as risk factor for AD in Italy and suggests that promoter genotypes and APOE haplotypes might have a complex function in AD-associated genetic risk factors.