Presenilin mutations in Alzheimer's disease

The presenilins (PS-1 and PS-2) are 2 members of a novel family of genes encoding integral membrane proteins recently implicated in Alzheimer's disease (AD) pathology. To date, 43 mutations have been identified in PS-1 and 2 in PS-2 that lead to familial presenile AD (onset before age 65 years). The normal and pathological functions of the PS proteins (ps-1 and ps-2) are unknown, but their high degree of homology predicts similar biological activities. Homologies with ps from other species suggest that they may play a role in intracellular protein sorting and trafficking, in intercellular cell signaling, or in cell death. Since to date only missense mutations and in-frame deletions were identified, it is believed that mutated ps act through either a gain of (dys-)function or a dominant negative effect. In vivo and in vitro studies have linked PS mutations to amyloid deposition, an early pathological event in AD brains. Hum Mutat 11:183–190, 1998. © 1998 Wiley-Liss, Inc.     

ABCA7 gene and the risk of Alzheimer's disease in Han Chinese in Taiwan

The ATP-binding cassette, subfamily A, member 7 gene (ABCA7) was recently identified as a susceptible gene of Alzheimer's disease (AD) in the Caucasian population and African Americans. To test its genetic effect in the Han-Chinese population, 536 AD cases and 307 cognitive-intact, elder controls were genotyped for ABCA7 rs3764650 and apolipoprotein E (APOE) ε2/ε3/ε4 alleles. Global cognitive performance was assessed by the Mini-Mental State Examination in both AD patients and controls. For AD patients, comprehensive evaluation of each cognitive domain was further conducted as the following: (1) attention (forward and backward digit span); (2) memory (12-item word recall test); (3) executive function (category verbal fluency); (4) processing speed (Trail making test, part A); and (5) naming task (Boston naming test). ABCA7 rs3764650 was significantly associated with AD and the GG genotype carried a reduced risk for AD (odds ratio = 0.52, p = 0.0026). The association was further confirmed in 1802 population-based, healthy controls from Taiwan Biobank as a replicate (odds ratio = 0.70, p = 0.032). After adjustment of age, sex, and APOE ε4 allele, rs3764650 remained to be an independent predictor of AD (p = 0.001). The influence of ABCA7 was only evident in individuals without APOE ε4 alleles (p = 0.0004) but absent in ε4 carriers (p = 0.91). None of the cognitive tests was related to ABCA7 rs3764650 genotypes. The minor allele frequency and effect size of rs3764650 disclosed in the Han-Chinese population differed from those reported in the Caucasians and African Americans. Further studies were warranted to elucidate ABCA7's effect among different ethnic groups.     

Octapeptide repeat alteration mutations of the prion protein gene in clinically diagnosed Alzheimer's disease and frontotemporal dementia

Studies focusing on octapeptide repeat alteration mutations in PRNP in Alzheimer's disease (AD) and frontotemporal dementia (FTD) cohorts have been rare. We aim to screen sporadic AD and FTD patients with unknown etiology for the octapeptide repeat insertions and deletions in PRNP. Two hundred and six individuals were screened for alterations to the repeat region in the PRNP gene, including 146 sporadic AD and 60 sporadic FTD patients. Our study showed a 1.5% (3/206) occurrence of the octapeptide repeat alteration mutations in PRNP in a Chinese cohort of sporadic dementia. One late-onset FTD patient and one early-onset AD patient each had a two-octapeptide repeat deletion in PRNP, while one early-onset AD patient had a five-octapeptide repeat insertion mutation. PRNP octapeptide repeat alteration mutations are present in sporadic AD and FTD patients. The genetic investigation for PRNP octapeptide repeat alteration mutations in sporadic dementia patients should be carried out in future clinical studies.     

Relationship of the Ubiquilin 1 gene with Alzheimer's and Parkinson's disease and cognitive function

Ubiquilin 1 (UBQLN1) is involved in the ubiquitination machinery, which has been implicated in Alzheimer's disease (AD) as well as Parkinson's disease (PD). A polymorphism in the gene encoding for UBQLN1 has been previously associated with a higher risk of AD. We studied the role of the SNP rs12344615 on the UBQLN 1 gene in AD, PD and cognitive function in a population-based study, the Rotterdam Study, and a family-based study embedded in the genetic research in isolated population (GRIP) program. The Rotterdam Study includes 549 patients with AD and 157 patients with PD. The GRIP program includes a series of 123 patients with AD and a study of 1049 persons who are characterized for cognitive function. Data were analysed using logistic and multiple regression analysis. We found no significant difference in risk of AD or PD by the UBQLN1 SNP rs12344615 in our overall and stratified analyses in the Rotterdam Study. In our family-based study, we did not find evidence for linkage of AD to the region including the UBQLN1 gene. In the family-based study we also failed to detect an effect of this polymorphism on cognitive function. Our results suggest that it is unlikely that the SNP rs12344615 of the UBQLN1 gene is related to the onset of AD, PD or cognitive function.     

Epigenetic changes in the progression of Alzheimer's disease

The formation of 5-hydroxymethylcytosine (5hmC), a key intermediate of DNA demethylation, is driven by the ten eleven translocation (TET) family of proteins that oxidize 5-methylcytosine (5mC) to 5hmC. To determine whether methylation/demethylation status is altered during the progression of Alzheimer's disease (AD), levels of TET1, 5mC and subsequent intermediates, including 5hmC, 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC) were quantified in nuclear DNA from the hippocampus/parahippocampal gyrus (HPG) and the cerebellum of 5 age-matched normal controls, 5 subjects with preclinical AD (PCAD) and 7 late-stage AD (LAD) subjects by immunochemistry. The results showed significantly (p < 0.05) increased levels of TET1, 5mC, and 5hmC in the HPG of PCAD and LAD subjects. In contrast, levels of 5fC and 5caC were significantly (p < 0.05) decreased in the HPG of PCAD and LAD subjects. Overall, the data suggest altered methylation/demethylation patterns in vulnerable brain regions prior to the onset of clinical symptoms in AD suggesting a role in the pathogenesis of the disease.     

Association between somatostatin gene polymorphisms and sporadic Alzheimer's disease in Chinese population

Recent evidence has suggested that down-regulation of somatostatin (SST) expression in the human brain during early stages of aging leads to an elevation in the steady-state levels of Aβ and therefore may be involved in Alzheimer's disease (AD) progression. We hypothesized that alterations in the SST gene might alter its expression or function and also play a role in the pathogenesis of sporadic AD (SAD). First, we sequenced the entire SST gene in 25 randomly selected controls and 25 SAD patients and then screened for C/T polymorphisms (rs4988514) in the 3′ un-translated region. We genotyped rs4988514 polymorphisms as well as apolipoprotein ?4 (APOE ?4) status in 309 SAD patients and 276 normal controls with restriction fragment length polymorphism (RFLP) analysis. Results showed that the C allele of the rs4988514 polymorphism had an increased incidence in the SAD group compared to the control group (p = 0.042). In subjects with the APOE ?4 allele, the presence of both the CC genotype and the C allele of this polymorphism were elevated in the SAD group compared to the control group (genotype p = 0.027, allele p = 0.011). In the whole study group, the age, sex, and APOE ?4 adjusted OR for the risk of AD in C allele carriers was 1.313 (95%CI = 1.068–2.234, p = 0.027) whereas within only APOE ?4 allele carriers, the adjusted OR increased to 2.734 (95%CI = 1.236–5.862, p = 0.012). Our results supported the notion that the C allele of the rs4988514 polymorphism may increase the risk for AD in the Chinese population and possibly have additive effect with the APOE ?4 allele.     

Expression and localization of lactotransferrin messenger RNA in the cortex of Alzheimer's disease

We and others have previously reported that lactotransferrin (LF), acting both as an iron-binding protein and inflammatory modulator, is greatly up-regulated in the brain of patients with Alzheimer's disease (AD). However, it remains unknown which type of cells express LF in the brain of AD. In this study, therefore, we investigated the expression and localization of LF messenger RNA (mRNA) in the cerebral cortex of AD and control cases using real-time polymerase chain reaction (PCR) and in situ hybridization histochemistry. Real-time PCR demonstrated that LF mRNA expression in the cortex of AD cases was significantly greater than that in control cases. LF mRNA-positive granules were observed in the cortex by in situ hybridization histochemistry, and the number of positive granules was increased in AD cases compared to controls. The double staining technique of LF mRNA in situ hybridisation and D-related human leukocyte antigen (HLA-DR) immunohistochemistry revealed that positive granules were localized in a subpopulation of HLA-DR-positive reactive microglia. In addition, LF mRNA-positive granules were observed in some cells that were negative for HLA-DR. These cells were also negative for CD4 and CD8 but positive for leukocyte common antigen (CD45RB), suggesting they were monocytes/macrophages. These results indicate that reactive microglia in the cerebral cortex and monocytes/macrophages infiltrating from the circulation might be responsible for synthesizing LF in AD brain.     

Androgen receptor gene and sex-specific Alzheimer's disease

Women are at a 2-fold risk of developing late-onset Alzheimer's disease (AD) (onset at 65 years of age or older) compared with men. During perimenopausal years, women undergo hormonal changes that are accompanied by metabolic, cardiovascular, and inflammatory changes. These all together have been suggested as risk factors for late-onset AD. However, not all perimenopausal women develop AD; we hypothesize that certain genetic factors might underlie the increased susceptibility for developing AD in postmenopausal women. We investigated the Androgen Receptor gene (AR) in a clinical cohort of male and female AD patients and normal control subjects by sequencing all coding exons and evaluating the length and distribution of the CAG repeat in exon 1. We could not establish a correlation between the repeat length, sex, and the disease status, nor did we identify possible pathogenic variants. AR is located on the X chromosome; to assess its role in AD, X-inactivation patterns will need to be studied to directly correlate the actual expressed repeat length to a possible sex-specific phenotypic effect.     

Missense mutations in the chromosome 14 familial Alzheimer's disease presenilin 1 gene

Mutations in the presenilin genes (PS-1 and PS-2) cause early onset autosomal dominant Alzheimer's disease (AD). Eight early-onset, autopsy-documented familial AD kindreds were screened for mutations in PS-1, and seven different mutations were identified. Three of these were new mutations (G209V, A426P, and E120D), two were previously reported mutations in new families, and three mutations were confirmed in previously published families. Two of these new mutations are found within predicted transmembrane domains (TMDs 4, 7, and 8). The A426P mutation is the most C-terminal PS-1 mutation identified to date. Hum Mutat 11:216–221, 1998. © 1998 Wiley-Liss, Inc.     

Plasma oxidized low-density lipoprotein levels and risk of Alzheimer's disease

This study examines the association of plasma oxidized low-density lipoprotein (OxLDL) levels with all-cause dementia, including Alzheimer's disease (AD) and vascular dementia. Data are taken from the Canadian Study of Health and Aging, a population-based study of a representative sample of persons aged more than 65 years conducted from 1991 to 2002. The present study sample included 670 subjects of which, 155 developed all-cause dementia with 109 cases of AD and 32 of vascular dementia. In Cox regression models, no association between OxLDL and risks of dementia or subtypes was found. A triple interaction between OxLDL, sex, and history of cardiovascular disease on the risk of AD (p = 0.0077) was found. Increased levels of OxLDL were significantly associated with an increased risk of AD in men with a history of cardiovascular disease (hazard ratio = 1.11; 95% confidence interval 1.04–1.19); no association in women was found. These findings suggest that increased levels of OxLDL are not associated with the risk of dementia, AD, and vascular dementia. The association of OxLDL with AD in men with a history of cardiovascular disease merits further investigation.     

Alzheimer's disease risk genes and the age-at-onset phenotype

Despite the recent identification of several novel risk genes for Alzheimer's disease (AD), little is known about their influence on the age at onset (AAO) of AD. The AAO is a phenotype with a heritable component distinct from disease risk and may be a useful trait to study in the context of developing interventions for delaying the onset of AD. We studied the influence of 10 recently identified AD risk genes and APOE in relation to AAO in a large cohort of AD patients (N = 2569). We find that the novel AD risk gene, PICALM, exerts a small effect on the AAO of AD with earlier disease onset in risk allele carriers. In addition, we confirmed the previously reported association between the APOE ε4 allele and earlier disease onset. None of the other AD risk genes influenced AAO of AD. Our results suggest that besides APOE, other genes associated with AD risk do not exert large effects on the AAO phenotype of AD.     

Deposition of lactoferrin in fibrillar-type senile plaques in the brains of transgenic mouse models of Alzheimer's disease

We and others have previously reported that lactoferrin (LF), which acts as both an iron-binding protein and an inflammatory modulator, is strongly up-regulated in the brains of patients with Alzheimer's disease (AD). We have also studied the expression and localization of LF mRNA in the brain cortices of patients with AD. In this study, we investigated immunohistochemically the localization of LF in the brains of APP-transgenic mice, representing a model of AD. No LF immunoreactivity was detected in the brains of the wild-type mice. In the transgenic AD mice, LF deposition was detected in the brains. Double-immunofluorescence staining with antibodies directed against the amyloid-β peptide (Aβ) and LF localized the LF depositions to amyloid deposits (senile plaques) and regions of amyloid angiopathy. Senile plaque formation precedes LF deposition in AD. In the transgenic mice aged <18 months, most of senile plaques were negative for LF. LF deposits appeared weakly at about 18 months of age in these mice. Both the intensity and number of LF-positive depositions in the transgenic mice increased with age. Double-staining for LF and thioflavin-S revealed that LF accumulated in thioflavin-S-positive, fibrillar-type senile plaques. The up-regulation of LF in the brains of both AD patients and the transgenic mouse model of AD provides evidence of an important role for LF in AD-affected brain tissues.     

Lack of an association between Paraoxonase 1 gene polymorphisms (Q192R, L55M) and Alzheimer's disease: a meta-analysis

The association between Paraoxonase 1 (PON1) gene polymorphisms (Q192R, L55M) and Alzheimer's disease (AD) risk has been reported inconsistent results. To assess the association between PON1 polymorphisms and AD risk, a meta-analysis was performed. Based on comprehensive searches of the PubMed, Embase, Web of Science, Weipu, and CBM databases, a total of 10 studies including 3081 AD cases and 3054 controls were identified. The pooled odds ratio (OR) with 95% confidence interval (95% CI) were performed. There was no significant association between PON1 Q192R polymorphism and AD risk in all comparison models (R vs. Q, OR=0.89, 95% CI=0.82-0.96; RR vs. QQ, OR=0.83, 95% CI=0.68-1.01; RR+RQ vs. QQ, OR=0.86, 95% CI=0.75-0.97; and RR vs. QR+QQ, OR=0.94, 95% CI=0.81-1.11). For the PON1 L55M polymorphism, lack of an association was also found (L vs. M, OR=0.95, 95% CI=0.86-1.05; LL vs. MM, OR=0.67, 95% CI=0.51-0.88; LL vs. ML+MM, OR=0.82, 95% CI=0.69-0.98; and LL+ML vs. MM, OR=0.75, 95% CI=0.58-0.96). On subgroup analysis by ethnicity, similar results were found. Conclusively, the present meta-analysis revealed that PON1 gene polymorphisms (Q192R, L55M) were unlikely to contribute to AD susceptibility.     

Genetic variation in Clusterin gene and Alzheimer's disease risk in Han Chinese

Clusterin gene (CLU), also known as apolipoprotein J (ApoJ), is a strong candidate gene for late-onset Alzheimer's disease (LOAD) according to the Alzgene database. To further characterize this association and to isolate the variants contributing to the pathogenesis of LOAD in Han Chinese, we first sequenced a small sample (n = 100) to discover variants in the promoter, exons, the 5′ and 3′ untranslated regions, and exon–intron boundaries of CLU. Follow-up genotyping of identified variants in a larger sample (n = 1592). Sequencing analysis identified 18 variants. Analysis in the larger population revealed that only the rs9331949 C allele was significantly associated with an increased risk of LOAD, even after adjusting for multiple testing (p = 0.026). Logistic analysis identified the rs9331949 polymorphism was still strongly associated with LOAD (additive model: p = 0.004, odds ratio = 1.274; dominant model: p = 0.039, odds ratio = 1.239; recessive model: p = 0.002, OR = 1.975) after adjusting for sex, age, and APOE ε4 status. Our findings implicate CLU as a susceptibility gene for LOAD in Han Chinese.     

Iron,copper, and iron regulatory protein 2 in Alzheimer's disease and related dementias

Accumulating evidence implicates a role for altered iron and copper metabolism in the pathogenesis of neurodegenerative disorders such as Alzheimer's disease (AD). However, imbalances in the levels of the various forms of iron at different stages of AD have not been examined. In this pilot study we extracted and measured the levels of loosely bound, non-heme and total iron and copper in the frontal cortex and hippocampus of patients with mild–moderate AD (n = 3), severe AD (n = 8) and dementia with Lewy bodies (DLB, n = 6), using graphite furnace atomic absorption spectrometry (GFAAS). Additionally, the expression of iron regulatory protein 2 (IRP2) was examined in relation to the pathological hallmarks of AD and DLB, amyloid plaques, neurofibrillary tangles (NFT), and Lewy bodies, by immunohistochemistry. We found significantly decreased loosely bound iron in the hippocampal white matter of mild–moderate and severe AD patients and a trend towards increased non-heme iron in the hippocampal gray matter of severe AD patients. Furthermore, decreased levels of total copper were seen in severe AD and DLB frontal cortex compared to controls, suggesting an imbalance in brain metal levels in both AD and DLB. The decrease in loosely bound iron in mild–moderate AD patients may be associated with myelin breakdown seen in the beginning stages of AD and implicates that iron dysregulation is an early event in AD pathogenesis.     

Hallucinations,loneliness, and social isolation in Alzheimer's disease

Introduction: Cognitive and functional compromise, as frequently observed in Alzheimer's disease (AD), hinders communication and social interactions. One consequence of this hindrance may be a feeling of loneliness. Moreover, emptiness and boredom, as observed in social isolation and loneliness, may thus be compensated for by creating imagined stimuli. Conditions of loneliness may be viewed as potentially generating hallucinatory experiences. To assess this assumption, the present study explored the relationship between social isolation, loneliness, and hallucinations in a sample of 22 mild AD participants and 24 elderly, healthy controls. Methods: Participants were assessed using the Launay–Slade Hallucination Scale, the UCLA Loneliness Scale, and a scale exploring contact with others and social participation. Results: More hallucinatory experiences, social isolation, and loneliness were found in the AD group than in the healthy control group. Moreover, significant correlations were observed between hallucinations and loneliness and between hallucinations and social isolation in both groups. Finally, hallucinations were predicted by social isolation. Discussion: Hallucinations may constitute a compensatory mechanism that aims to fulfil communication needs in lonely, elderly participants. Hallucinations may also be regarded as experiences that allow certain participants to escape the cycle of boredom, emptiness, and affective deprivation caused by social isolation.     

Genetic risk score modifies the effect of APOE on risk and age onset of Alzheimer's disease

Single nucleotide polymorphism (SNP)-based genetic risk score (GRS) and APOE genotype are both important in risk prediction of Alzheimer's disease (AD); however, the interaction between GRS and APOE has not been extensively investigated. Our objective was to determine whether GRS modifies the APOE effect on AD risk and age at onset (AAO). The study included 774 AD cases and 767 controls of European descent. Population standardized GRS was calculated based on 17 previously implicated AD risk-associated SNPs. Association was analyzed using logistic regression, Cox proportional hazards model and Kaplan-Meier curve. We found that GRS was significantly associated with AD risk and the association was stronger among APOE ε4 carriers. Compared to ε4 non-carriers, the Odds Ratio (OR) for AD was 8.09 (95% Confidence Interval [CI]: 4.98-13.63) for ε4 carriers with high-GRS (≥1.5). In contrast, the OR was 2.55 (95% CI: 1.46-4.49) for ε4 carriers with low-GRS (<0.6). In conclusion, these results suggest SNP-based GRS may supplement APOE for better assessment of inherited risk and age of onset of AD.     

Association studies between common variants in prolyl isomerase Pin1 and the risk for late-onset Alzheimer's disease

Alzheimer's disease (AD) pathology is associated with two proteins, the microtubule-binding protein tau and the beta-amyloid-precursor protein (APP). When tau becomes hyperphosphorylated, it forms neuritic aggregates, called neurofibrillary tangles. APP is cleaved by several enzymes to generate Abeta peptides, which are - depending on their length - more or less amyloidogenic and form senile plaques. Pin1, a peptidyl-propyl cis/trans-isomerase, seems to be involved in both pathologies. Pin1 may facilitate dephosphorylation of tau by PP2A phosphatase, while cellular overexpression of Pin1 causes a reduction in the amyloidogenic processing of APP, making this enzyme an interesting target for pharmaceutical intervention. The gene encoding Pin1 maps to 19p13.2, a region previously linked to late-onset Alzheimer's disease (LOAD). Therefore, Pin1 is an excellent positional and functional candidate for LOAD. In this study, we investigated whether common single nucleotide polymorphisms (SNPs) in Pin1 can influence the risk for developing late-onset Alzheimer's disease. No association was observed with any of six polymorphisms or their resulting haplotypes. A meta-analysis of two promoter SNPs, which combined the data from this study with two previous ones, did not show any association either suggesting that common SNPs in Pin1 do not increase the risk for LOAD.