Ε4 Noncarriers Research Articles

P4‐190: Monoacylglycerol lipase contributes to pathogenesis of Alzheimer's disease

between aging, health, cognition and lifestyle (Schaie, 2005). The sample included 111 participants, Mage 1⁄4 67 (age range 52 84), imaged on 3 occasions over 4 years. In our sample, there were 32 APOE e4 carriers and 79 APOE e4 noncarriers. Magnetization prepared rapid gradient echo (MPRAGE) imaging was performed on a Philips 3.0 TAchieva scanner. Cortical reconstruction and volumetric segmentation was performedwith the longitudinal pipeline of the FreeSurfer image analysis suite version 5.1.0 (http:// surfer.nmr.mgh.harvard.edu/). Cortical thickness values for each of the 68 parcels defined by the Desikan parcellation (Desikan et al., 2006) were extracted by subject and timepoint. We fit a linear mixed effects model for each parcel that included fixed effects of intercept, age, and APOE e4 carrier status, and the interaction of age andAPOE e4 carrier status to predict slope in cortical thickness of each parcel.Results: The mean estimated cortical thickness at age 60 (intercept) was thinner for APOE e4 carriers than APOE e4 non-carriers in the left inferior parietal parcel and left and right frontal pole. Slope differences (age X e4 carrier status interaction) were found in: left temporal pole and superior frontal regions, and right transverse temporal and caudal anterior cingulate (Figure 1). In all regions except the right transverse temporal, APOE e4 carriers had a steeper rate of decline than non-carriers.Conclusions: The APOE 4 allelemodulatesmean thickness and rates of change both in areas associated with normal aging and in areas associated with progression to AD.

Cerebrospinal fluid markers for Alzheimer's disease in a cognitively healthy cohort of young and old adults

Low amyloid β42 (Aβ42) and high total tau and phosphorylated tau (p-tau) concentrations in the cerebrospinal fluid (CSF) are biomarkers of Alzheimer's disease (AD), reflecting brain deposition of amyloid plaques and tangles. Age and apolipoprotein E allele E4 are two strong risk factors for AD, but few data are still available on their effect on CSF markers in normal aging. To study the effect of age on CSF Aβ42, total tau, and p-tau levels in a well-characterized group of cognitively normal subjects. CSF Aβ42 levels of 81 subjects (27% female, 53 ± 15.3 years, range: 21-88) were determined with sandwich enzyme-linked immunosorbent assay; of these, total tau and p-tau levels were measured in 61 (75%) and 42 (52%) cases, respectively. A linear regression analysis between age and CSF markers was carried out on the whole sample and separately in apolipoprotein E allele ɛ4 carriers and noncarriers. The median levels of all markers were significantly different between young (<65 years) and old (≥65 years) subjects (Aβ42: P = .03; tau: P = .02; p-tau: P = .002; tau/Aβ42: P = .004; p-tau/Aβ42: P = .03). The association of marker levels with age was confirmed in linear regression models, where a positive relationship with age was observed for total tau (B = 2.3; 95% confidence interval [CI]: 0.89 to 3.7; P = .002), p-tau (B = 0.5; 95% CI: 0.1 to 0.9; P = .02), and tau/Aβ42 ratio (B = 0.006; 95% CI: 0.002 to 0.01; P = .002). No subjects showed abnormal tau, whereas 19% showed abnormal CSF Aβ42 concentrations. In cognitively normal subjects, the concentrations of CSF biomarkers of AD are associated with age. Further longitudinal studies could clarify whether Aβ42 low levels represent a preclinical AD biomarker.

Morphological and Pathological Evolution of the Brain Microcirculation in Aging and Alzheimer’s Disease

Key pathological hallmarks of Alzheimer’s disease (AD), including amyloid plaques, cerebral amyloid angiopathy (CAA) and neurofibrillary tangles do not completely account for cognitive impairment, therefore other factors such as cardiovascular and cerebrovascular pathologies, may contribute to AD. In order to elucidate the microvascular changes that contribute to aging and disease, direct neuropathological staining and immunohistochemistry, were used to quantify the structural integrity of the microvasculature and its innervation in three oldest-old cohorts: 1) nonagenarians with AD and a high amyloid plaque load; 2) nonagenarians with no dementia and a high amyloid plaque load; 3) nonagenarians without dementia or amyloid plaques. In addition, a non-demented (ND) group (average age 71 years) with no amyloid plaques was included for comparison. While gray matter thickness and overall brain mass were reduced in AD compared to ND control groups, overall capillary density was not different. However, degenerated string capillaries were elevated in AD, potentially suggesting greater microvascular “dysfunction” compared to ND groups. Intriguingly, apolipoprotein ε4 carriers had significantly higher string vessel counts relative to non-ε4 carriers. Taken together, these data suggest a concomitant loss of functional capillaries and brain volume in AD subjects. We also demonstrated a trend of decreasing vesicular acetylcholine transporter staining, a marker of cortical cholinergic afferents that contribute to arteriolar vasoregulation, in AD compared to ND control groups, suggesting impaired control of vasodilation in AD subjects. In addition, tyrosine hydroxylase, a marker of noradrenergic vascular innervation, was reduced which may also contribute to a loss of control of vasoconstriction. The data highlight the importance of the brain microcirculation in the pathogenesis and evolution of AD.

How can elderly apolipoprotein E ε4 carriers remain free from dementia?

Apolipoprotein E (APOE) ε4 is a major risk factor for Alzheimer's disease (AD) and dementia, but not all ε4 carriers develop dementia. We sought to identify factors that may play a role in modifying the risk of dementia due to ε4. A cognitively intact cohort (n = 932, age ≥ 75) was followed for 9 years to detect incident dementia cases. At baseline, information on education, leisure activities, and vascular risk factors was collected, and APOE was genotyped. During the follow-up, 324 subjects developed dementia, including 247 AD cases. The hazard ratio (HR, 95% confidence interval [95% CI]) of dementia related to the ε4 was 1.39 (1.11–1.76), while the risk was reduced when ε4 carriers had high education, no vascular risk factors, or high score of leisure activities. Among ε4 carriers, the multiadjusted HRs of dementia that were associated with high education, high level of leisure activities, and absence of vascular risk factors were 0.59 (0.40–0.87), 0.49 (0.29–0.85), and 0.61 (0.41–0.90), respectively. The ε4 carriers with these factors had about 1.2 years delayed time to dementia onset compared with those without these factors. High education, active leisure activities, or maintaining vascular health seems to reduce the risk of dementia related to APOE ε4. The ε4 carriers with these characteristics appear to have similar dementia-free survival time to non-ε4 carriers.

Gray matter network associated with risk for Alzheimer's disease in young to middle-aged adults

The apolipoprotein E (APOE) ε4 allele increases the risk for late-onset Alzheimer's disease (AD) and age-related cognitive decline. We investigated whether ε4 carriers show reductions in gray matter volume compared with ε4 non-carriers decades before the potential onset of AD dementia or healthy cognitive aging. Fourteen cognitively normal ε4 carriers, aged 26 to 45 years, were compared with 10 age-matched, ε4 non-carriers using T1-weighted volumetric magnetic resonance imaging (MRI) scans. All had reported first- or second-degree family histories of dementia. Group differences in gray matter were tested using voxel-based morphometry (VBM) and a multivariate model of regional covariance, the Scaled Subprofile Model (SSM). A combination of the first two SSM MRI gray matter patterns distinguished the APOE ε4 carriers from non-carriers. This combined pattern showed gray matter reductions in bilateral dorsolateral and medial frontal, anterior cingulate, parietal, and lateral temporal cortices with covarying relative increases in cerebellum, occipital, fusiform, and hippocampal regions. With these gray matter differences occurring decades before the potential onset of dementia or cognitive aging, the results suggest longstanding, gene-associated differences in brain morphology that may lead to preferential vulnerability for the later effects of late-onset AD or healthy brain aging.

Correlations between FDG PET glucose uptake-MRI gray matter volume scores and apolipoprotein E ε4 gene dose in cognitively normal adults: A cross-validation study using voxel-based multi-modal partial least squares

We previously introduced a voxel-based, multi-modal application of the partial least square algorithm (MMPLS) to characterize the linkage between patterns in a person's complementary complex datasets without the need to correct for multiple regional comparisons. Here we used it to demonstrate a strong correlation between MMPLS scores to characterize the linkage between the covarying patterns of fluorodeoxyglucose positron emission tomography (FDG PET) measurements of regional glucose metabolism and magnetic resonance imaging (MRI) measurements of regional gray matter associated with apolipoprotein E (APOE) ε4 gene dose (i.e., three levels of genetic risk for late-onset Alzheimer's disease (AD)) in cognitively normal, late-middle-aged persons. Coregistered and spatially normalized FDG PET and MRI images from 70% of the subjects (27 ε4 homozygotes, 36 ε4 heterozygotes and 67 ε4 non-carriers) were used in a hypothesis-generating MMPLS analysis to characterize the covarying pattern of regional gray matter volume and cerebral glucose metabolism most strongly correlated with APOE-ε4 gene dose. Coregistered and spatially normalized FDG PET and MRI images from the remaining 30% of the subjects were used in a hypothesis-testing MMPLS analysis to generate FDG PET-MRI gray matter MMPLS scores blind to their APOE genotype and characterize their relationship to APOE-ε4 gene dose. The hypothesis-generating analysis revealed covarying regional gray matter volume and cerebral glucose metabolism patterns that resembled those in traditional univariate analyses of AD and APOE-ε4 gene dose and PET-MRI scores that were strongly correlated with APOE-ε4 gene dose (p<1×10−16). The hypothesis-testing analysis results showed strong correlations between FDG PET-MRI gray matter scores and APOE-ε4 gene dose (p=8.7×10−4). Our findings support the possibility of using the MMPLS to analyze complementary datasets from the same person in the presymptomatic detection and tracking of AD.

Sequence variants of interleukin 6 (IL-6) are significantly associated with a decreased risk of late-onset Alzheimer's disease.

BackgroundInterleukin 6 (IL-6) has been related to beta-amyloid aggregation and the appearance of hyperphosphorylated tau in Alzheimer's disease (AD) brain. However, previous studies relating IL-6 genetic polymorphisms to AD included few and unrepresentative single nucleotide polymorphisms (SNPs) and the results were inconsistent.MethodsThis is a case-control study. A total of 266 patients with AD, aged≧65, were recruited from three hospitals in Taiwan (2007-2010). Controls (n = 444) were recruited from routine health checkups and volunteers of the hospital during the same period of time. Three common IL-6 haplotype-tagging SNPs were selected to assess the association between IL-6 polymorphisms and the risk of late-onset AD (LOAD).ResultsVariant carriers of IL-6 rs1800796 and rs1524107 were significantly associated with a reduced risk of LOAD [(GG + GC vs. CC): adjusted odds ratio (AOR) = 0.64 and (CC + CT vs. TT): AOR = 0.60, respectively]. Haplotype CAT was associated with a decreased risk of LOAD (0 and 1 copy vs. 2 copies: AOR = 0.65, 95% CI = 0.44-0.95). These associations remained significant in ApoE e4 non-carriers only. Hypertension significantly modified the association between rs2069837 polymorphisms and the risk of LOAD (pinteraction = 0.03).ConclusionsIL-6 polymorphisms are associated with reduced risk of LOAD, especially in ApoE e4 non-carriers. This study identified genetic markers for predicting LOAD in ApoE e4 non-carriers.

Genetic polymorphisms of nerve growth factor receptor (NGFR) and the risk of Alzheimer's disease

BackgroundLoss of basal forebrain cholinergic neurons is attributable to the proapoptotic signaling induced by nerve growth factor receptor (NGFR) and may link to Alzheimer's disease (AD) risk. Only one study has investigated the association between NGFR polymorphisms and the risk of AD in an Italian population. Type 2 diabetes mellitus (DM) may modify this association based on previous animal and epidemiologic studies.MethodsThis was a case-control study in a Chinese population. A total of 264 AD patients were recruited from three teaching hospitals between 2007 to 2010; 389 controls were recruited from elderly health checkup and volunteers of the hospital during the same period of time. Five common (frequency≥5%) haplotype-tagging single nucleotide polymorphisms (htSNPs) were selected from NGFR to test the association between NGFR htSNPs and the risk of AD.ResultsVariant NGFR rs734194 was significantly associated with a decreased risk of AD [GG vs. TT copies: adjusted odds ratio (OR) = 0.43, 95% confidence interval (CI) = 0.20-0.95]. Seven common haplotypes were identified. Minor haplotype GCGCG was significantly associated with a decreased risk of AD (2 vs. 0 copies: adjusted OR = 0.39, 95% CI = 0.17-0.91). Type 2 DM significantly modified the association between rs2072446, rs741072, and haplotype GCTTG and GTTCG on the risk of AD among ApoE ε4 non-carriers (Pinteraction < 0.05).ConclusionInherited polymorphisms of NGFR were associated with the risk of AD; results were not significant after correction for multiple tests. This association was further modified by the status of type 2 DM.

NEDD9 Gene Polymorphism Influences the Risk of Alzheimer Disease and Cognitive Function in Chinese Older Persons

Neural precursor cell expressed, developmentally down-regulated (NEDD9) gene was a new candidate risk gene for Alzheimer disease (AD). The CC genotype of a single nucleotide polymorphism rs760678 within this gene was associated with increasing risk of AD in a large study with white population. Our study aimed to replicate the initial report in Chinese population and explore its effect on cognitive performance. A total of 262 patients with AD, 293 patients with mild cognitive impairment, and 434 cognitive intact controls were recruited in the study. The result showed that G allele had a greater risk of AD (χ for trend test=5.61, df 1, P=0.018). The effects were mainly observed among Apolipoprotein E (APOE) ε4 noncarriers (χ for trend test=4.30, df 1, P=0.038). After adjustment of sex, age, education year, and APOE ε4 status by logistic regression, significant association between NEDD9 GG genotype and AD remained [OR=2.04, 95% confidence interval (CI)=1.02-4.08, P=0.044]. The scores of Cantonese version of the Mini-mental State Examination and Alzheimer's Disease Assessment Subscale-Cognitive subscale were associated with N polymorphism after adjusting for sex, age, education year, and ApoE ε4 status (Linear regression model, P<0.05). Our study identified rs760678 within NEDD9 gene in association with the risk of AD and cognitive performance in Chinese older persons. The fact that different alleles accounted for the risk in different population might suggest that there were ethnic group specific haplotypes that were primarily responsible for the predisposition.

APOE modifies the association between Aβ load and cognition in cognitively normal older adults

To determine the relationship between β-amyloid (Aβ) load as measured by [(11)C]-Pittsburgh compound B (PiB) PET and cognitive function in cognitively normal older adults. We studied 408 cognitively normal older adults who participated in the population-based Mayo Clinic Study of Aging (MCSA) from January 2009 through March 2011. The participants underwent PiB PET and neuropsychometric testing within 6 months. The association between PiB retention and cognitive function was measured by partial correlation and an interaction with APOE status was tested using linear regression after adjusting for age, sex, and education. Higher PiB retention was associated with cognitive performance (Spearman partial r = -0.18; p < 0.01), specifically the memory, language, attention/executive, and visual-spatial processing domains in the whole group of participants. The association between PiB retention and cognition was modified by the APOE status on linear regression analysis even after controlling for the differences in the distribution of PiB values among APOE ε4 carriers and noncarriers (p = 0.02). Cognitive performance was associated with the Aβ deposition in the frontal, temporal, and parietal lobe association cortices in APOE ε4 carriers on SPM analysis (p < 0.001). There is a modest association between PiB retention and cognitive function in cognitively normal older adults and this relationship between Aβ load and cognitive function is modified by APOE status. Whereas Aβ load is associated with greater cognitive impairment in APOE ε4 carriers, the cognitive function in APOE ε4 noncarriers is influenced less by the Aβ load, suggesting that APOE isoforms modulate the harmful effects of Aβ on cognitive function.

Glucose metabolism and gray-matter concentration in apolipoprotein E ε4 positive normal subjects

Apolipoprotein E (ApoE) ε4 is known as a genetic risk factor for Alzheimer's disease (AD). This study investigated the prevalence of imaging abnormalities suggestive of AD in cognitively normal ApoE ε4 carriers using 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) and voxel-based morphometry (VBM). Forty-five cognitive normal ApoE ε4 allele carriers and 45 noncarriers underwent both FDG positron emission tomography and magnetic resonance imaging (MRI). A total of 90 normal database sets were generated for the individual 45 ε4 carriers and 45 noncarriers. Mean z-scores in the predefined AD-specific regions of interest (ROI) were calculated for each ε4 carrier and noncarrier using the individually defined normal database. The prevalence of AD-like hypometabolism and atrophy in the ε4 carriers was 8.9% and 17.7%, respectively, and did not differ significantly from those in the noncarriers (8.9%, 8.8%). The majority of ε4 carriers showed preserved FDG uptake or gray matter concentration.

Olfactory ERPs in an odor/visual congruency task differentiate ApoE ε4 carriers from non-carriers

Alzheimer's disease (AD) is a progressive, neurodegenerative disorder that impairs memory and semantic processing. AD patients and MCI patients at risk for AD show altered N400 ERP responses to incongruent visual and verbal stimuli. AD patients exhibit neuropathology in olfactory brain areas before cognitive symptoms, suggesting the potential for olfactory processing to reflect early pathology. Despite this, odor congruency has not been examined. We investigated odor–image congruency in older adults at genetic risk for AD. ApoE ε4 carriers and non-carriers were screened for anosmia, severe hyposmia, and dementia. Olfactory ERPs were measured 600–1300ms following odor–image pairs. Odors were each presented once congruently and once incongruently via an olfactometer. Pz amplitude significantly decreased on incongruent trials in e4 carriers. Pz amplitude differences on congruous and incongruous trials were larger in non carriers. Regression indicated that congruency showed very high sensitivity and specificity for correctly classifying ε4 carriers from non-carriers.

Education and occupation provide reserve in both ApoE ε4 carrier and noncarrier patients with probable Alzheimer’s disease

According to the reserve hypothesis, a high educational/occupational attainment can modulate Alzheimer's disease (AD) clinical expression. The impact of the Apolipoprotein E (ApoE) ε4 allele on the reserve mechanism in AD has not been assessed. Aim of this European multicenter study was to evaluate the metabolic correlates of reserve and ApoE genotype in early probable AD. 51 AD subjects, 27 ε4 carriers, and 24 noncarriers, underwent FDG-PET brain imaging. We used the general linear model as implemented in SPM2 to test for the linear correlation of a reserve index, accounting for both educational and occupational level, with brain glucose metabolism, controlling for demographic variables (age and gender) and for cognitive performance. We found an inverse correlation between a reserve index, accounting for educational/occupational level, and metabolism in the posterior cingulate cortex and precuneus in both ε4 carriers and noncarriers, and no significant difference between the groups. We show that education and occupation act as proxies for reserve in ε4 carriers, compensating for an unfavorable genetic background; we also show that the degree of compensation does not differ significantly by ApoE ε4 status.

Functional connectivity during recognition memory in individuals genetically at risk for Alzheimer's disease

The medial temporal lobes (MTL) and frontal cortex have been shown to subserve memory processes. Neurodegenerative diseases, such as Alzheimer's disease (AD), disrupt the neuronal networks that underlie memory processing. The ε4 allele of the apolipoprotein E gene is a genetic risk factor for AD and is associated with decrements in memory and in olfactory function. The present study utilized EQS, a structural equation modeling software program, to examine differences in the neuronal networks between non-demented ε4 carriers and ε4 noncarriers during a cross-modal olfactory recognition memory paradigm. Prior to fMRI scanning, participants were presented with 16 odors. During two scans, participants discriminated between names of odors presented before scanning (targets) or not presented (foils). The results indicate significant connections between bilateral frontal lobes and MTL for ε4 carriers when they misidentified a foil as a target. When ε4 noncarriers correctly identified a target, there were greater associations between the amygdala, MTL, and right frontal lobe; these associations also modeled the brain's response when ε4 noncarriers misidentified a foil as a target. During memory retrieval, affective cues may facilitate retrieval in ε4 noncarriers relative to ε4 carriers. Last, no model was found that best represented the functional network used by ε4 carriers when they correctly identified a target, which may reflect variability of neuronal recruitment within this population.

Genetic Variation in the Tau Kinases Pathway May Modify the Risk and Age at Onset of Alzheimer's Disease

Tau abnormal hyperphosphorylation and the formation of neurofibrillary tangles in the Alzheimer's disease (AD) brain is the result of upregulation of tau kinases. In a group of 729 Spanish late-onset AD patients and 670 healthy controls, we examined variations into a set of 20 candidate genes of kinases involved in tau phosphorylation at AD-related sites (PRKACB; CAMK2A; MARK1, 2, 3 and 4; CSNK1D; CDC2; RPS6KB1 and 2; p38α and β; IB1; JNK1, 2 and 3; MEK1 and 2; ERK1 and 2), to address hypotheses of genetic variation that might influence both AD risk and age at disease onset. There was an increased frequency of RPS6KB2 (intron 2, rs917570) minor allele in patients (50%) versus controls (39%) (OR = 1.52; 95% CI 1.30-1.77; p = 1.24 × 10-5 Bonferroni corrected), and the presence of this minor allele was significantly (p = 4.2 × 10-5) associated with a 3-years later onset of AD (mean age 74.1 years) when compared to age at onset of non-minor allele carriers (mean age 71.1 years). In APOE non-ε4 allele carriers, the combined effect of AD-associated risk alleles from the genes of CDC2, RPS6KB1 and 2, p38α, JNK (1, 2 and 3), MEK2, and ERK2 was significantly (p = 0.002) associated with a late-onset (>76 years) of AD. The CDC2 AGC haplotype derived from SNPs in introns 3 (rs2448347), 5 (rs2456772), and 7 (rs1871447) showed a protective effect against AD in APOE non-ε4 allele carriers (permutation p = 1.0 × 10-4) with a frequency of 9% in cases and 15% in controls. Common genetic variation in the tau kinases pathway does underlie individual differences not only in susceptibility to AD but also in disease phenotype (age at disease onset).

The Association of APOE Genotype with Cognitive Function in Persons Aged 35 Years or Older

APOE genotype is associated with the risk of Alzheimer's disease. In the present study, we investigated whether APOE genotype was associated with cognitive function in predominantly middle-aged persons. In a population-based cohort of 4,135 persons aged 35 to 82 years (mean age (SD), 55 (12) years), cognitive function was measured with the Ruff Figural Fluency Test (RFFT; worst score, 0 points; best score, 175 points). APOE genotype (rs429358 and rs7412) was determined by polymerase chain reaction. The mean RFFT score (SD) of the total cohort was 69 (26) points. Unadjusted, the mean RFFT score in homozygous APOE ε4 carriers was 4.66 points lower than in noncarriers (95% confidence interval, -9.84 to 0.51; p = 0.08). After adjustment for age and other risk factors, the mean RFFT score in homozygous APOE ε4 carriers was 5.24 points lower than in noncarriers (95% confidence interval, -9.41 to -1.07; p = 0.01). The difference in RFFT score was not dependent on age. There was no difference in RFFT score between heterozygous APOE ε4 carriers and noncarriers. The results indicated that homozygous APOE ε4 carriers aged 35 years or older had worse cognitive function than heterozygous carriers and noncarriers.

Toll-like receptor 2 -196 to -174 del polymorphism influences the susceptibility of Han Chinese people to Alzheimer's disease

BackgroundToll-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 functionally is involved in the microglia-mediated inflammatory response and amyloid-β clearance. The -196 to -174 del polymorphism affects the TLR2 gene and alters its promoter activity.MethodsWe recruited 800 unrelated Northern Han Chinese individuals comprising 400 late-onset AD (LOAD) patients and 400 healthy controls matched for gender and age. The -196 to -174 del polymorphism in the TLR2 gene was genotyped using the polymerase chain reaction (PCR) method.ResultsThere were significant differences in genotype (P = 0.026) and allele (P = 0.009) frequencies of the -196 to -174 del polymorphism between LOAD patients and controls. The del allele was associated with an increased risk of LOAD (OR = 1.31, 95% CI = 1.07-1.60, Power = 84.9%). When these data were stratified by apolipoprotein E (ApoE) ε4 status, the observed association was confined to ApoE ε4 non-carriers. Logistic regression analysis suggested an association of LOAD with the polymorphism in a recessive model (OR = 1.64, 95% CI = 1.13-2.39, Bonferroni corrected P = 0.03).ConclusionsOur data suggest that the -196 to -174 del/del genotype of TLR2 may increase risk of LOAD in a Northern Han Chinese population.

Levels of cerebrospinal fluid neurofilament light protein in healthy elderly vary as a function of TOMM40 variants

Neurofilament light (NFL) proteins in cerebrospinal fluid (CSF) are a marker of neuronal damage, especially subcortical axonal injury and white matter disease. Subjects with Alzheimer's disease (AD) have shown elevated levels of CSF NFL as compared to controls. However, the presence of the APOE ε4 allele, an established risk factor for AD, was not found to associate with higher CSF NFL concentrations. We examined whether TOMM40 variants, which have been reported to influence age of onset of AD and are in linkage disequilibrium with APOE, have an effect on CSF NFL levels, in 47 healthy, cognitively intact individuals with or without APOE ε4. Our results show that the presence of APOE ε4 alone does not affect CSF NFL levels significantly; however APOE and TOMM40 appear to interact. Subjects with APOE ε4 have higher CSF NFL levels than non-ε4 carriers, only when they do not carry a short poly-T variant of TOMM40, which is associated with later age of onset of AD, and may act as protective against the dose effect of ε4.

CETP polymorphisms associate with brain structure, atrophy rate, and Alzheimer's disease risk in an APOE-dependent manner.

Two alleles in cholesteryl ester transfer protein (CETP) gene polymorphisms have been disputably linked to enhanced cognition and decreased risk of Alzheimer's disease (AD): the V and A alleles of I405V and C-629A. This study investigates whether these polymorphisms affect brain structure in 188 elderly controls and 318AD or mild cognitive impairment (MCI) subjects from the Alzheimer's Disease Neuroimaging Initiative cohort. Nominally signficant associations were dependent on APOE ε4 carrier status. In APOE ε4 carriers, the V and A alleles, both of which decrease CETP and increase HDL, associated with greater baseline cortical thickness and less 12-month atrophy in the medial temporal lobe. Conversely, in APOE ε4 non-carriers, the I allele, which increases CETP and decreases HDL, associated with greater baseline thickness, less atrophy and lower risk of dementia. These results suggest CETP may contribute to the genetic variability of brain structure and dementia susceptibility in an APOE-dependent manner.

PEMT G523A (V175M) Is Associated with Sporadic Alzheimer's Disease in a Chinese Population

There is evidence that increased concentrations of circulating homocysteine are associated with Alzheimer's disease (AD). Phosphatidylethanolamine N-methyltransferase (PEMT) is an important catalyst involved in the production of homocysteine. We investigated the association of a functional single nucleotide polymorphism (rs7946) in PEMT with sporadic AD risk in a Han Chinese population that included 386AD patients and 366 controls. PEMT G523A was genotyped by either sequencing or PCR-restriction fragment length polymorphism analysis. The plasma homocysteine concentrations of 210 subjects were determined by high-performance liquid chromatography. Significant higher frequency of the A allele was detected in AD cases than in controls (A vs. G, p = 0.007, OR = 1.482, 95% CI 1.114-1.972). After adjusting for gender, age/age at onset, and APOE ε4 status, logistic analysis showed rs7946 was associated with AD in a dominant model (AA + GA vs. GG, p = 0.007, OR = 1.596, 95% CI 1.138-2.240). When stratified by APOE ε4 status or gender, the significant difference was only observed in the APOE ε4 non-carriers and in the female subjects, respectively. We did not find a relationship of this polymorphism with plasma homocysteine levels. These results suggested that PEMT G523A is associated with AD and that the A allele is an APOE ε4-independent risk factor for AD among Han Chinese women.