Alzheimer's Disease Risk Genes Research Articles

Genome-wide haplotype association study identify TNFRSF1A, CASP7, LRP1B, CDH1 and TG genes associated with Alzheimer's disease in Caribbean Hispanic individuals.

Alzheimer's disease (AD) is an acquired disorder of cognitive and behavioral impairment. It is considered to be caused by variety of factors, such as age, environment and genetic factors. In order to identify the genetic affect factors of AD, we carried out a bioinformatic approach which combined genome-wide haplotype-based association study with gene prioritization. The raw SNP genotypes data was downloaded from GEO database (GSE33528). It contains 615 AD patients and 560 controls of Caribbean Hispanic individuals. Firstly, we identified the linkage disequilibrium (LD) haplotype blocks and performed genome-wide haplotype association study to screen significant haplotypes that were associated with AD. Then we mapped these significant haplotypes to genes and obtained candidate genes set for AD. At last, we prioritized AD candidate genes based on their similarity with 36 known AD genes, so as to identify AD related genes. The results showed that 141 haplotypes on 134 LD blocks were significantly associated with AD (P<1E-4), and these significant haplotypes were mapped to 132 AD candidate genes. After prioritizing these candidate genes, we found seven AD related genes: APOE, APOC1, TNFRSF1A, LRP1B, CDH1, TG and CASP7. Among these genes, APOE and APOC1 are known AD risk genes. For the other five genes TNFRSF1A, CDH1, CASP7, LRP1B and TG, this is the first genetic association study which showed the significant association between these five genes and AD susceptibility in Caribbean Hispanic individuals. We believe that our findings can provide a new perspective to understand the genetic affect factors of AD.

Influence of family history of dementia in the development and progression of late‐onset Alzheimer's disease

Family history of dementia (FH) is a recognized risk factor for developing late-onset Alzheimer's disease (AD). We asked whether having FH increases AD risk and influences disease severity (age at onset and cognitive impairment) in 420 AD patients and 109 controls with (FH+) or without (FH-). The relationships of APOE and other AD risk genes with FH were analyzed as well. The proportion of APOE e4 allele carriers was higher among the FH+ than the FH- AD patients (49.6% vs. 38.9%; P = 0.04). The distribution of the risk genotypes of nine AD susceptibility genes previously examined (CHAT, CYP17, CYP19, ESR1, FSHR, P53, P73, P21, PPARG) did not differ between the FH+ and the FH- AD patients, indicating that none contributed significantly to familial clustering of disease. FH was associated with an increased AD risk (odds ratio [OR] 2.71, 95% confidence interval [CI] 1.44-5.09; P = 0.002) independent of carrying the APOE e4 allele (OR 2.61, 95%CI 1.53-4.44; P = 0.0004). Having a first-degree relative or a parent with dementia was significantly associated with AD risk (OR 2.9, 95%CI 1.3-6.4; P = 0.009 and OR 2.7, 95%CI 1.1-6.2; P = 0.02) but having a sibling with dementia was not (OR 1.7, 95%CI 0.2 to 14.7; P = 0.6). Among the FH+ AD patients, having one or both parents affected seemed to raise the risk of earlier onset age (P = 0.02) and greater cognitive impairment (P = 0.02) than having only an affected sibling, whereas having two or more affected relatives did not.

MRI-based brain atrophy rates in ADNI phase 2: acceleration and enrichment considerations for clinical trials

The goal of this work was to assess statistical power to detect treatment effects in Alzheimer's disease (AD) clinical trials using magnetic resonance imaging (MRI)–derived brain biomarkers. We used unbiased tensor-based morphometry (TBM) to analyze n = 5,738 scans, from Alzheimer's Disease Neuroimaging Initiative 2 participants scanned with both accelerated and nonaccelerated T1-weighted MRI at 3T. The study cohort included 198 healthy controls, 111 participants with significant memory complaint, 182 with early mild cognitive impairment (EMCI) and 177 late mild cognitive impairment (LMCI), and 155 AD patients, scanned at screening and 3, 6, 12, and 24 months. The statistical power to track brain change in TBM-based imaging biomarkers depends on the interscan interval, disease stage, and methods used to extract numerical summaries. To achieve reasonable sample size estimates for potential clinical trials, the minimal scan interval was 6 months for LMCI and AD and 12 months for EMCI. TBM-based imaging biomarkers were not sensitive to MRI scan acceleration, which gave results comparable with nonaccelerated sequences. ApoE status and baseline amyloid-beta positron emission tomography data improved statistical power. Among healthy, EMCI, and LMCI participants, sample size requirements were significantly lower in the amyloid+/ApoE4+ group than for the amyloid–/ApoE4– group. ApoE4 strongly predicted atrophy rates across brain regions most affected by AD, but the remaining 9 of the top 10 AD risk genes offered no added predictive value in this cohort.

Alzheimer risk genes modulate the relationship between plasma apoE and cortical PiB binding.

Objective:We investigated the association between apoE protein plasma levels and brain amyloidosis and the effect of the top 10 Alzheimer disease (AD) risk genes on this association.Methods:Our dataset consisted of 18 AD, 52 mild cognitive impairment, and 3 cognitively normal Alzheimer's Disease Neuroimaging Initiative 1 (ADNI1) participants with available [11C]-Pittsburgh compound B (PiB) and peripheral blood protein data. We used cortical pattern matching to study associations between plasma apoE and cortical PiB binding and the effect of carrier status for the top 10 AD risk genes.Results:Low plasma apoE was significantly associated with high PiB SUVR, except in the sensorimotor and entorhinal cortex. For BIN1 rs744373, the association was observed only in minor allele carriers. For CD2AP rs9349407 and CR1 rs3818361, the association was preserved only in minor allele noncarriers. We did not find evidence for modulation by CLU, PICALM, ABCA7, BIN1, and MS4A6A.Conclusions:Our data show that BIN1 rs744373, CD2AP rs9349407, and CR1 rs3818361 genotypes modulate the association between apoE protein plasma levels and brain amyloidosis, implying a potential epigenetic/downstream interaction.

Inflammation in Alzheimer's Disease and Molecular Genetics: Recent Update.

Alzheimer's disease (AD) is a complex age-related neurodegenerative disorder of the central nervous system. Since the first description of AD in 1907, many hypotheses have been established to explain its causes. The inflammation theory is one of them. Pathological and biochemical studies of brains from AD individuals have provided solid evidence of the activation of inflammatory pathways. Furthermore, people with long-term medication of anti-inflammatory drugs have shown a reduced risk to develop the disease. After three decades of genetic study in AD, dozens of loci harboring genetic variants influencing inflammatory pathways in AD patients has been identified through genome-wide association studies (GWAS). The most well-known GWAS risk factor that is responsible for immune response and inflammation in AD development should be APOE ε4 allele. However, a growing number of other GWAS risk AD candidate genes in inflammation have recently been discovered. In the present study, we try to review the inflammation in AD and immunity-associated GWAS risk genes like HLA-DRB5/DRB1, INPP5D, MEF2C, CR1, CLU and TREM2.

R47H Variant of TREM2 Associated With Alzheimer Disease in a Large Late-Onset Family: Clinical, Genetic, and Neuropathological Study.

The R47H variant in the triggering receptor expressed on myeloid cells 2 gene (TREM2), a modulator of the immune response of microglia, is a strong genetic risk factor for Alzheimer disease (AD) and possibly other neurodegenerative disorders. To investigate a large family with late-onset AD (LOAD), in which R47H cosegregated with 75% of cases. This study includes genetic and pathologic studies of families with LOAD from 1985 to 2014. A total of 131 families with LOAD (751 individuals) were included from the University of Washington Alzheimer Disease Research Center. To identify LOAD genes/risk factors in the LOAD123 family with 21 affected members and 12 autopsies, we sequenced 4 exomes. Candidate variants were tested for cosegregation with the disease. TREM2 R47H was genotyped in an additional 130 families with LOAD. We performed clinical and neuropathological assessments of patients with and without R47H and evaluated the variant's effect on brain pathology, cellular morphology, and expression of microglial markers. We assessed the effect of TREM2 genotype on age at onset and disease duration. We compared Braak and Consortium to Establish a Registry for Alzheimer's Disease scores, presence of α-synuclein and TAR DNA-binding protein 43 aggregates, and additional vascular or Parkinson pathology in TREM2 R47H carriers vs noncarriers. Microglial activation was assessed by quantitative immunohistochemistry and morphometry. Twelve of 16 patients with AD in the LOAD123 family carried R47H. Eleven patients with dementia had apolipoprotein E 4 (ApoE4) and R47H genotypes. We also found a rare missense variant, D353N, in a nominated AD risk gene, unc-5 homolog C (UNC5C), in 5 affected individuals in the LOAD123 family. R47H carriers demonstrated a shortened disease duration (mean [SD], 6.7 [2.8] vs 11.1 [6.6] years; 2-tailed t test; P = .04) and more frequent α-synucleinopathy. The panmicroglial marker ionized calcium-binding adapter molecule 1 was decreased in all AD cases and the decrease was most pronounced in R47H carriers (mean [SD], in the hilus: 0.114 [0.13] for R47H_AD vs 0.574 [0.26] for control individuals; 2-tailed t test; P = .005 and vs 0.465 [0.32] for AD; P = .02; in frontal cortex gray matter: 0.006 [0.004] for R47H_AD vs 0.016 [0.01] for AD; P = .04 and vs 0.033 [0.013] for control individuals; P < .001). Major histocompatibility complex class II, a marker of microglial activation, was increased in all patients with AD (AD: 2.5, R47H_AD: 2.7, and control: 1.0; P < .01). Our results demonstrate a complex genetic landscape of LOAD, even in a single pedigree with an apparent autosomal dominant pattern of inheritance. ApoE4, TREM2 R47H, and rare variants in other genes, such as UNC5C D353N, are likely responsible for the notable occurrence of AD in this family. Our findings support the role of the TREM2 receptor in microglial clearance of aggregation-prone proteins that is compromised in R47H carriers and may accelerate the course of disease.

Transethnic genome-wide meta-analysis for Alzheimer disease

Genetic risk factors for late-onset Alzheimer disease (AD) shared across different ethnic populations are not well understood. Previously published genome-wide association (GWA) studies for AD by the Alzheimer Disease Genetics Consortium (ADGC) including European American (EA; 13,798 cases and 13,364 controls), African American (AA; 1,675 cases and 3,604 controls), Japanese (JPN; 951 cases and 894 controls), and Israeli-Arab (IA; 86 cases and 84 controls) cohorts were meta-analyzed. Transethnic GWA analyses at a single nucleotide polymorphism (SNP)-level and at a gene-level were conducted for the total sample (ALL) and subgroups of APOE ε4-positive (E4P) and ε4-negative (E4N) subjects in a logistic regression model adjusting for age and sex. Top ranked SNPs (P<10−5) and genes (P<10−4) were replicated using 4,259 subjects including 2,467 AD cases and 1,792 cognitively normal controls in an independent Hispanic cohort. Genome-wide significant SNPs (P<5.4x10−8) in transethnic meta-analysis (TE-P) were identified in the GJC1 gene using E4P subjects (best SNP, rs11871429: TE-P=2.7 x10−8). The association with rs11871429 in E4P was primarily from the EA ethnic group (ethnic specific P value: PEA=5.0x10−9, PAA=0.81, PJPN=0.13), noting that all IA subjects were ε4-negative. No other SNPs in genes were genome-wide significant except for previously established AD genes. Genome-wide significant gene-based tests (P<1.6x10−6) in transethnic meta-analysis were observed in three novel loci, SPDYE3 (P=1.3x10−6), PHOSPHO1 (P=3.7x10−7), and C20orf43 (P=1.5x10−6) in ALL subjects, and GJC1 in E4P subjects (P=5.7x10−7). Gene-based association tests in transethnic meta-analysis were also significant with CR1, BIN1, PTK2B, CLU, MS4A6E, PICALM, and ABCA7 in ALL subjects and with KANSL1 in E4N subjects. Suggestive evidence of association (gene-based P<10−5) was also observed with one novel gene (PLEKHG5) and three previously established AD risk genes (CD2AP, ZCWPW1, and CD33) in ALL subjects. Eleven novel top-ranked genes in the discovery sample were nominally significant (P<0.05) in the replication sample (best result, C20orf43, gene-based P: discovery=1.5x10−6, replication=4.0x10−3, meta-analysis=2.1x10−8). This study suggests that the transethnic analysis is a powerful approach to detect novel LOAD susceptibility genes. Future studies are needed to establish the precise roles of these loci in AD pathogenesis.

Effect of APOE and CD33 on Cognitive Decline

ObjectiveAn Alzheimer’s disease (AD) diagnosis is preceded by a long period of cognitive decline. We previously demonstrated increased risk of decline among individuals possessing one or more APOE ε4 alleles together with a family history of AD. The objective of this study is to investigate the possibility that such an increased risk might be due to AD risk genes with small effects in combination with APOE.MethodsParticipants in the Health and Retirement Study (HRS) over the age of 65, who contributed DNA, and had two or more evaluations with an abbreviated version of the modified Telephone Interview for Cognitive Status (TICS-m) were eligible for the study (n = 7451). A genetic risk score (g-score) was derived using AD risk genes’ meta-analyses data, assigning risk according to the number of risk alleles and summed over all the risk genes. Trajectories of cognitive function were modeled in four groups of Caucasian participants with and without one or more APOE ε4 alleles and either a high or low g-score: APOE ε4-/low g-score; APOE ε4-/high g-score; APOE ε4+/low g-score; and APOE ε4+/high g-score. Post hoc analyses evaluated interactions between individual genes and APOE.ResultsIndividuals in the APOE ε4+/high g-score group exhibited the greatest cognitive decline over time (p<.0001). This risk appeared to be greater than the sum of the effects of either high g-score or APOE ε4 alone. When gene interactions were individually tested with APOE, a statistically significant interaction with CD33 was discovered (p = 0.04) although the interaction was no longer significant when adjusted for multiple comparisons.ConclusionsIndividuals with multiple AD risk genes in addition to having one or more APOE ε4 alleles are at greater risk of cognitive decline than individuals with either APOE ε4 or a high genetic risk score. Among those with one or more APOE ε4 alleles, having one or more copies of the CD33 C (risk) allele may further increase the risk of cognitive decline.

Activity-dependent neuroprotective protein (ADNP): from autism to Alzheimer's disease.

We have originally discovered activity-dependent neuroprotective protein (ADNP) as a major regulatory gene, a component of the SWI/SNF chromatin remodeling complex, essential for brain formation. Others found ADNP as a most frequent autism spectrum disorder (ASD)-associated gene. Furthermore, ADNP is the only protein significantly decreasing in the serum of Alzheimer’s disease (AD) patients. Our most recent results revealed sex-related learning/memory differences in mice, reflecting hippocampal expression changes in ADNP and ADNP-controlled AD/ASD risk genes1. Hippocampal ADNP transcript content was doubled in male vs. female mice, with females showing equal expression to ADNP+/- males and no significant genotype-associated reduction. Increased male ADNP expression was replicated in human postmortem hippocampal samples. The hippocampal transcript for ApoE (the major risk gene for AD) was doubled in female mice compared with males, and further doubled in the ADNP+/- females, contrasting a decrease in young ADNP+/- males. ADNP regulates >400 genes during embryonic development, with ApoE being a major target. Other AD related proteins regulated by ADNP include tau (with pathological tau constituting the neurofibrillary tangles and with AD being the major tauopathy). Furthermore, ADNP associates with microtubule end binding proteins, controlling dendritic spine density, which is compromised in AD and ASD. Previously, overexpression of the eukaryotic translation initiation factor 4E (eIF4E) led to ASD-like phenotype in mice and we have shown that hippocampal eIF4E expression was specifically increased in young ADNP+/- male mice. Understanding ADNP expression, positioned as a master regulator of key ASD and AD risk genes, introduces a novel concept of hippocampal gene-regulated sexual dimorphism toward gender-based biology and therapeutics.

DAP12 Stabilizes the C-terminal Fragment of the Triggering Receptor Expressed on Myeloid Cells-2 (TREM2) and Protects against LPS-induced Pro-inflammatory Response

Triggering receptor expressed on myeloid cells 2 (TREM2) is a DAP12-associated receptor expressed in microglia, macrophages, and other myeloid-derived cells. Previous studies have suggested that TREM2/DAP12 signaling pathway reduces inflammatory responses and promotes phagocytosis of apoptotic neurons. Recently, TREM2 has been identified as a risk gene for Alzheimer disease (AD). Here, we show that DAP12 stabilizes the C-terminal fragment of TREM2 (TREM2-CTF), a substrate for γ-secretase. Co-expression of DAP12 with TREM2 selectively increased the level of TREM2-CTF with little effects on that of full-length TREM2. The interaction between DAP12 and TREM2 is essential for TREM2-CTF stabilization as a mutant form of DAP12 with disrupted interaction with TREM2 failed to exhibit such an effect. Silencing of either Trem2 or Dap12 gene significantly exacerbated pro-inflammatory responses induced by lipopolysaccharides (LPS). Importantly, overexpression of either full-length TREM2 or TREM2-CTF reduced LPS-induced inflammatory responses. Taken together, our results support a role of DAP12 in stabilizing TREM2-CTF, thereby protecting against excessive pro-inflammatory responses.

AD genetic risk factors and tau spreading.

Development of tau pathology is associated with progressive neuronal loss and cognitive decline. In the brains of Alzheimer's disease (AD) patients, tau pathology propagates according to an anatomically defined pattern with relatively uniform distribution, and contributes to cognitive decline in age-associated tauopathy (Braak and Braak, 1991; Saito et al., 2004). Recently, it has been revealed that tau, which is an intracellular protein, can appear in the extracellular space, likely due to an exocytosis mechanism. Such extracellular tau could then be internalized into neighboring cells in at least two different ways depending on its aggregation state. In the case of soluble monomeric or small oligomeric tau protein, the endocytosis appears to be clathrin dependent (reviewed in Rubinsztein, 2006). In contrast, larger aggregates of tau could bind heparin in the extracellular matrix and be internalized through macropinocytosis (Holmes et al., 2014). As a result of exocytosis and endocytosis, the spreading of tau can occur in various neurodegenerative diseases (tauopathies) including AD. In this opinion article we have focused on the endocytosis mechanism. Several genetic risk factors have been associated with a higher probability of developing sporadic Alzheimer's disease (SAD). The Alzheimer Association (http://www.alzforum.org/) has ranked the top six risk genes, shown in Table ​Table1,1, based on genome-wide association studies (GWAS). Table 1 The top six AD risk genes that interact with tau.

Fyn inhibition rescues established memory and synapse loss in Alzheimer mice.

Currently no effective disease-modifying agents exist for the treatment of Alzheimer disease (AD). The Fyn tyrosine kinase is implicated in AD pathology triggered by amyloid-ß oligomers (Aßo) and propagated by Tau. Thus, Fyn inhibition may prevent or delay disease progression. Here, we sought to repurpose the Src family kinase inhibitor oncology compound, AZD0530, for AD. The pharmacokinetics and distribution of AZD0530 were evaluated in mice. Inhibition of Aßo signaling to Fyn, Pyk2, and Glu receptors by AZD0530 was tested by brain slice assays. After AZD0530 or vehicle treatment of wild-type and AD transgenic mice, memory was assessed by Morris water maze and novel object recognition. For these cohorts, amyloid precursor protein (APP) metabolism, synaptic markers (SV2 and PSD-95), and targets of Fyn (Pyk2 and Tau) were studied by immunohistochemistry and by immunoblotting. AZD0530 potently inhibits Fyn and prevents both Aßo-induced Fyn signaling and downstream phosphorylation of the AD risk gene product Pyk2, and of NR2B Glu receptors in brain slices. After 4 weeks of treatment, AZD0530 dosing of APP/PS1 transgenic mice fully rescues spatial memory deficits and synaptic depletion, without altering APP or Aß metabolism. AZD0530 treatment also reduces microglial activation in APP/PS1 mice, and rescues Tau phosphorylation and deposition abnormalities in APP/PS1/Tau transgenic mice. There is no evidence of AZD0530 chronic toxicity. Targeting Fyn can reverse memory deficits found in AD mouse models, and rescue synapse density loss characteristic of the disease. Thus, AZD0530 is a promising candidate to test as a potential therapy for AD.

Activity-dependent neuroprotective protein (ADNP) exhibits striking sexual dichotomy impacting on autistic and Alzheimer's pathologies.

Activity-dependent neuroprotective protein (ADNP) is a most frequent autism spectrum disorder (ASD)-associated gene and the only protein significantly decreasing in the serum of Alzheimer's disease (AD) patients. Is ADNP associated with ASD being more prevalent in boys and AD more prevalent in women? Our results revealed sex-related learning/memory differences in mice, reflecting hippocampal expression changes in ADNP and ADNP-controlled AD/ASD risk genes. Hippocampal ADNP transcript content was doubled in male vs female mice, with females showing equal expression to ADNP haploinsufficient (ADNP+/−) males and no significant genotype-associated reduction. Increased male ADNP expression was replicated in human postmortem hippocampal samples. The hippocampal transcript for apolipoprotein E (the major risk gene for AD) was doubled in female mice compared with males, and further doubled in the ADNP+/− females, contrasting a decrease in ADNP+/− males. Previously, overexpression of the eukaryotic translation initiation factor 4E (eIF4E) led to ASD-like phenotype in mice. Here, we identified binding sites on ADNP for eIF4E and co-immunoprecipitation. Furthermore, hippocampal eIF4E expression was specifically increased in young ADNP+/− male mice. Behaviorally, ADNP+/− male mice exhibited deficiencies in object recognition and social memory compared with ADNP+/+ mice, while ADNP+/− females were partially spared. Contrasting males, which preferred novel over familiar mice, ADNP+/+ females showed no preference to novel mice and ADNP+/− females did not prefer mice over object. ADNP expression, positioned as a master regulator of key ASD and AD risk genes, introduces a novel concept of hippocampal gene-regulated sexual dimorphism and an ADNP+/− animal model for translational psychiatry.

A kernel machine method for detecting effects of interaction between multidimensional variable sets: An imaging genetics application

Measurements derived from neuroimaging data can serve as markers of disease and/or healthy development, are largely heritable, and have been increasingly utilized as (intermediate) phenotypes in genetic association studies. To date, imaging genetic studies have mostly focused on discovering isolated genetic effects, typically ignoring potential interactions with non-genetic variables such as disease risk factors, environmental exposures, and epigenetic markers. However, identifying significant interaction effects is critical for revealing the true relationship between genetic and phenotypic variables, and shedding light on disease mechanisms. In this paper, we present a general kernel machine based method for detecting effects of the interaction between multidimensional variable sets. This method can model the joint and epistatic effect of a collection of single nucleotide polymorphisms (SNPs), accommodate multiple factors that potentially moderate genetic influences, and test for nonlinear interactions between sets of variables in a flexible framework. As a demonstration of application, we applied the method to the data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) to detect the effects of the interactions between candidate Alzheimer's disease (AD) risk genes and a collection of cardiovascular disease (CVD) risk factors, on hippocampal volume measurements derived from structural brain magnetic resonance imaging (MRI) scans. Our method identified that two genes, CR1 and EPHA1, demonstrate significant interactions with CVD risk factors on hippocampal volume, suggesting that CR1 and EPHA1 may play a role in influencing AD-related neurodegeneration in the presence of CVD risks.

Validating GWAS-Identified Risk Loci for Alzheimer's Disease in Han Chinese Populations.

In recent years, genome-wide association studies (GWASs) have identified many novel susceptible genes/loci for Alzheimer's disease (AD). However, most of these studies were conducted in European and populations of European origin, and limited studies have been performed in Han Chinese. In this study, we genotyped 14 single-nucleotide polymorphisms (SNPs) in eight GWAS-reported AD risk genes in 1509 individuals comprising two independent Han Chinese case-control cohorts. Four SNPs (rs11234495, rs592297, rs676733, and rs3851179) in the PICALM gene were significantly associated with late-onset (LO)-AD in populations from Southwest China, whereas SNPs rs744373 (BIN1), rs9331942 (CLU), and rs670139 (MS4A4E) were linked to LO-AD in populations from East China. In the combined Han Chinese population, positive associations were observed between PICALM, CLU, MS4A4E genes, and LO-AD. The association between rs3851179 (PICALM), rs744373 (BIN1), and AD was further confirmed by meta-analysis of Asian populations. Our study verified the association between PICALM, BIN1, CLU, and MS4A4E variants and AD susceptibility in Han Chinese populations. We also discerned some regional differences concerning AD susceptibility SNPs.

Two Alzheimer's disease risk genes increase entorhinal cortex volume in young adults.

Alzheimer’s disease (AD) risk genes alter brain structure and function decades before disease onset. Apolipoprotein E (APOE) is the strongest known genetic risk factor for AD, and a related gene, apolipoprotein J (APOJ), also affects disease risk. However, the extent to which these genes affect brain structure in young adults remains unclear. Here, we report that AD risk alleles of these two genes, APOE-ε4 and APOJ-C, cumulatively alter brain volume in young adults. Using voxel-based morphometry (VBM) in 57 individuals, we examined the entorhinal cortex, one of the earliest brain regions affected in AD pathogenesis. Apolipoprotein E-ε4 carriers exhibited higher right entorhinal cortex volume compared to non-carriers. Interestingly, APOJ-C risk genotype was associated with higher bilateral entorhinal cortex volume in non-APOE-ε4 carriers. To determine the combined disease risk of APOE and APOJ status per subject, we used cumulative odds ratios as regressors for volumetric measurements. Higher disease risk corresponded to greater right entorhinal cortex volume. These results suggest that, years before disease onset, two key AD genetic risk factors may exert influence on the structure of a brain region where AD pathogenesis takes root.

Opposing effects of membrane-anchored CX3CL1 on amyloid and tau pathologies via the p38 MAPK pathway.

Several Alzheimer's disease (AD) risk genes are specifically expressed by microglia within the CNS. However, the mechanisms by which microglia regulate the pathological hallmarks of AD--extracellular deposition of β-amyloid (Aβ) and intraneuronal hyperphosphorylation of microtubule-associated protein tau (MAPT)--remain to be established. Notably, deficiency for the microglial CX3CR1 receptor has opposing effects on Aβ and MAPT pathologies. CX3CL1, the neuronally derived cognate ligand for CX3CR1, signals both in membrane-anchored and soluble forms. In this study, we sought to determine the relative contribution on membrane-anchored versus soluble CX3CL1 in regulating the microglia-mediated amelioration of Aβ pathology, as well as provide insight into the potential downstream microglial-based mechanisms. As expected, CX3CL1 deficiency reduced Aβ deposition in APPPS1 animals in a similar manner to CX3CR1 deficiency. Surprisingly, however, CX3CL1-deficient APPPS1 animals exhibited enhanced neuronal MAPT phosphorylation despite reduced amyloid burden. Importantly, neither of these phenotypes was altered by transgenic expression of the soluble CX3CL1 isoform, suggesting that it is the membrane-anchored version of CX3CL1 that regulates microglial phagocytosis of Aβ and neuronal MAPT phosphorylation. Analysis of transcript levels in purified microglia isolated from APPPS1 mice with the various CX3CL1/CX3CR1 genotypes revealed increased expression of inflammatory cytokines and phagocytic markers, which was associated with activation of p38 mitogen-activated protein kinase and Aβ internalization within microglia. Together, these studies challenge the "frustrated phagocytosis" concept and suggest that neuronal-microglial communication link the two central AD pathologies.

Transcriptomics and mechanistic elucidation of Alzheimer's disease risk genes in the brain and in vitro models

In this study, we have assessed the expression and splicing status of genes involved in the pathogenesis or affecting the risk of Alzheimer's disease (AD) in the postmortem inferior temporal cortex samples obtained from 60 subjects with varying degree of AD-related neurofibrillary pathology. These subjects were grouped based on neurofibrillary pathology into 3 groups: Braak stages 0-II, Braak stages III-IV, and Braak stages V-VI. We also examined the right frontal cortical biopsies obtained during life from 22 patients with idiopathic shunt-responding normal pressure hydrocephalus, a disease that displays similar pathologic alterations as seen in AD. These 22 patients were categorized according to dichotomized amyloid-β positive or negative pathology in the biopsies. We observed that the expression of FRMD4A significantly decreased, and the expression of MS4A6A significantly increased in relation to increasing AD-related neurofibrillary pathology. Moreover, the expression of 2 exons in both CLU and TREM2 significantly increased with increase in AD-related neurofibrillary pathology. However, a similar trend toward increased expression in CLU and TREM2 was observed with most of the studied exons, suggesting a global change in the expression rather than altered splicing. Correlation of gene expression with well-established AD-related factors, such as α-, β-, and γ-secretase activities, brain amyloid-β42 levels, and cerebrospinal fluid biomarkers, revealed a positive correlation between β-secretase activity and the expression of TREM2 and BIN1. In expression quantitative trait loci analysis, we did not detect significant effects of the risk alleles on gene expression or splicing. Analysis of the normal pressure hydrocephalus biopsies revealed no differences in the expression or splicing profiles of the studied genes between amyloid-β positive and negative patients. Using the protein-protein interaction-based in vitro pathway analysis tools, we found that downregulation of FRMD4A associated with increased APP-β-secretase interaction, increased amyloid-β40 secretion, and altered phosphorylation of tau. Taken together, our results suggest that the expression of FRMD4A, MS4A6A, CLU, and TREM2 is altered in relation to increasing AD-related neurofibrillary pathology, and that FRMD4A may play a role in amyloidogenic and tau-related pathways in AD. Therefore, investigation of gene expression changes in the brain and effects of the identified genes on disease-associated pathways in vitro may provide mechanistic insights on how alterations in these genes may contribute to AD pathogenesis.

Influence of Alzheimer's disease genes on cognitive decline: the Guangzhou Biobank Cohort Study

Cognitive decline is a reduction in cognitive ability usually associated with aging, and those with more extreme cognitive decline either have or are at risk of progressing to mild cognitive impairment and dementia including Alzheimer's disease (AD). We hypothesized that genetic variants predisposing to AD should be predictive of cognitive decline in elderly individuals. We selected 1325 subjects with extreme cognitive decline and 1083 well-matched control subjects from the Guangzhou Biobank Cohort Study in which more than 30,000 southern Chinese older people have been recruited and followed up. Thirty single-nucleotide polymorphisms in 29 AD-associated genes were genotyped. No statistically significant allelic associations with cognitive decline were found by individual variant analysis. At the level of genotypic association, we confirmed that the APOE ε4 homozygote significantly accelerated cognitive decline and found that carriers of the ACE rs1800764_C allele were more likely to show cognitive decline than noncarriers, particularly in those without college education. However, these effects do not survive after multiple testing corrections, and together they only explain 1.7% of the phenotypic variance in cognitive score change. This study suggests that AD risk variants and/or genes are not powerful predictors of cognitive decline in our Chinese sample.

A combined effect of two Alzheimer's risk genes on medial temporal activity during executive attention in young adults

A recent history of failed clinical trials suggests that waiting until even the early stages of onset of Alzheimer's disease may be too late for effective treatment, pointing to the importance of early intervention in young people. Early intervention will require markers of Alzheimer's risk that track with genotype but are capable of responding to treatment. Here, we sought to identify a functional MRI signature of combined Alzheimer's risk imparted by two genetic risk factors. We used a task of executive attention during fMRI in participants genotyped for two Alzheimer's risk alleles: APOE-ε4 and CLU-C. Executive attention is a sensitive indicator of the progression of Alzheimer's even in the early stages of mild cognitive impairment, but has not yet been investigated as a marker of Alzheimer's risk in young adults. Functional MRI revealed that APOE-ε4 and CLU-C had an additive effect on brain activity such that increased combined genetic risk was associated with decreased brain activity during executive attention, including in the medial temporal lobe, a brain area affected early in Alzheimer's pathogenesis.