Alzheimer's Disease Risk Variants Research Articles

Alzheimer's disease genetic pathways impact cerebrospinal fluid biomarkers and imaging endophenotypes in non-demented individuals.

Unraveling how Alzheimer's disease (AD) genetic risk is related to neuropathological heterogeneity, and whether this occurs through specific biological pathways, is a key step toward precision medicine. We computed pathway-specific genetic risk scores (GRSs) in non-demented individuals and investigated how AD risk variants predict cerebrospinal fluid (CSF) and imaging biomarkers reflecting AD pathology, cardiovascular, white matter integrity, and brain connectivity. CSF amyloidbeta and phosphorylated tau were related to most GRSs. Inflammatory pathways were associated with cerebrovascular disease, whereas quantitative measures of white matter lesion and microstructure integrity were predicted by clearance and migration pathways. Functional connectivity alterations were related to genetic variants involved in signal transduction and synaptic communication. This study reveals distinct genetic risk profiles in association with specific pathophysiological aspects in predementia stages of AD, unraveling the biological substrates of the heterogeneity of AD-associated endophenotypes and promoting a step forward in disease understanding and development of personalized therapies. Polygenic risk for Alzheimer's disease encompasses six biological pathways that can be quantified with pathway-specific genetic risk scores, and differentially relate to cerebrospinal fluid and imaging biomarkers. Inflammatory pathways are mostly related to cerebrovascular burden. White matter health is associated with pathways of clearance and membrane integrity, whereas functional connectivity measures are related to signal transduction and synaptic communication pathways.

CRISPR/Cas9-mediated knock-in cells of the late-onset Alzheimer's disease-risk variant, SHARPIN G186R, reveal reduced NF-κB pathway and accelerated Aβ secretion.

CRISPR/Cas9-mediated knock-in cells of the late-onset Alzheimer's disease-risk variant, SHARPIN G186R, reveal reduced NF-κB pathway and accelerated Aβ secretion.

Functional characterization of Alzheimer's disease genetic variants in microglia.

Candidate cis-regulatory elements (cCREs) in microglia demonstrate the most substantial enrichment for Alzheimer's disease (AD) heritability compared to other brain cell types. However, whether and how these genome-wide association studies (GWAS) variants contribute to AD remain elusive. Here we prioritize 308 previously unreported AD risk variants at 181 cCREs by integrating genetic information with microglia-specific 3D epigenome annotation. We further establish the link between functional variants and target genes by single-cell CRISPRi screening in microglia. In addition, we show that AD variants exhibit allelic imbalance on target gene expression. In particular, rs7922621 is the effective variant in controlling TSPAN14 expression among other nominated variants in the same cCRE and exerts multiple physiological effects including reduced cell surface ADAM10 and altered soluble TREM2 (sTREM2) shedding. Our work represents a systematic approach to prioritize and characterize AD-associated variants and provides a roadmap for advancing genetic association to experimentally validated cell-type-specific phenotypes and mechanisms.

Genetic variants of phospholipase C-γ2 alter the phenotype and function of microglia and confer differential risk for Alzheimer’s disease

Genetic association studies have demonstrated the critical involvement of the microglial immune response in Alzheimer's disease (AD) pathogenesis. Phospholipase C-gamma-2 (PLCG2) is selectively expressed by microglia and functions in many immune receptor signaling pathways. In AD, PLCG2 is induced uniquely in plaque-associated microglia. A genetic variant of PLCG2, PLCG2P522R, is a mild hypermorph that attenuates AD risk. Here, we identified a loss-of-function PLCG2 variant, PLCG2M28L, that confers an increased AD risk. PLCG2P522R attenuated disease in an amyloidogenic murine AD model, whereas PLCG2M28L exacerbated the plaque burden associated with altered phagocytosis and Aβ clearance. The variants bidirectionally modulated disease pathology by inducing distinct transcriptional programs that identified microglial subpopulations associated with protective or detrimental phenotypes. These findings identify PLCG2M28L as a potential AD risk variant and demonstrate that PLCG2 variants can differentially orchestrate microglial responses in AD pathogenesis that can be therapeutically targeted.

APOE ε4 is associated with earlier symptom onset in LOAD but later symptom onset in EOAD.

We studied the effect of apolipoprotein E (APOE) ε4 status and sex on age of symptom onset (AO) in early- (EO) and late- (LO) onset Alzheimer's disease (AD). A total of 998 EOAD and 2562 LOAD participants from the National Alzheimer's Coordinating Center (NACC) were included. We used analysis of variance to examine AO differences between sexes and APOE genotypes and the effect of APOE ε4, sex, and their interaction on AO in EOAD and LOAD, separately. APOE ε4 carriers in LOAD had younger AO and in EOAD had older AO. Female EOAD APOE ε4 carriers had older AO compared to non-carriers (P<0.0001). There was no difference for males. Both male and female LOAD APOE ε4 carriers had younger AO relative to non-carriers (P<0.0001). The observed earlier AO in EOAD APOE ε4 non-carriers relative to carriers, particularly in females, suggests the presence of additional AD risk variants.

Association of APOE-Independent Alzheimer Disease Polygenic Risk Score With Brain Amyloid Deposition in Asymptomatic Older Adults.

Background and ObjectivesBrain amyloid deposition, a major risk factor for Alzheimer disease (AD), is currently estimated by measuring CSF or plasma amyloid peptide levels or by PET imaging. Assessing genetic risks relating to amyloid deposition before any accumulation has occurred would allow for earlier intervention in persons at increased risk for developing AD. Previous work linking amyloid burden and genetic risk relied almost exclusively on APOE, a major AD genetic risk factor. Here, we ask whether a polygenic risk score (PRS) that incorporates an optimized list of common variants linked to AD and excludes APOE is associated with brain amyloid load in cognitively unimpaired older adults.MethodsWe included 291 asymptomatic older participants from the INveStIGation of AlzHeimer's PredicTors (INSIGHT pre-AD) cohort who underwent amyloid imaging, including 83 amyloid-positive (+) participants. We used an Alzheimer's (A) PRS composed of 33 AD risk variants excluding APOE and selected the 17 variants that showed the strongest association with amyloid positivity to define an optimized (oA) PRS. Participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) study (228 participants, 90 amyloid [+]) were tested as a validation cohort. Finally, 2,300 patients with AD and 6,994 controls from the European Alzheimer's Disease Initiative (EADI) were evaluated.ResultsA-PRS was not significantly associated with amyloid burden in the INSIGHT or ADNI cohorts with or without correction for the APOE genotype. However, oA-PRS was significantly associated with amyloid status independently of APOE adjustment (INSIGHT odds ratio [OR]: 5.26 [1.71–16.88]; ADNI OR: 3.38 [1.02–11.63]). Of interest, oA-PRS accurately discriminated amyloid (+) and (−) APOE ε4 carriers (INSIGHT OR: 181.6 [7.53–10,674.6]; ADNI OR: 44.94 [3.03–1,277]). A-PRS and oA-PRS showed a significant association with disease status in the EADI cohort (OR: 1.68 [1.53–1.85] and 2.06 [1.73–2.45], respectively). Genes assigned to oA-PRS variants were enriched in ontologies related to β-amyloid metabolism and deposition.DiscussionPRSs relying on AD genetic risk factors excluding APOE may improve risk prediction for brain amyloid, allowing stratification of cognitively unimpaired individuals at risk of AD independent of their APOE status.

Tau polygenic risk scoring: a cost-effective aid for prognostic counseling in Alzheimer's disease.

Tau deposition is one of two hallmark features of biologically defined Alzheimer's disease (AD) and is more closely related to cognitive decline than amyloidosis. Further, not all amyloid-positive individuals develop tauopathy, resulting in wide heterogeneity in clinical outcomes across the population with AD. We hypothesized that a polygenic risk score (PRS) based on tau PET (tau PRS) would capture the aggregate inherited susceptibility/resistance architecture influencing tau accumulation, beyond solely the measurement of amyloid-β burden. Leveraging rich multimodal data from a population-based sample of older adults, we found that this novel tau PRS was a strong surrogate of tau PET deposition and captured a significant proportion of the variance in tau PET levels as compared with amyloid PET burden, APOE (apolipoprotein E) ε4 (the most common risk allele for AD), and a non-APOE PRS of clinical case-control AD risk variants. In independent validation samples, the tau PRS was associated with cerebrospinal fluid phosphorylated tau levels in one cohort and with postmortem Braak neurofibrillary tangle stage in another. We also observed an association of the tau PRS with longitudinal cognitive trajectories, including a statistical interaction of the tau PRS with amyloid burden on cognitive decline. Although additional study is warranted, these findings demonstrate the potential utility of a tau PRS for capturing the collective genetic background influencing tau deposition in the general population. In the future, a tau PRS could be leveraged for cost-effective screening and risk stratification to guide trial enrollment and clinical interventions in AD.

Genome-wide association study identifies APOE locus influencing plasma p-tau181 levels.

As a promising diagnostic and prognostic biomarker for Alzheimer's Disease (AD), plasma p-tau181 is robustly differentiated AD dementia from non-AD neurodegenerative diseases. We aimed to discover single nucleotide polymorphisms (SNPs) associated with plasma phosphorylated tau at threonine 181 (p-tau181) levels that affect the risk of developing AD. We carried out a genome-wide association study for plasma p-tau181 levels using participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI). The thresholds of P < 5 × 10-6 was used for suggestive associations, and thresholds of P < 5 × 10-8 was used for significant associations. Subsequently, we tested whether the associations remained significant in subgroup analysis and examined the impact of SNPs on the longitudinal changes in plasma p-tau181 levels. A total of 714 eligible non-Hispanic white participants with plasma p-tau181 data were included. The most significant SNP (rs769449, P = 6.26 × 10-8) in APOE gene was suggestively associated with plasma p-tau181, which is close to the genome-wide significance threshold. The minor allele (A) of rs769449 in the APOE was associated with higher plasma p-tau181 levels in a dose-dependent fashion. Besides, rs769449- A carriers were more likely to exhibit a greater longitudinal cognitive decline (P = 0.03). Our results suggest that the AD risk variant in the APOE gene participates in the regulation of plasma p-tau181. The plasma p-tau181 concentration could be a useful endophenotype for identifying risk for AD in elderly individuals.

An association test of the spatial distribution of rare missense variants within protein structures identifies Alzheimer's disease-related patterns.

More than 90% of genetic variants are rare in most modern sequencing studies, such as the Alzheimer's Disease Sequencing Project (ADSP) whole-exome sequencing (WES) data. Furthermore, 54% of the rare variants in ADSP WES are singletons. However, both single variant and unit-based tests are limited in their statistical power to detect an association between rare variants and phenotypes. To best use missense rare variants and investigate their biological effect, we examine their association with phenotypes in the context of protein structures. We developed a protein structure–based approach, protein optimized kernel evaluation of missense nucleotides (POKEMON), which evaluates rare missense variants based on their spatial distribution within a protein rather than their allele frequency. The hypothesis behind this test is that the three-dimensional spatial distribution of variants within a protein structure provides functional context to power an association test. POKEMON identified three candidate genes (TREM2, SORL1, and EXOC3L4) and another suggestive gene from the ADSP WES data. For TREM2 and SORL1, two known Alzheimer's disease (AD) genes, the signal from the spatial cluster is stable even if we exclude known AD risk variants, indicating the presence of additional low-frequency risk variants within these genes. EXOC3L4 is a novel AD risk gene that has a cluster of variants primarily shared by case subjects around the Sec6 domain. This cluster is also validated in an independent replication data set and a validation data set with a larger sample size.

Evaluation of late-onset Alzheimer's disease risk variants in mouse models.

The MODEL-AD Center was created to develop, characterize, and distribute more precise preclinical models for late-onset AD by engineering disease-associated variants into mouse models, and characterizing the phenotypes using clinically relevant assays (Oblak et al, 2020). While rare familial causative mutations have been known for decades, the genetic etiology of the common (>95%) late-onset AD (LOAD) is still unknown. Numerous AD risk loci and variants have been identified by large-scale genetic studies, but few have been functionally verified and models to study their mechanism of action are lacking. Criteria to prioritize risk variants include replication in multiple studies, predicted pathogenicity of variant, sequence conservation between human and mouse, and expression in relevant cell types. We have created variants in coding regions in the Abca7, Clasp2, Kif21b, Mthfr, Mtmr4, Picalm, Plcg2, Shc2, Slc6a17, Snx1, Sorl1 and other loci. Knockouts of Abca7, Ceacam1, Il1rap, Meox2, and Plcg2 have been created to model human loss-of-function variants. These variants have been engineered into a mouse model that expresses the AD risk variants APOE4 and Trem2*R47H (as well as a humanized Aβ allele in the newer models). Primary screening was completed by transcriptomic analysis using the nanoString Mouse AD Panel at 4 and 12 months (Preuss et al, 2020). Transcriptomic analysis demonstrated that the Abca7*A1527G, Mthfr*C677T, and Plcg2*M28L models exhibited age-dependent similarities to transcriptomic changes observed in post-mortem human samples from the AMP-AD cohort (Wan et al, 2020). These are now being aged for comprehensive phenotyping at 18 and 24 months of age to include biomarker analysis, transcriptomics, proteomics, metabolomics, in vivo neuroimaging of glucose utilization, blood flow, and amyloid deposition, neuropathology and cognitive assays. Additional models will be added as primary screening is completed. We have screened a significant number of novel models of late-onset AD and prioritized a few of them for more extensive characterization in old age. All models are made available for both academic and for-profit use from The Jackson Laboratory, and all validation protocols and data will be shared via the AD knowledge portal (https://adknowledgeportal.synapse.org/ ). For more information see www.model-ad.org.

Accelerated epigenetic aging in adults with Down Syndrome in the Argentine population

AbstractBackgroundLife expectancy of individuals with Down Syndrome (DS) is currently 60 years. From age 40 they have an increased risk of dementia and almost all of them have histopathological features of Alzheimer's disease (AD) in their brains. Also, it is known that the ε4 allele of the APOE gene and the R47H variant of TREM2 increase the risk of AD. DS is also associated with a group of clinical manifestations of accelerated aging. DNA methylation‐based biomarkers of ageing (epigenetic clocks) can be assessed by different models. It is known that DNA methylation age (DNAm) has a positive correlation with chronological age in disomic individuals while DS subjects exhibit an age acceleration effect in blood and brain.MethodWe determined the DNAm age of a cohort of seven participants with chromosome 21 trisomy (confirmed by G‐banding karyotyping). Median age was 49 years. Their cognitive status was assessed by clinical and neuropsychological evaluations. AD risk variants in APOE and TREM2 were analyzed by RFLP‐PCR. DNAm age was assessed in peripheral blood leukocytes, using the Illumina 850K platform. We used the Horvath’s epigenetic clock, based on the DNAm levels of 353 specific CpG sites.ResultFive participants exhibited the ε3/ε3 genotype in APOE and two of them the ε3/ε4 genotype. We did not observe the R47H risk variant in TREM2 in this group. Five participants showed a significant biological age acceleration and one participant’s DNAm age was similar to his chronological age. Of note, one participant showed a deceleration in the DNAm age. This participant also had multiple myeloma. It is known that the DNA methylation profile of multiple myeloma cells differs from normal plasma cells. On the other hand, we did not find a trend towards a greater presence of the risk allele ε4 or cognitive impairment in participants with a significant DNAm age acceleration.ConclusionThe majority participants presented an acceleration in their biological age, but this fact was not correlated with a greater presence of the risk allele ε4 or cognitive impairment. This is the first dataset of DNA methylation ages of a cohort of people with Down Syndrome in Latin America.

Alzheimer’s disease genetic risk variants show brain cell type‐specific associations with protein levels in cerebrospinal fluid

Neuronal dysfunction is central to the clinical manifestation of Alzheimer's disease (AD). However, genome-wide studies also suggest important roles for non-neuronal brain cell-types such as microglia and astrocytes. Our objective was to study whether brain cell type-specific polygenic risk scores (PGRS) for AD, including single nucleotide polymorphisms (SNPs) of genes expressed in one brain cell type, showed relationships with levels of cerebrospinal fluid (CSF) AD markers in individuals across the clinical spectrum of AD. We selected 1,535 subjects (552 controls/709 mild cognitive impairment/274 AD-dementia, age 71±8 years, 48%female) from the ADNI (N=617) and EMIF-AD MBD (N=918) study, who had genetic data available. We labelled AD risk genes as specific for neurons, astrocytes, microglia, oligodendrocytes or endothelial cells when more than 50% of the gene expression was produced by one cell type (otherwise as 'non-specific') according to the BRAIN RNASeq database (Zhang et al., 2014). We calculated cell type-specific-PGRS with cell type-corresponding SNPs (P<5e-8 ) using weights from De Rojas et al., (2020) AD case-control summary statistics. Associations between cell type-specific-PGRS and CSF biomarkers (amyloid-beta, total tau (t-tau), phosphorylated tau (p-tau), neurofilament light, neurogranin and YKL-40) were examined using linear regressions, adjusted for population structure, study, age and sex. Of 40 AD risk genes, 26 had detectable RNA levels in at least one brain cell type. Of these, sixteen were cell type-specific: 11 were microglia-specific, 4 astrocyte-specific (including APOE) and 1 neuron-specific (Figure 1). Astrocyte-PGRS (P=1.4e-6 , Pwithout_APOE =.1) and microglia-PGRS (P=6.3e-3 ) were increased in AD-type dementia compared to controls, whereas other PGRS were not (Figure 2). Astrocyte-PGRS (including APOE) were most strongly associated with CSF amyloid-beta (P=1.4e-31 ), t-tau (P=6.3e-10 ), p-tau (P=4.9e-9 ), and neurogranin (P=0.01). Astrocyte-specific (excluding APOE) and microglia-specific PGRS-AD also associated with CSF amyloid-beta (P<0.05), and with p-tau at trend-level (Figure 2). Apart from the tentative association between neuron-PGRS and CSF YKL-40, no other associations were observed. Findings indicate that AD risk variants have cell type-specific associations with amyloid and tau pathology, which seems mostly expressed by astrocytes (also without APOE) and microglia, suggesting that these cell types play a role in amyloid pathogenesis.

Genomics of Alzheimer's disease implicates the innate and adaptive immune systems.

Alzheimer's disease (AD) is a chronic neurodegenerative disease characterised by cognitive impairment, behavioural alteration, and functional decline. Over 130 AD-associated susceptibility loci have been identified by genome-wide association studies (GWAS), while whole genome sequencing (WGS) and whole exome sequencing (WES) studies have identified AD-associated rare variants. These variants are enriched in APOE, TREM2, CR1, CD33, CLU, BIN1, CD2AP, PILRA, SCIMP, PICALM, SORL1, SPI1, RIN3, and more genes. Given that aging is the single largest risk factor for late-onset AD (LOAD), the accumulation of somatic mutations in the brain and blood of AD patients have also been explored. Collectively, these genetic findings implicate the role of innate and adaptive immunity in LOAD pathogenesis and suggest that a systemic failure of cell-mediated amyloid-β (Aβ) clearance contributes to AD onset and progression. AD-associated variants are particularly enriched in myeloid-specific regulatory regions, implying that AD risk variants are likely to perturbate the expression of myeloid-specific AD-associated genes to interfere Aβ clearance. Defective phagocytosis, endocytosis, and autophagy may drive Aβ accumulation, which may be related to naturally-occurring antibodies to Aβ (Nabs-Aβ) produced by adaptive responses. Passive immunisation is providing efficiency in clearing Aβ and slowing cognitive decline, such as aducanumab, donanemab, and lecanemab (ban2401). Causation of AD by impairment of the innate immunity and treatment using the tools of adaptive immunity is emerging as a new paradigm for AD, but immunotherapy that boosts the innate immune functions of myeloid cells is highly expected to modulate disease progression at asymptomatic stage.

APOE signaling in neurodegenerative diseases: an integrative approach targeting APOE coding and noncoding variants for disease intervention.

APOE (apolipoprotein E) is a key regulator of lipid metabolism and a leading genetic risk factor for Alzheimer's disease. While APOE participates in multiple biological pathways, its roles in diseases are largely due to the mutant protein encoded by APOE-ε4. However, emerging evidence suggests that some noncoding Alzheimer's disease risk variants residing in APOE and its nearby regions exert APOE-ε4-independent risks and modify APOE gene expression. Moreover, intervention strategies targeting APOE are being explored. In this review, we summarize the literature on the genetic risks and roles of APOE in biological systems. Moreover, we propose an integrative approach to evaluate disease risk and tailor interventions to aid research on APOE-associated diseases.

Imaging genomics in the ENIGMA Consortium

AbstractBackgroundWe offer an update on recent work by the ENIGMA Consortium, CHARGE Consortium, and UK Biobank ‐ and a worldwide alliance of over 1,400 scientists ‐ to understand how human genetic and epigenetic variation affect biomarkers of brain aging and Alzheimer's disease (AD).MethodFor 10 years, ENIGMA, CHARGE, and (more recently) the UK Biobank have screened the genomes and neuroimaging data from over 50,000 persons worldwide, as well as epigenome‐wide methylation data, to ask: (1) which common and rare genetic variants affect the brain throughout life? (2) which variants affect brain aging and biomarkers of AD ‐ such as hippocampal volume, longitudinal brain atrophy rates over time, and white matter hyperintensities? (3) how do AD risk variants, in APOE and elsewhere, affect brain biomarkers from youth to old age? For 10 years, we harmonized analyses of worldwide anaotmical MRI, diffusion MRI, rsFMRI, and EEG markers across over 200 cohorts, to examine how genome‐wide genomic variation and epigenetic variants affect structural and functional biomarkers of aging and AD.ResultGWAS in over 51,662 persons revealed over 200 common genetic variants affecting cortical architecture; of 255 nominally significant loci (P ≤ 5 × 10−8); 199 survived multiple testing correction (P ≤ 8.3 × 10−10; 187 surface area; 12 thickness). Variation in cortical and hippocampal structure is genetically correlated with cognitive function, AD, Parkinson’s disease, insomnia, major depression and ADHD. ENIGMA's Plasticity Working Group analyzed longitudinal MRI data of 10,163 persons aged 4 to 99 years, and discovered 5 genome‐wide significant loci and 15 genes influencing brain change rates at different times throughout life, and an age‐dependent effect of the APOE haplotype on brain structure. These age‐dependent influences of common genetic variants implicate immunological and metabolic processes. Epigenome‐wide screens revealed additional loci where methylation levels robustly associate with hippocampal volume in cohorts worldwide.ConclusionCommon genetic variants affect rates of brain change, hippocampal and regional cortical measures, throughout life; coordinated analyses of harmonized data are revealing the timing of genetic and epigenetic drivers of brain aging, and the first catalogs of common variants that associate with longitudinal markers of brain aging.

Association of Alzheimer's disease risk variants on the PICALM gene with PICALM expression, core biomarkers, and feature neurodegeneration.

It is still unclear how PICALM mutations influence the risk of Alzheimer’s disease (AD). We tested the association of AD risk variants on the PICALM gene with PICALM expression and AD feature endophenotypes. Bioinformatic methods were used to annotate the functionalities and to select the tag single nucleotide polymorphisms (SNPs). Multiple regressions were used to examine the cross-sectional and longitudinal influences of tag SNPs on cerebrospinal fluid (CSF) AD biomarkers and neurodegenerations. A total of 59 SNPs, among which 75% were reported in Caucasians, were associated with AD risk. Of these, 73% were linked to PICALM expression in the whole blood (p < 0.0001) and/or brain regions (p < 0.05). Eleven SNPs were selected as tag SNPs in Caucasians. rs510566 (T allele) was associated with decreased CSF ptau and ptau/abeta42 ratio. The G allele of rs1237999 and rs510566 was linked with greater reserve capacities of the hippocampus, parahippocampus, middle temporal lobe, posterior cingulate, and precuneus. The longitudinal analyses revealed four loci that could predict dynamic changes of CSF ptau and ptau/abeta42 ratio (rs10501610, p = 0.0001) or AD feature neurodegeneration (rs3851179, rs592297, and rs7480193, p < 0.005). Overall, the genetic, bioinformatic, and association studies tagged four SNPs (rs3851179, rs7480193, rs510566, and rs1237999) as the most prominent PICALM loci contributing to AD in Caucasians.

Greater effect of polygenic risk score for Alzheimer's disease among younger cases who are apolipoprotein E-ε4 carriers

To evaluate how age and apolipoprotein E-ε4 (APOE4) status interact with APOE-independent polygenic risk score (PRSnon-APOE), we estimated PRSnon-APOE in superagers (age ≥ 90 years, N = 346), 89− controls (age 60–89, N = 2930), and Alzheimer's disease (AD) cases (N = 1760). Using superagers, we see a nearly 5 times greater odds ratio (OR) for AD comparing the top PRSnon-APOE decile to the lowest decile (OR = 4.82, p = 2.5 × 10−6), which is twice the OR as using 89− controls (OR = 2.38, p = 4.6 × 10−9). Thus PRSnon-APOE is correlated with age, which in turn is associated with APOE. Further exploring these relationships, we find that PRSnon-APOE modifies age at onset among APOE4 carriers, but not among noncarriers. More specifically, PRSnon-APOE in the top decile predicts an age at onset 5 years earlier compared with the lowest decile (70.1 vs. 75.0 years; t-test p = 2.4 × 10−5) among APOE4 carriers. This disproportionally large PRSnon-APOE among younger APOE4-positive cases is reflected in a significant statistical interaction between APOE4 status and age at onset (β = −0.02, p = 4.8 × 10−3) as a predictor of PRSnon-APOE. Thus, the known AD risk variants are particularly detrimental in young APOE4 carriers.

Genome-wide association study of rate of cognitive decline in Alzheimer's disease patients identifies novel genes and pathways.

Variability exists in the disease trajectories of Alzheimer's disease (AD) patients. We performed a genome-wide association study to examine rate of cognitive decline (ROD) in patients with AD. We tested for interactions between genetic variants and time since diagnosis to predict the ROD of a composite cognitive score in 3946 AD cases and performed pathway analysis on the top genes. Suggestive associations (P < 1.0 × 10-6 ) were observed on chromosome 15 in DNA polymerase-γ (rs3176205, P = 1.11 × 10-7 ), chromosome 7 (rs60465337,P = 4.06 × 10-7 ) in contactin-associated protein-2, in RP11-384F7.1 on chromosome 3 (rs28853947, P = 5.93 × 10-7 ), family with sequence similarity 214 member-A on chromosome 15 (rs2899492, P = 5.94 × 10-7 ), and intergenic regions on chromosomes 16 (rs4949142, P = 4.02 × 10-7 ) and 4 (rs1304013, P = 7.73 × 10-7 ). Significant pathways involving neuronal development and function, apoptosis, memory, and inflammation were identified. Pathways related to AD, intelligence, and neurological function determine AD progression, while previously identified AD risk variants, including the apolipoprotein (APOE) ε4 and ε2 variants, do not have a major impact.

MAPT haplotype-stratified GWAS reveals differential association for AD risk variants.

Introduction MAPT H1 haplotype is implicated as a risk factor for neurodegenerative diseases including Alzheimer's disease (AD).MethodsUsing Alzheimer's Disease Genetics Consortium (ADGC) genome‐wide association study (GWAS) data (n = 18,841), we conducted a MAPT H1/H2 haplotype–stratified association to discover MAPT haplotype–specific AD risk loci.ResultsWe identified 11 loci—5 in H2‐non‐carriers and 6 in H2‐carriers—although none of the MAPT haplotype–specific associations achieved genome‐wide significance. The most significant H2 non‐carrier–specific association was with a NECTIN2 intronic (P = 1.33E‐07) variant, and that for H2 carriers was near NKX6‐1 (P = 1.99E‐06). The GABRG2 locus had the strongest epistasis with MAPT H1/H2 variant rs8070723 (P = 3.91E‐06). Eight of the 12 genes at these loci had transcriptome‐wide significant differential expression in AD versus control temporal cortex (q < 0.05). Six genes were members of the brain transcriptional co‐expression network implicated in “synaptic transmission” (P = 9.85E‐59), which is also enriched for neuronal genes (P = 1.0E‐164), including MAPT.DiscussionThis stratified GWAS identified loci that may confer AD risk in a MAPT haplotype–specific manner. This approach may preferentially enrich for neuronal genes implicated in synaptic transmission.

Genetic Association Between Alzheimer's Disease Risk Variant of the PICALM Gene and EEG Functional Connectivity in Non-demented Adults.

Genome wide association studies (GWAS) have identified and validated the association of the PICALM genotype with Alzheimer’s disease (AD). The PICALM rs3851179 A allele is thought to have a protective effect, whereas the G allele appears to confer risk for AD. The influence of the PICALM genotype on brain functional connectivity in non-demented subjects remains largely unknown. We examined the association of the PICALM rs3851179 genotype with the characteristics of lagged linear connectivity (LLC) of resting EEG sources in 104 non-demented adults younger than 60 years of age. The EEG analysis was performed using exact low-resolution brain electromagnetic tomography (eLORETA) freeware (Pascual-Marqui et al., 2011). We found that the carriers of the A PICALM allele (PICALM AA and AG genotypes) had higher widespread interhemispheric LLC of alpha sources compared to the carriers of the GG PICALM allele. An exploratory correlation analysis showed a moderate positive association between the alpha LLC interhemispheric characteristics and the corpus callosum size and between the alpha interhemispheric LLC characteristics and the Luria word memory scores. These results suggest that the PICALM rs3851179 A allele provides protection against cognitive decline by facilitating neurophysiological reserve capacities in non-demented adults. In contrast, lower functional connectivity in carriers of the AD risk variant, PICALM GG, suggests early functional alterations in alpha rhythm networks.