Objective
Common single nucleotide polymorphisms in the SORL1 gene have been associated with late onset Alzheimer disease (LOAD), but causal variants have not been fully characterized nor has the ...mechanism been established. The study was undertaken to identify functional SORL1 mutations in patients with LOAD.
Methods
This was a family‐ and cohort‐based genetic association study. Caribbean Hispanics with familial and sporadic LOAD and similarly aged controls were recruited from the United States and the Dominican Republic, and patients with sporadic disease of Northern European origin were recruited from Canada. Prioritized coding variants in SORL1 were detected by targeted resequencing and validated by genotyping in additional family members and unrelated healthy controls. Variants transfected into human embryonic kidney 293 cell lines were tested for Aβ40 and Aβ42 secretion, and the amount of the amyloid precursor protein (APP) secreted at the cell surface was determined.
Results
Seventeen coding exonic variants were significantly associated with disease. Two rare variants (rs117260922‐E270K and rs143571823‐T947M) with minor allele frequency (MAF) < 1% and 1 common variant (rs2298813‐A528T) with MAF = 14.9% segregated within families and were deemed deleterious to the coding protein. Transfected cell lines showed increased Aβ40 and Aβ42 secretion for the rare variants (E270K and T947M) and increased Aβ42 secretion for the common variant (A528T). All mutants increased the amount of APP at the cell surface, although in slightly different ways, thereby failing to direct full‐length APP into the retromer‐recycling endosome pathway.
Interpretation
Common and rare variants in SORL1 elevate the risk of LOAD by directly affecting APP processing, which in turn can result in increased Aβ40 and Aβ42 secretion. Ann Neurol 2015;77:215–227
Objective
To detect rare coding variants underlying loci detected by genome‐wide association studies (GWAS) of late onset Alzheimer disease (LOAD).
Methods
We conducted targeted sequencing of ABCA7, ...BIN1, CD2AP, CLU, CR1, EPHA1, MS4A4A/MS4A6A, and PICALM in 3 independent LOAD cohorts: 176 patients from 124 Caribbean Hispanics families, 120 patients and 33 unaffected individuals from the 129 National Institute on Aging LOAD Family Study; and 263 unrelated Canadian individuals of European ancestry (210 sporadic patients and 53 controls). Rare coding variants found in at least 2 data sets were genotyped in independent groups of ancestry‐matched controls. Additionally, the Exome Aggregation Consortium was used as a reference data set for population‐based allele frequencies.
Results
Overall we detected a statistically significant 3.1‐fold enrichment of the nonsynonymous mutations in the Caucasian LOAD cases compared with controls (p = 0.002) and no difference in synonymous variants. A stop‐gain mutation in ABCA7 (E1679X) and missense mutation in CD2AP (K633R) were highly significant in Caucasian LOAD cases, and mutations in EPHA1 (P460L) and BIN1 (K358R) were significant in Caribbean Hispanic families with LOAD. The EPHA1 variant segregated completely in an extended Caribbean Hispanic family and was also nominally significant in the Caucasians. Additionally, BIN1 (K358R) segregated in 2 of the 6 Caribbean Hispanic families where the mutations were discovered.
Interpretation
Targeted sequencing of confirmed GWAS loci revealed an excess burden of deleterious coding mutations in LOAD, with the greatest burden observed in ABCA7 and BIN1. Identifying coding variants in LOAD will facilitate the creation of tractable models for investigation of disease‐related mechanisms and potential therapies. Ann Neurol 2015;78:487–498
Objective
Polygenic risk scores (PRSs) assess the individual genetic propensity to a condition by combining sparse information scattered across genetic loci, often displaying small effect sizes. Most ...PRSs are constructed in European‐ancestry populations, limiting their use in other ethnicities. Here we constructed and validated a PRS for late‐onset Alzheimer's Disease (LOAD) in Caribbean Hispanics (CH).
Methods
We used a CH discovery (n = 4,312) and independent validation sample (n = 1,850) to construct an ancestry‐specific PRS (“CH‐PRS”) and evaluated its performance alone and with other predictors using the area under curve (AUC) and logistic regression (strength of association with LOAD and statistical significance). We tested if CH‐PRS predicted conversion to LOAD in a subsample with longitudinal data (n = 1,239). We also tested the CH‐PRS in an independent replication CH cohort (n = 200) and brain autopsy cohort (n = 33). Finally, we tested the effect of ancestry on PRS by using European and African American discovery cohorts to construct alternative PRSs (“EUR‐PRS”, “AA‐PRS”).
Results
The full model (LOAD ~ CH‐PRS + sex + age + APOE‐ɛ4), achieved an AUC = 74% (ORCH‐PRS = 1.51 95%CI = 1.36–1.68), raising to >75% in APOE‐ɛ4 non‐carriers. CH‐PRS alone achieved an AUC = 72% in the autopsy cohort, raising to AUC = 83% in full model. Higher CH‐PRS was significantly associated with clinical LOAD in the replication CH cohort (OR = 1.61, 95%CI = 1.19–2.17) and significantly predicted conversion to LOAD (HR = 1.93, CI = 1.70–2.20) in the longitudinal subsample. EUR‐PRS and AA‐PRS reached lower prediction accuracy (AUC = 58% and 53%, respectively).
Interpretation
Enriching diversity in genetic studies is critical to provide an effective PRS in profiling LOAD risk across populations. ANN NEUROL 2021;90:366–376
Introduction
Blood‐based Alzheimer's disease (AD) biomarkers provide opportunities for community studies and across ethnic groups. We investigated blood biomarker concentrations in the Washington ...Heights‐Inwood Columbia Aging Project (WHICAP), a multi‐ethnic community study of aging and dementia.
Methods
We measured plasma amyloid beta (Aβ)40, Aβ42, total tau (t‐tau), phosphorylated tau (p‐tau)181, and p‐tau217, and neurofilament light chain (NfL) in 113 autopsied participants (29% with high AD neuropathological changes) and in 300 clinically evaluated individuals (42% with clinical AD). Receiver operating characteristics were used to evaluate each biomarker. We also investigated biomarkers as predictors of incident clinical AD.
Results
P‐tau181, p‐tau217, and NfL concentrations were elevated in pathologically and clinically diagnosed AD. Decreased Aβ42/Aβ40 ratio and increased p‐tau217 and p‐tau181 were associated with subsequent AD diagnosis.
Discussion
Blood‐based AD biomarker concentrations are associated with pathological and clinical diagnoses and can predict future development of clinical AD, providing evidence that they can be incorporated into multi‐ethnic, community‐based studies.
Blood‐based phosphorylated tau (Ptau) 181 and 217 biomarkers are sensitive and specific for Alzheimer's disease. In this racial/ethnically diverse cohort study, participants were classified as ...biomarker positive (Ptau+) or negative (Ptau‐) based on Ptau 181 and 217 concentrations and as cognitively impaired (Sym) or unimpaired (Asym). The four groups, Ptau‐/Asym, Ptau+/Asym, Ptau‐/Sym, and Ptau+/Sym, differed by age, APOE‐4 allele frequency, total tau, neurofilament light chain, and cortical thickness measured by MRI. Our results add to increasing evidence that plasma Ptau 181 and 217 concentrations are valid Alzheimer's disease biomarkers in diverse populations.
Introduction
We investigated metabolites in plasma to capture systemic biochemical changes associated with Alzheimer's disease (AD).
Methods
Metabolites in plasma were measured in 59 AD cases and 60 ...healthy participants of African American (AA), Caribbean Hispanic (CH), and non‐Hispanic white (NHW) ancestry using untargeted liquid‐chromatography–based ultra‐high‐resolution mass spectrometry. Metabolite differences between AD and healthy, ethnic groups and apolipoprotein E gene (APOE) ε4 status were analyzed. Untargeted network analysis identified pathways enriched in AD‐associated metabolites.
Results
A total of 5929 annotated metabolites were measured. Partial least squares discriminant analysis (PLS‐DA) inferred that AD clustered separately from healthy controls (area under the curve AUC = 0.9816); discriminating pathways included glycerophospholipid, sphingolipid, and non‐essential amino acid (alanine, aspartate, glutamate) metabolism. Metabolic features in AA clustered differently from CH and NHW (AUC = 0.9275), and differed between APOE ε4 carriers and non‐carriers (AUC = 0.9972).
Discussion
Metabolites, specifically lipids, were associated with AD, APOE ε4, and ethnic group. Metabolite profiling can identify perturbed AD pathways, but genetic and ancestral background need to be considered.
Objective
To identify rare causal variants underlying known loci that segregate with late‐onset Alzheimer's disease (LOAD) in multiplex families.
Methods
We analyzed whole genome sequences (WGS) from ...351 members of 67 Caribbean Hispanic (CH) families from Dominican Republic and New York multiply affected by LOAD. Members of 67 CH and additional 47 Caucasian families underwent WGS as a part of the Alzheimer's Disease Sequencing Project (ADSP). All members of 67 CH families, an additional 48 CH families and an independent CH case‐control cohort were subsequently genotyped for validation. Patients met criteria for LOAD, and controls were determined to be dementia free. We investigated rare variants segregating within families and gene‐based associations with disease within LOAD GWAS loci.
Results
A variant in AKAP9, p.R434W, segregated significantly with LOAD in two large families (OR = 5.77, 95% CI: 1.07–30.9, P = 0.041). In addition, missense mutations in MYRF and ASRGL1 under previously reported linkage peaks at 7q14.3 and 11q12.3 segregated completely in one family and in follow‐up genotyping both were nominally significant (P < 0.05). We also identified rare variants in a number of genes associated with LOAD in prior genome wide association studies, including CR1 (P = 0.049), BIN1 (P = 0.0098) and SLC24A4 (P = 0.040).
Conclusions and Relevance
Rare variants in multiple genes influence the risk of LOAD disease in multiplex families. These results suggest that rare variants may underlie loci identified in genome wide association studies.
Objective
To compute penetrance and recurrence risk using a genome‐wide PRS (including and excluding the APOE region) in families with Alzheimer's disease.
Methods
Genotypes from the National ...Institute on Aging Late‐Onset Alzheimer's Disease Family‐Based Study and a study of familial Alzheimer's disease in Caribbean Hispanics were used to compute PRS with and without variants in the 2 MB region flanking APOE. PRS was calculated in using clumping/thresholding and Bayesian methods and was assessed for association with Alzheimer's disease and age at onset. Penetrance and recurrence risk for carriers in highest and lowest PRS quintiles were compared separately within APOE‐ε4 carriers and non‐carriers.
Results
PRS excluding the APOE region was strongly associated with clinical and neuropathological diagnosis of AD. PRS association with AD was similar in participants who did not carry an APOE‐ε4 allele (OR = 1.74 1.53–1.91) compared with APOE‐ε4 carriers (1.53 1.4–1.68). Compared to the lowest quintile, the highest PRS quintile had a 10% higher penetrance at age 70 (p = 0.0006) and a 20% higher penetrance at age 80 (p < 10e‐05). Stratifying by APOE‐ε4 allele, PRS in the highest quintile was significantly more penetrant than the lowest quintile, both, within APOE‐ε4 carriers (14.5% higher at age 80, p = 0.002) and non‐carriers (26% higher at 80, p < 10e‐05). Recurrence risk for siblings conferred by a co‐sibling in the highest PRS quintile increased from 4% between the ages of 65–74 years to 39% at age 85 and older.
Interpretation
PRS can be used to estimate penetrance and recurrence risk in familial Alzheimer's disease among carriers and non‐carries of APOE‐ε4.
Objective
In the context of late‐onset Alzheimer's disease (LOAD) over 20 genes have been identified but, aside APOE, all show small effect sizes, leaving a large part of the genetic component ...unexplained. Admixed populations, such as Caribbean Hispanics, can provide a valuable contribution because of their unique genetic profile and higher incidence of the disease. We aimed to identify novel loci associated with LOAD.
Methods
About 4514 unrelated Caribbean Hispanics (2451 cases and 2063 controls) were selected for genome‐wide association analysis. Significant loci were further tested in the expanded cohort that also included related family members (n = 5300). Two AD‐like transgenic mice models (J20 and rTg4510) were used to study gene expression. Independent data sets of non‐Hispanic Whites and African Americans were used to further validate findings, along with publicly available brain expression data sets.
Results
A novel locus, rs75002042 in FBXL7 (5p15.1), was found genome‐wide significant in the case–control cohort (odd ratio OR = 0.61, P = 6.19E‐09) and confirmed in the related members cohorts (OR = 0.63, P = 4.7E‐08). Fbxl7 protein was overexpressed in both AD‐like transgenic mice compared to wild‐type littermates. Publicly available microarray studies also showed significant overexpression of Fbxl7 in LOAD brains compared to nondemented controls. single‐nucleotide polymorphism (SNP) rs75002042 was in complete linkage disequilibrium with other variants in two independent non‐Hispanic White and African American data sets (0.0005 < P < 0.02) used for replication.
Interpretation
FBXL7, encodes a subcellular protein involved in phosphorylation‐dependent ubiquitination processes and displays proapoptotic activity. F‐box proteins also modulate inflammation and innate immunity, which may be important in LOAD pathogenesis. Further investigations are needed to validate and understand its role in this and other populations.
Introduction
Asymptomatic and mildly symptomatic dominantly inherited Alzheimer's disease mutation carriers (DIAD‐MC) are ideal candidates for preventative treatment trials aimed at delaying or ...preventing dementia onset. Brain atrophy is an early feature of DIAD‐MC and could help predict risk for dementia during trial enrollment.
Methods
We created a dementia risk score by entering standardized gray‐matter volumes from 231 DIAD‐MC into a logistic regression to classify participants with and without dementia. The score's predictive utility was assessed using Cox models and receiver operating curves on a separate group of 65 DIAD‐MC followed longitudinally.
Results
Our risk score separated asymptomatic versus demented DIAD‐MC with 96.4% (standard error = 0.02) and predicted conversion to dementia at next visit (hazard ratio = 1.32, 95% confidence interval CI: 1.15, 1.49) and within 2 years (area under the curve = 90.3%, 95% CI 82.3%–98.2%) and improved prediction beyond established methods based on familial age of onset.
Discussion
Individualized risk scores based on brain atrophy could be useful for establishing enrollment criteria and stratifying DIAD‐MC participants for prevention trials.
PDF
