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.
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
BACKGROUND
Alzheimer's disease (AD) biomarkers can help differentiate cognitively unimpaired (CU) individuals from mild cognitive impairment (MCI) and dementia. The role of AD biomarkers in ...predicting cognitive impairment and AD needs examination.
METHODS
In 628 CU individuals from a multi‐ethnic cohort, amyloid beta (Aβ)42, Aβ40, phosphorylated tau‐181 (p‐tau181), glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL) were measured in plasma.
RESULTS
Higher baseline levels of p‐tau181/Aβ42 ratio were associated with an increased risk of incident dementia. A biomarker pattern (with elevated Aβ42/Aβ40 but low p‐tau181/Aβ42) was associated with decreased dementia risk. Compared to CU, participants who developed MCI or dementia had a rapid decrease in this protective biomarker pattern reflecting AD‐specific pathological change.
DISCUSSION
Elevated levels of AD biomarker p‐tau181/Aβ42, by itself or combined with a low Aβ42/Aβ40 level, predicts clinically diagnosed AD. Individuals with a rapid change in these biomarkers may need close monitoring for the potential downward trajectory of cognition.
Highlights
We discuss a multi‐ethnic, urban community study of elderly individuals.
The study consisted of a longitudinal assessment over 6 years with repeated clinical assessments.
The study used blood‐based biomarkers as predictors of mild cognitive impairment and Alzheimer's disease.
Introduction
The National Institute on Aging Late‐Onset Alzheimer's Disease Family Based Study (NIA‐LOAD FBS) was established to study the genetic etiology of Alzheimer's disease (AD).
Methods
...Recruitment focused on families with two living affected siblings and a third first‐degree relative similar in age with or without dementia. Uniform assessments were completed, DNA was obtained, as was neuropathology, when possible. Apolipoprotein E (APOE) genotypes, genome‐wide single nucleotide polymorphism (SNP) arrays, and sequencing was completed in most families.
Results
APOE genotype modified the age‐at‐onset in many large families. Novel variants and known variants associated with early‐ and late‐onset AD and frontotemporal dementia were identified supporting an international effort to solve AD genetics.
Discussion
The NIA‐LOAD FBS is the largest collection of familial AD worldwide, and data or samples have been included in 123 publications addressing the genetic etiology of AD. Genetic heterogeneity and variability in the age‐at‐onset provides opportunities to investigate the complexity of familial AD.
Background
Recent studies have evaluated Alzheimer’s disease (AD) associated with cerebrovascular and cardiovascular risk factors. Stroke history mediates association between late‐onset AD and ...cardiovascular disease risk factors (Tosto et al., 2016). Our research investigated stroke as a potential moderator between polygenic risk score (PRS) and Alzheimer’s disease.
Method
Participants were enrolled in the multi‐ethnic Washington Heights‐Inwood Columbia Aging Project (WHICAP). 653 non‐Hispanic white and 2285 Caribbean Hispanic participants were included based on GWAS data and stroke status (self‐reported history of stroke or MRI‐visualized stroke). A concordance analysis assessed stroke group agreement. PRS from GWAS statistics was calculated for both populations. Following calculation of moderators by stroke status on population‐specific PRS, binomial logistic regression models were conducted. Model outcome was Alzheimer’s disease, which incorporated four diagnoses: Pure Alzheimer’s disease, Probable Alzheimer’s disease with Stroke, Alzheimer’s disease with Parkinsonism, and Atypical Alzheimer’s disease. Another set of models was conducted for the Caribbean Hispanic population towards a general outcome of Alzheimer’s disease alone.
Result
Concordance analyses among all 4987 WHICAP participants showed Cohen’s kappa of ‐0.033 and p of 0.001* (p* < 0.05), indicating no concordance between self‐reported and MRI‐visualized stroke groups; this is consistent with observation by Reitz et al., 2009. Within the Caribbean Hispanic population, MRI‐visualized stroke models for Alzheimer’s disease (four types) showed moderator significance (p of 0.002*, 0.007*, and 0.001* for Models 1, 2, 3 respectively) and MRI‐visualized stroke models towards generalized Alzheimer’s disease showed moderator significance (p of 0.152, 0.041*, and 0.020* for Models 1, 2, 3 respectively).
Conclusion
Stroke is likely to be an important moderator of PRS and Alzheimer’s disease risk in MRI‐visualized stroke models, while a self‐reported history of stroke was not related.
Identifying genes underlying memory function will help characterize cognitively resilient and high‐risk declining subpopulations contributing to precision medicine strategies. We estimated episodic ...memory trajectories in 35,245 ethnically diverse older adults representing eight independent cohorts. We conducted apolipoprotein E (APOE)‐stratified genome‐wide association study (GWAS) analyses and combined individual cohorts’ results via meta‐analysis. Three independent transcriptomics datasets were used to further interpret GWAS signals. We identified DCDC2 gene significantly associated with episodic memory (Pmeta = 3.3 x 10‐8) among non‐carriers of APOE ε4 (N = 24,941). Brain transcriptomics revealed an association between episodic memory maintenance and (1) increased dorsolateral prefrontal cortex DCDC2 expression (P = 3.8 x 10‐4) and (2) lower burden of pathological Alzheimer's disease (AD) hallmarks (paired helical fragment tau P = .003, and amyloid beta load P = .008). Additional transcriptomics results comparing AD and cognitively healthy brain samples showed a downregulation of DCDC2 levels in superior temporal gyrus (P = .007) and inferior frontal gyrus (P = .013). Our work identified DCDC2 gene as a novel predictor of memory maintenance.
Introduction
Progranulin (GRN) mutations occur in frontotemporal lobar degeneration (FTLD) and in Alzheimer's disease (AD), often with TDP‐43 pathology.
Methods
We determined the frequency of rs5848 ...and rare, pathogenic GRN mutations in two autopsy and one family cohort. We compared Braak stage, β‐amyloid load, hyperphosphorylated tau (PHFtau) tangle density and TDP‐43 pathology in GRN carriers and non‐carriers.
Results
Pathogenic GRN mutations were more frequent in all cohorts compared to the Genome Aggregation Database (gnomAD), but there was no evidence for association with AD. Pathogenic GRN carriers had significantly higher PHFtau tangle density adjusting for age, sex and APOE ε4 genotype. AD patients with rs5848 had higher frequencies of hippocampal sclerosis and TDP‐43 deposits. Twenty‐two rare, pathogenic GRN variants were observed in the family cohort.
Discussion
GRN mutations in clinical and neuropathological AD increase the burden of tau‐related brain pathology but show no specific association with β‐amyloid load or AD.
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.
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