Ethics Review began a decade ago with a mission to identify ethical concerns that hold back innovation and to promote solutions that would move the field forward. Over this time, blood biomarkers for brain pathology and medications that treat that pathology promise to transform research and care. A central problem is that the evidence needed to guide test interpretation and practice is accumulating and there are unanswered questions. At the same time, people living with and at risk for dementia want access to their test results and involvement in their care. We promote dialog among diverse people across many institutions through collaboration with the Advisory Group on Risk Evidence Education for Dementia (AGREEDementia.org). Over the years Ethics Review continues to publish these dialogs and solutions to overcome the paralysis of indecision and ethical concerns.
Abstract Introduction One goal of the Longitudinal Early Onset Alzheimer's Disease Study (LEADS) is to define the fluid biomarker characteristics of early‐onset Alzheimer's disease (EOAD). Methods Cerebrospinal fluid (CSF) concentrations of Aβ1‐40, Aβ1‐42, total tau (tTau), pTau181, VILIP‐1, SNAP‐25, neurogranin (Ng), neurofilament light chain (NfL), and YKL‐40 were measured by immunoassay in 165 LEADS participants. The associations of biomarker concentrations with diagnostic group and standard cognitive tests were evaluated. Results Biomarkers were correlated with one another. Levels of CSF Aβ42/40, pTau181, tTau, SNAP‐25, and Ng in EOAD differed significantly from cognitively normal and early‐onset non‐AD dementia; NfL, YKL‐40, and VILIP‐1 did not. Across groups, all biomarkers except SNAP‐25 were correlated with cognition. Within the EOAD group, Aβ42/40, NfL, Ng, and SNAP‐25 were correlated with at least one cognitive measure. Discussion This study provides a comprehensive analysis of CSF biomarkers in sporadic EOAD that can inform EOAD clinical trial design.
The Longitudinal Early-Onset Alzheimer's Disease Study (LEADS) aims to enroll and study participants with sporadic early-onset Alzheimer's disease (EOAD) or early-onset non-Alzheimer's dementia (EOnonAD). Study exclusion criteria include having two or more first degree relatives with early-onset dementia in absence of genetic screening. LEADS conducts genetic screening for EOAD/EOnonAD participants to identify those with known pathogenic mutations and disenroll subjects eligible for the Dominantly Inherited Alzheimer Network Trials Unit (DIAN-TU) and the ARTFL-LEFFTDS Longitudinal Frontotemporal Lobar Degeneration (ALLFTD), and to prioritize EOAD/EOnonAD without known mutations for follow up and participation in clinical trials. Five genes were screened for known pathogenic mutations, amyloid beta precursor protein (APP), presenilin 1 (PSEN1), presenilin 2 (PSEN2), granulin precursor (GRN), and microtubule associated protein tau (MAPT). Participants were also screened for repeat expansion in C9orf72-SMCR8 complex subunit (C9orf72). Pathogenic mutations for GRN and MAPT were curated from the Human Gene Mutation Database (HGMD), ClinVar, and the Leiden Open Variation Database. Pathogenic mutations for APP, PSEN1, and PSEN2 were obtained from the DIAN-TU Trial Eligible List. Whole exome sequencing (WES) was performed at the Center for Medical Genomics at Indiana University School of Medicine, and processed using GenomeAnalysisToolkit (GATK) best practices. C9orf72 repeat expansion was tested for using repeat primed PCR at the Emory Center for Neurodegenerative Disease. Of the 150 participants screened for mutations and 144 screened for C9orf72 repeat expansion, three individuals with pathogenic mutations (one heterozygous for PSEN1, c.487C>T, p.His163Tyr; one heterozygous for GRN c.933+1G>C; and one heterozygous for GRN c.1145delC, p.Thr382Serfs*30) and one C9orf72 pathogenic repeat expansion were identified. Mutation carriers were White non-Hispanic with age-at-onset between 55 and 58 years, Clinical Dementia Rating (CDR) scale global score of 0.5 or 1, and Mini-Mental State Examination (MMSE) score between 25-28. Two mutation carriers had Apolipoprotein E (APOE) genotypes of ε3/ε3, while two were ε3/ε4. Strict adherence to the current LEADS inclusion/exclusion criteria assures that most cognitively impaired LEADS participants do not have a known pathogenic mutation, and that this cohort may be enriched for novel early-onset dementia-related pathogenic mutations.
Several genome-wide association studies (GWAS) have associated variants in late-onset Alzheimer disease (LOAD) susceptibility genes; however, these single nucleotide polymorphisms (SNPs) have very modest effects, suggesting that single SNP approaches may be inadequate to identify genetic risks. An alternative approach is the use of multilocus genotype patterns (MLGPs) that combine SNPs at different susceptibility genes.Using data from 1,365 subjects in the National Institute on Aging Late-Onset Alzheimer's Disease Family Study, we conducted a family-based association study in which we tabulated MLGPs for SNPs at CR1, BIN1, CLU, PICALM, and APOE. We used generalized estimating equations to model episodic memory as the dependent endophenotype of LOAD and the MLGPs as predictors while adjusting for sex, age, and education.Several genotype patterns influenced episodic memory performance. A pattern that included PICALM and CLU was the strongest genotypic profile for lower memory performance (β = -0.32, SE = 0.19, p = 0.021). The effect was stronger after addition of APOE (p = 0.016). Two additional patterns involving PICALM, CR1, and APOE and another pattern involving PICALM, BIN1, and APOE were also associated with significantly poorer memory performance (β = -0.44, SE = 0.09, p = 0.009 and β = -0.29, SE = 0.07, p = 0.012) even after exclusion of patients with LOAD. We also identified genotype pattern involving variants in PICALM, CLU, and APOE as a predictor of better memory performance (β = 0.26, SE = 0.10, p = 0.010).MLGPs provide an alternative analytical approach to predict an individual's genetic risk for episodic memory performance, a surrogate indicator of LOAD. Identifying genotypic patterns contributing to the decline of an individual's cognitive performance may be a critical step along the road to preclinical detection of Alzheimer disease.
Investigation of learning slopes in early-onset dementias has been limited. The current study aimed to highlight the sensitivity of learning slopes to discriminate disease severity in cognitively normal participants and those diagnosed with early-onset dementia with and without β-amyloid positivity METHOD: Data from 310 participants in the Longitudinal Early-Onset Alzheimer's Disease Study (aged 41 to 65) were used to calculate learning slope metrics. Learning slopes among diagnostic groups were compared, and the relationships of slopes with standard memory measures were determined RESULTS: Worse learning slopes were associated with more severe disease states, even after controlling for demographics, total learning, and cognitive severity. A particular metric-the learning ratio (LR)-outperformed other learning slope calculations across analyses CONCLUSIONS: Learning slopes appear to be sensitive to early-onset dementias, even when controlling for the effect of total learning and cognitive severity. The LR may be the learning measure of choice for such analyses. Learning is impaired in amyloid-positive EOAD, beyond cognitive severity scores alone. Amyloid-positive EOAD participants perform worse on learning slopes than amyloid-negative participants. Learning ratio appears to be the learning metric of choice for EOAD participants.
Abstract Background Much of the genetic etiology of sporadic early onset Alzheimer’s disease and frontotemporal dementia is largely unknown. Genetic investigation using whole exome sequencing (WES) data in the Longitudinal Early Onset Alzheimer’s Disease Study (LEADS) aims to address this gap, with the hypothesis that some individuals with early onset cognitive impairment may carry pathogenic, potentially causative variants in Parkinson’s disease (PD) genes. Methods Whole exome sequencing data for cognitively impaired LEADS participants (N = 301) was processed using the GATK best practices pipeline with Sentieon software; joint‐called VCFs were annotated with Annovar, and the results were filtered to prioritize amino acid code‐altering variants with minor allele frequencies <1% that have not been reported as benign or likely benign in ClinVar. Variants in the acid beta‐glucocerebrosidase (GBA), leucine‐rich repeat kinase 2 (LRRK2), Parkin RBR E3 ubiquitin protein ligase (PRKN), PTEN‐induced putative kinase 1 (PINK1), protein kinase, interferon‐inducible double‐stranded rna‐dependent activator (PRKRA), and Parkinson disease 7, autosomal recessive early‐onset (PARK7) were reviewed. Heterozygous or homozygous carriers of variants meeting these criteria in GBA and LRRK2, as well as homozygous or potentially compound heterozygous variant carriers in the other genes, were reviewed for the presence of PD‐related symptoms documented with the National Alzheimer’s Coordinating Center (NACC) Uniform Data Set (UDS) collected at baseline (N = 283). Results There were no variants meeting inclusion criteria for PINK1, PARK7, PRKN, or PRKRA. However, we observed 21 individuals with predicted or reported functional variant(s) in GBA or LRRK2. The mean screening visit age for these carriers was 59 (range 53‐64), and all but two were amyloid positive. While only one case was documented with motor symptoms, several participants had peripheral nervous symptoms such as neuropathy. 17 carriers had amnestic‐type dementia, with similar frequency to non‐carriers. Conclusions While there are a small subset of individuals carrying functional variants in PD genes, they do not appear to substantially influence the phenotype of most cases at baseline. Future planned research efforts include assessing alpha synuclein pathology via alpha synuclein seeding assays, which will help clarify the potential role of mixed genetic etiology and pathology in risk for non‐familial early onset dementia.
Late onset AD (LOAD) is generally considered multifactorial and polygenic. However, some families have an unusually large number of affected persons that resemble a simple Mendelian autosomal dominant inheritance pattern (LOADED families). A few mutations in PSEN1 and PSEN2 have been associated with somewhat later onset, but these mutations are rare and do not account for the majority of these kindreds. Clinical, pathologic and genetic study of eight families with late onset multigenerational AD. Eight families have had 95 demented persons (BCR 21, BL 12, NRB 15, BEH 13, CJE 7, FBB 10, HTB 9, SGA 8) with mean age onset 71.7 years ± 8.3, mean age death 79.8 years ± 8.1, and duration 9.5 years ± 5.4. All families have 2-4 affected generations. The male/female ratio was nearly equal (46% male). There have been 32 autopsies in affected persons, all showing AD with neuritic plaques, Braak stage 4-6 and variable Lewy body (alpha-synuclein) pathology ranging from absent to diffuse. Three unaffected persons had no AD changes at autopsy. ApoE4 is clearly playing a role in these families, but does not explain all cases (9 had no e4 allele). The largest family (BCR) has no mutation in PSEN1. Further mutation analysis of APP, PSEN1, PSEN2 and linkage analysis are all in progress. These families are included in other studies such as the NIA LOAD Genetics Initiative. Familial late onset AD may have multiple distinct causes and some heavily involved families (LOADED) may have unknown autosomal dominant genes generating the disease in addition to ApoE.
Abstract Background Only a small percentage of early‐onset Alzheimer’s disease (EOAD) participants are known to carry autosomal dominant pathogenic variants in the amyloid beta precursor protein (APP) gene or in presenilin 1 or 2 (PSEN1/2); more research is needed to identify additional causative genetic variants. This study presents results of the initial genetic analyses in the Longitudinal Early Onset Alzheimer’s Disease Study (LEADS) and planned next steps. Methods Whole exome sequencing (WES) is being performed for all cognitively impaired participants, including individuals with EOAD or frontotemporal dementia. Sequencing data is processed using GATK best practices and all variants for APP , PSEN1/2 , progranulin (GRN), and microtubule associated protein tau (MAPT) are reviewed for previously reported pathogenic variants. C9ORF72 is also assessed for pathogenic repeat expansions. WES was analyzed with CANOES and CoNIFER for copy number variants (CNVs). WES data has been reviewed for reported pathogenic variants in other neurodegenerative disease‐associated genes. Gene burden testing is being done for the LEADS cases and age‐matched controls from the Parkinson’s Progression Markers Initiative for rare variants in these genes. Results To date, WES has been generated for 301 cases, and GWAS for 384 participants (290 cases, 89 controls). Reported pathogenic variants or repeat expansions in C9ORF72 , PSEN1 , GRN , and MAPT were identified in 2% of cases for the six screened genes. No CNVs were detected in APP, PSEN1/2 , GRN , or MAPT . Review also identified individuals with pathogenic variants or CNVs in genes linked with diseases including Parkinson’s disease and Niemann‐Pick disease, including reported or predicted pathogenic variants in GBA , LRRK2 , and SMPD1 . Surprisingly, results do not show enrichment of functional TREM2 variants compared to population frequency. Conclusions Initial results indicate that LEADS is strongly enriched for novel genetic risk and/or causative factors, as only 2% have a reported pathogenic variant or repeat expansion in APP , PSEN1/2 , GRN , MAPT , or C9ORF72 . Review of reported pathogenic variants in other neurodegenerative disease‐associated genes indicates that while a small portion of disease etiology may be explained by these variants, more research is needed to identify additional causative and risk factors contributing to EOAD.
Abstract Objective The Longitudinal Early‐Onset Alzheimer's Disease Study (LEADS) seeks to provide comprehensive understanding of early‐onset Alzheimer's disease (EOAD; onset <65 years), with the current study profiling baseline clinical, cognitive, biomarker, and genetic characteristics of the cohort nearing the data‐collection mid‐point. Methods Data from 371 LEADS participants were compared based on diagnostic group classification (cognitively normal [ n = 89], amyloid‐positive EOAD [ n = 212], and amyloid‐negative early‐onset non‐Alzheimer's disease [EOnonAD; n = 70]). Results Cognitive performance was worse for EOAD than other groups, and EOAD participants were apolipoprotein E ( APOE ) ε4 homozygotes at higher rates. An amnestic presentation was common among impaired participants (81%), with several clinical phenotypes present. LEADS participants generally consented at high rates to optional trial procedures. Conclusions We present the most comprehensive baseline characterization of sporadic EOAD in the United States to date. EOAD presents with widespread cognitive impairment within and across clinical phenotypes, with differences in APOE ε4 allele carrier status appearing to be relevant. HIGHLIGHTS Findings represent the most comprehensive baseline characterization of sporadic early‐onset Alzheimer's disease (EOAD) to date. Cognitive impairment was widespread for EOAD participants and more severe than other groups. EOAD participants were homozygous apolipoprotein E ( APOE ) ε4 carriers at higher rates than the EOnonAD group. Amnestic presentation predominated in EOAD and EOnonAD participants, but other clinical phenotypes were present.
