Background: TOMM40 ‘523 has been associated with cognitive performance and risk for developing Alzheimer’s disease independent of the effect of APOE genotype. Few studies have considered the longitudinal effect of this genotype on change in cognition over time. Objective: Our objective was to evaluate the relationship between TOMM40 genotype status and change in cognitive performance in the TOMMORROW study, which was designed to prospectively evaluate an algorithm that includes TOMM40 ‘523 for genetic risk for conversion to mild cognitive impairment. Methods: We used latent growth curve models to estimate the effect of TOMM40 allele carrier (short, very long) status on the intercept and slope of change in cognitive performance in four broad cognitive domains (attention, memory, executive function, and language) and a combined overall cognitive score over 30 months. Results: TOMM40 very long allele carriers had significantly lower baseline performance for the combined overall cognitive function score (B = –0.088, p = 0.034) and for the executive function domain score (B = –0.143, p = 0.013). Slopes for TOMM40 very long carriers had significantly greater increases over time for the executive function domain score only. In sensitivity analyses, the results for executive function were observed in participants who remained clinically stable, but not in those who progressed clinically over the study duration. Conclusions: Our results add to the growing body of evidence that TOMM40, in the absence of APOE ɛ4, may contribute to cognitive changes with aging and dementia and support the view that mitochondrial function is an important contributor to Alzheimer’s disease risk.

Alzheimer's disease is a quintessential 'unmet medical need', accounting for ∼65% of progressive cognitive impairment among the elderly, and 700,000 deaths in the United States in 2020. In 2019, the cost of caring for Alzheimer's sufferers was $244B, not including the emotional and physical toll on caregivers. In spite of this dismal reality, no treatments are available that reduce the risk of developing AD or that offer prolonged mitiagation of its most devestating symptoms. This review summarizes key aspects of the biology and genetics of Alzheimer's disease, and we describe how pioglitazone improves many of the patholophysiological determinants of AD. We also summarize the results of pre-clinical experiments, longitudinal observational studies, and clinical trials. The results of animal testing suggest that pioglitazone can be corrective as well as protective, and that its efficacy is enhanced in a time- and dose-dependent manner, but the dose-effect relations are not monotonic or sigmoid. Longitudinal cohort studies suggests that it delays the onset of dementia in individuals with pre-existing type 2 diabetes mellitus, which small scale, unblinded pilot studies seem to confirm. However, the results of placebo-controlled, blinded clinical trials have not borne this out, and we discuss possible explanations for these discrepancies.

Background The identification of people at risk of cognitive impairment is essential for improving recruitment in secondary prevention trials of Alzheimer's disease. We aimed to test and qualify a biomarker risk assignment algorithm (BRAA) to identify participants at risk of developing mild cognitive impairment due to Alzheimer's disease within 5 years, and to evaluate the safety and efficacy of low-dose pioglitazone to delay onset of mild cognitive impairment in these at-risk participants. Methods In this phase 3, multicentre, randomised, double-blind, placebo-controlled, parallel-group study, we enrolled cognitively healthy, community living participants aged 65-83 years from 57 academic affiliated and private research clinics in Australia, Germany, Switzerland, the UK, and the USA. By use of the BRAA, participants were grouped as high risk or low risk. Participants at high risk were randomly assigned 1:1 to receive oral pioglitazone (0.8 mg/day sustained release) or placebo, and all low-risk participants received placebo. Study investigators, site staff, sponsor personnel, and study participants were masked to genotype, risk assignment, and treatment assignment. The planned study duration was the time to accumulate 202 events of mild cognitive impairment due to Alzheimer's disease in White participants who were at high risk (the population on whom the genetic analyses that informed the BRAA development was done). Primary endpoints were time-to-event comparisons between participants at high risk and low risk given placebo ( for the BRAA objective), and between participants at high risk given pioglitazone or placebo (for the efficacy objective). The primary analysis included all participants who were randomly assigned, received at least one dose of study drug, and had at least one valid post-baseline visit, with significance set at p=0.01. The safety analysis included all participants who were randomly assigned and received at least one dose of study medication. An efficacy futility analysis was planned for when approximately 33% of the anticipated events occurred in the high-risk, White, non-Hispanic or Latino group. This trial is registered with ClinicalTrials.gov, NCT01931566. Findings Between Aug 28, 2013, and Dec 21, 2015, we enrolled 3494 participants (3061 at high risk and 433 at low risk). Of those participants, 1545 were randomly assigned to pioglitazone and 1516 to placebo. 1104 participants discontinued treatment (464 assigned to the pioglitazone group, 501 in the placebo high risk group, and 139 in the placebo low risk group). 3399 participants had at least one dose of study drug or placebo and at least one post-baseline follow-up visit, and were included in the efficacy analysis. 3465 participants were included in the safety analysis (1531 assigned to the pioglitazone group, 1507 in the placebo high risk group, and 427 in the placebo low risk group). In the full analysis set, 46 (3.3%) of 1406 participants at high risk given placebo had mild cognitive impairment due to Alzheimer's disease, versus four (1.0%) of 402 participants at low risk given placebo (hazard ratio 3.26, 99% CI 0.85-12.45; p=0.023). 39 (2.7%) of 1430 participants at high risk given pioglitazone had mild cognitive impairment, versus 46 (3.3%) of 1406 participants at high risk given placebo (hazard ratio 0.80, 99% CI 0.45-1.40; p=0.307). In the safety analysis set, seven (0.5%) of 1531 participants at high risk given pioglitazone died versus 21 (1.4%) of 1507 participants at high risk given placebo. There were no other notable differences in adverse events between groups. The study was terminated in January, 2018, after failing to meet the non-futility threshold. Interpretation Pioglitazone did not delay the onset of mild cognitive impairment. The biomarker algorithm demonstrated a 3 times enrichment of events in the high risk placebo group compared with the low risk placebo group, but did not reach the pre-specified significance threshold. Because we did not complete the study as planned, findings can only be considered exploratory. The conduct of this study could prove useful to future clinical development strategies for Alzheimer's disease prevention studies. Copyright (C) 2021 Elsevier Ltd. All rights reserved.

AbstractBackgroundA challenge with AD prevention is the timely identification of subjects at risk of cognitive symptom onset, mitigating prohibitive costs associated with the trial size and duration. A biomarker risk assignment algorithm (BRAA) consisting of genotypes at the apolipoprotein E (APOE) and translocase of outer mitochondrial membrane 40 homolog (TOMM40) rs10524523 loci (‘523) and current age was developed to enrich the TOMMORROW delay of AD onset clinical study. ‘523 is a poly‐T homopolymer of 14 to 50 residues. For the BRAA, the alleles were categorized by T length as “short” (S: <21), “long” (L: 21‐29), or “very long” (VL: >29).MethodThe TOMMORROW study (NCT 01931566) provided a large dataset to assess APOE‐‘523 haplotypes to improve the performance of the BRAA. The original BRAA used phased genetic information to determine risk categories (developed in 150 individuals, verified in 1018 individuals). Because phased haplotype data were not available from the samples genotyped in the TOMMORROW study, an optimized calibration was performed using APOE 3/3 and 4/4 homozygous individuals (n=1625). By maximizing the genetic congruency between the APOE and ‘523 genotypes, the calibration of the ‘523 categorical boundaries was optimized.ResultFrom these haplotype data, the ’523 categorical assignments were optimized to S: <19; L: 19‐31; and VL: >31. When these optimized categorical assignments were applied retrospectively to the TOMMORROW study cohort (n=1803), the hazard ratio for the time‐to‐event comparison between the high and low risk placebo groups improved from 3.3 (95% confidence interval [CI] 1.2‐9.0, P=0.023) to 4.3 (95%CI 1.3‐13.7, P=0.015). Applying the refined BRAA to a future delay of AD onset clinical trial would reduce enrollment by 26% for a 5‐year interventional study versus an all‐comers enrollment strategy. Furthermore, a streamlined, kit‐based genotyping assay for APOE and TOMM40 ‘523 was evaluated and found to yield congruent results with the sequencing‐based method used for genotyping in the TOMMORROW clinical trial.ConclusionUsing phase 3 clinical trial data, the TOMMORROW BRAA demonstrated the ability to enrich delay of onset/prevention of AD studies for subjects more likely to develop cognitive symptom onset during an acceptable timeframe with significant clinical trial cost savings.

Objective To test the hypothesis that rs573116164 will have disease-modifying effects in patients with superoxide dismutase 1 (SOD1) familial amyotrophic lateral sclerosis (fALS), we characterized rs573116164 within a cohort of 190 patients with fALS and 560 healthy age-matched controls to assess the variant for association with various measures of disease. Methods Using a previously described bioinformatics evaluation algorithm, a polymorphic short structural variant associated with SOD1 was identified according to its theoretical effect on gene expression. An 12–18 poly-T repeat (rs573116164) within the 3′ untranslated region of serine and arginine rich proteins-related carboxy terminal domain associated factor 4 (SCAF4), a gene that is adjacent to SOD1, was assessed for disease association and influence on survival and age at onset in an fALS cohort using PCR, Sanger sequencing, and capillary separation techniques for allele detection. Results In a North American cohort of predominantly SOD1 fALS patients (n =190) and age-matched healthy controls (n = 560), we showed that carriage of an 18T SCAF4 allele was associated with disease within this cohort (odds ratio [OR] 6.6; 95% confidence interval [CI] 3.9–11.2; p = 4.0e-11), but also within non-SOD1 cases (n = 27; OR 5.3; 95% CI 1.9–14.5; p = 0.0014). This finding suggests genetically SOD1-independent effects of SCAF4 on fALS susceptibility. Furthermore, carriage of an 18T allele was associated with a 26-month reduction in survival time (95% CI 6.6–40.8; p = 0.014), but did not affect age at onset of disease. Conclusions The findings in this fALS cohort suggest that rs573116164 could have SOD1-independent and broader relevance in ALS, warranting further investigation in other fALS and sporadic ALS cohorts, as well as studies of functional effects of the 18T variant on gene expression.

The underlying genetic and molecular mechanisms that drive amyotrophic lateral sclerosis (ALS) remain poorly understood. Structural variants within the genome can play a significant role in neurodegenerative disease risk, such as the repeat expansion in C9orf72 and the tri-nucleotide repeat in ATXN2, both of which are associated with familial and sporadic ALS. Many such structural variants reside in uncharacterized regions of the human genome, and have been under studied. Therefore, characterization of structural variants located in and around genes associated with ALS could provide insight into disease pathogenesis, and lead to the discovery of highly informative genetic tools for stratification in clinical trials. Such genomic variants may provide a deeper understanding of how gene expression can affect disease etiology, disease severity and trajectory, patient response to treatment, and may hold the key to understanding the genetics of sporadic ALS. This article outlines the current understanding of amyotrophic lateral sclerosis genetics and how structural variations may underpin some of the missing heritability of this disease.

Alzheimer's disease (AD) is a continuum with neuropathologies manifesting years before clinical symptoms; thus, AD research is attempting to identify more disease-modifying approaches to test treatments administered before full disease expression. Designing such trials in cognitively normal elderly individuals poses unique challenges. The TOMMORROW study was a phase 3 double-blind, parallel-group study designed to support qualification of a novel genetic biomarker risk assignment algorithm (BRAA) and to assess efficacy and safety of low-dose pioglitazone to delay onset of mild cognitive impairment due to AD. Eligible participants were stratified based on the BRAA (using TOMM40 rs 10524523 genotype, Apolipoprotein E genotype, and age), with high-risk individuals receiving low-dose pioglitazone or placebo and low-risk individuals receiving placebo. The primary endpoint was time to the event of mild cognitive impairment due to AD. The primary objectives were to compare the primary endpoint between high- and low-risk placebo groups (for BRAA qualification) and between high-risk pioglitazone and high-risk placebo groups (for pioglitazone efficacy). Approximately 300 individuals were also asked to participate in a volumetric magnetic resonance imaging substudy at selected sites. The focus of this paper is on the design of the study; study results will be presented in a separate paper. The design of the TOMMORROW study addressed many key challenges to conducting a dual-objective phase 3 pivotal AD clinical trial in presymptomatic individuals. Experiences from planning and executing the TOMMORROW study may benefit future AD prevention/delay-of-onset trials.

TOMMORROW was a phase 3, randomized, double-blind, placebo-controlled, parallel-group global clinical trial designed to assess a genetic biomarker risk assignment algorithm (BRAA) for risk prediction of mild cognitive impairment (MCI) due to Alzheimer's disease (AD) and to evaluate the efficacy of pioglitazone 0.8 mg to delay MCI due to AD onset. BRAA testing at screening determined risk status. Cognitively normal high-risk subjects were randomized 1:1 to pioglitazone sustained release 0.8 mg once daily or placebo; low-risk subjects received placebo. Project partners completed informant interviews and questionnaires. Subjects were assessed every 6 months to collect a target of 202 primary endpoint events of incident MCI due to AD in Non-Hispanic/Latino Caucasians, the primary analysis population. Conversion events were determined by an independent adjudication committee and required meeting MCI due to AD core clinical criteria across two consecutive study visits. Co-primary endpoints compared time-to-event (TTE) between the two placebo groups (for BRAA) and between pioglitazone 0.8 mg and placebo in the high-risk group (for drug efficacy). The study was terminated following efficacy futility in January 2018, after approximately one-third of the target event count had occurred. 24,235 individuals were screened, and 3494 randomized (95% non-Hispanic/Latino Caucasians). Most enrolled subjects (mean age = 74.0 years) were APOE ε3/3 or ε3/4. Overall, 96 conversion events occurred. MCI due to AD incidence was greater in the high- vs low-risk placebo group (3.3% vs 1.0% 95% confidence interval [CI] 0.009, 0.036). Converters’ mean age was 76.4 years, and most were ε3/ε4-L/VL (n=22; 23%), ε3/4-S/L (n=21; 22%), and ε3/3-S/VL (n=22; 23%). For BRAA TTE, adjusted hazard ratio (high vs. low) in the primary analysis population (95%CI) = 3.26 (1.177, 9.040). For drug efficacy TTE, adjusted hazard ratio (95%CI) = 0.8 (0.52, 1.23). Pioglitazone was safe and well-tolerated overall. Additional subgroup analyses will be presented. Although terminated early, TOMMORROW demonstrated that the BRAA is an effective enrichment tool and studies at early stages of the cognitive decline continuum are feasible. Lessons learned will benefit future AD clinical trials adopting early intervention strategies.

One challenge to interventional trials designed to delay the clinical onset of very early symptoms of Alzheimer's disease (AD) is determining meaningful endpoints to detect decline in putatively healthy individuals. The TOMMORROW study (NCT01931566) assessed the value of a biomarker algorithm to identify cognitively healthy adults at near-term risk of developing MCI-AD. The study used a battery of neuropsychological tests and incorporated a time-to-event design over approximately 4 years to define the time of MCI-AD conversion. We describe baseline (pre-randomization) cognitive performance results, underscoring the utility of the selected battery to enable the exclusion of cognitively impaired individuals and the effects of gender, age, and education on test performance. At the time of last subject in (December 2015) 4565 individuals with a mean age of 74.4 years (SD=5.31; range 65–83) had undergone baseline evaluation. Of these, 306 were baseline failures and were not enrolled in the study, primarily due to presence of a cognitive disorder. Neuropsychological performance was examined for men (n=1945) and women (n=2314) separately on key outcome measures for each of the 9 tests (MMSE, BVMT-R, CVLT-II, Lexical fluency, Semantic fluency, MINT, Clock Drawing, Digit Span, and Trail Making). We also examined the impact of low education (n=1143), defined as less than a high school education, on the above measures. Demographic differences were considered in the normative data used by investigators and adjudicators who confirmed diagnostic status. Approximately 6.7% of individuals were not eligible for randomization, primarily because of baseline cognitive impairment. At pre-randomization baseline, women scored significantly higher than men on verbal learning (CVLT-total p<0.001) and on some tests of executive function (Trails A p<0.0004; Trails B, p<0.001) after controlling for age and education. By contrast, men performed better on visual naming (MINT p<0.001). Low education was significantly associated with poorer performance on all tests in men and women except for Digit Span. The TOMMORROW study employed a neuropsychological battery to ensure the enrollment of only cognitively normal subjects; approximately 300 subjects failed to meet study randomization criteria. Patterns of gender and prior education testing effects were observed that are similar to previous studies.

Abstract Introduction Mitochondrial dysfunction is implicated in the pathophysiology of Alzheimer's disease (AD). Accordingly, drugs that positively influence mitochondrial function are being evaluated in delay‐of‐onset clinical trials with at‐risk individuals. Such ongoing clinical research can be advanced by developing a better understanding of how these drugs affect intermediate brain phenotypes associated with both AD risk and pathophysiology. Methods Using a randomized, parallel‐group, placebo‐controlled design in 55 healthy elderly volunteers, we explored the effects of oral, low‐dose pioglitazone, a thiazolidinedione with promitochondrial effects, on hippocampal activity measured with functional magnetic resonance imaging during the encoding of novel face–name pairs. Results Compared with placebo, 0.6 mg of pioglitazone (but not 2.1 mg, 3.9 mg, or 6.0 mg) administered daily for 14 days was associated with significant increases in right hippocampal activation during encoding of novel face–name pairs at day 7 and day 14, relative to baseline. Discussion Our exploratory analyses suggest that low‐dose pioglitazone has measurable effects on mnemonic brain function associated with AD risk and pathophysiology.

Development of novel therapies for Late Onset Alzheimer's disease (LOAD) requires the translation of genetic associations to a mechanistic understanding. Specific challenges include finding causal genetic variants in regions of high linkage disequilibrium (LD) and identifying their targets genes that contribute to LOAD pathogenesis. These models are based on diverse data types and a broad definition of genetic variation. Moreover, clinical trial design needs to adapt to new approaches that address the heterogeneity of LOAD and an emphasis on prevention. A strategy for progressing from GWAS association signals and phylogenetic analysis to target genes and specific causal variants for LOAD is presented. Using the region of chromosome 19 that is in high LD with the APOE coding variants we applied a strategy that combines in silico, in vitro, in vivo and clinical approaches to investigate the complex genetic architecture and regulatory structure. Phylogenetic analysis was used to identify specific genetic variants and haplotypes associated with LOAD risk. These variants were tested for effects on gene expression in brain tissues and in reporter systems. Further analyses included epigenomic characterization using bioinformatics tools and genomic technologies to define regulatory elements. Specific evolutionary signatures representing complex haplotypes including structural variants are mapped to phenotypes related to clinical AD including age of onset, likelihood to develop disease in a 5-year time frame, and cognitive decline in healthy aging. Genetic variants and phased haplotypes in the APOE-TOMM40 region exhibit regional effects on gene expression and DNA methylation. Integration of computational biology analysis with laboratory experiments allow us to progress from candidate causal genetic variants to mechanism-based assays using CRISPR/cas-9 editing to test causality and direct functional effects. Computational and experimental genetic approaches must be integrated into a cohesive strategy to unravel the etiology of LOAD. We show how molecular phylogenetic analysis coupled with experiments to investigate the cis-genetic regulation of genes are used to investigate the initiating events of LOAD pathophysiology and enable prevention clinical trials. Implications for discovery of new LOAD targets and translational research will be discussed.

Alzheimer's disease (AD) therapy approaches have evolved to shift focus from treating symptomatic patients to delaying clinical onset. Intervention at the pre-symptomatic stage of the AD continuum requires the ability to reliably discern when individuals transition from being cognitively normal to having mild cognitive impairment (MCI)-due-to-AD. The TOMMORROW study is a global, multicenter, randomized, double-blind, placebo-controlled clinical trial, with a novel study endpoint event that operationalizes core clinical criteria for MCI-due-to-AD. The MCI event criteria must be met at two consecutive study visits approximately 6 months apart. The study duration is event driven, requiring accrual of 202 MCI-due-to-AD events. Cognitively normal subjects (65-83 years) at baseline are assessed in person every 6 months to measure cognitive and functional status. Neuropsychologists are part of the study team at each site. The study utilizes normative standards to guide diagnostic inferences, investigator's clinical judgment, predefined sensitive cognitive trigger criteria, a prescribed subject flow process, and an independent adjudication committee to decide whether subjects have developed MCI-due-to-AD. The adjudication committee includes individuals with clinical expertise in neurology, psychiatry, and neuropsychology to provide consistent event harmonization across multiple countries and cultures over a multi-year timeframe. Unanimous committee agreement is required to determine an event, and formal mechanisms are in place to resolve differences in opinion. TOMMORROW enrolled a total of 3494 subjects. Currently, approximately 200 subjects are in the pipeline at any point in time as potential cases for review. Approximately 65 of these will meet criteria for adjudication. As of early December 2017, the adjudication committee had reviewed and provided endpoint decisions on over 500 cases. The average cycle time from subjects’ most recent study visit to adjudication outcome for Q4 in 2017 was 39 days: 21 days less than the expected timeframe. This procedural efficiency allows rapid determination of subject disposition. The process for determining the MCI-due-to-AD event is central to the phase 3 registration clinical trial, which targets the earliest transition point to clinically symptomatic AD. As more AD clinical trials move toward early intervention strategies, lessons learned from the TOMMORROW study process will be an invaluable resource.

INTRODUCTION:Assessment of preclinical Alzheimer's disease (AD) requires reliable and validated methods to detect subtle cognitive changes. The battery of standardized cognitive assessments that is used for diagnostic criteria for mild cognitive impairment due to AD in the TOMMORROW study have only been fully validated in English-speaking countries. We conducted a validation and normative study of the German language version of the TOMMORROW neuropsychological test battery, which tests episodic memory, language, visuospatial ability, executive function, and attention.METHODS:German-speaking cognitively healthy controls (NCs) and subjects with AD were recruited from a memory clinic at a Swiss medical center. Construct validity, test-retest, and alternate form reliability were assessed in NCs. Criterion and discriminant validities of the cognitive measures were tested using logistic regression and discriminant analysis. Cross-cultural equivalency of performance of the German language tests was compared with English language tests.RESULTS:A total of 198 NCs and 25 subjects with AD (aged 65-88 years) were analyzed. All German language tests discriminated NCs from persons with AD. Episodic memory tests had the highest potential to discriminate with almost twice the predictive power of any other domain. Test-retest reliability of the test battery was adequate, and alternate form reliability for episodic memory tests was supported. For most tests, age was a significant predictor of group effect sizes; therefore, normative data were stratified by age. Validity and reliability results were similar to those in the published US cognitive testing literature.DISCUSSION:This study establishes the reliability and validity of the German language TOMMORROW test battery, which performed similarly to the English language tests. Some variations in test performance underscore the importance of regional normative values. The German language battery and normative data will improve the precision of measuring cognition and diagnosing incident mild cognitive impairment due to AD in clinical settings in German-speaking countries.

Interventional approaches to Alzheimer's disease (AD) are broadening to include delay-of-onset and prevention strategies, creating substantial challenges to retain study subjects over typically very long study treatment durations. Studies of this type have a different risk-benefit calculus for cognitively normal subjects. Minimizing dropout is essential to scientific integrity and interpretable results. The TOMMORROW study (NCT01931566) is an interventional trial, designed to evaluate over approximately 4 years: 1) the usefulness of an algorithm to identify individuals at near term risk for MCI-AD and 2) effectiveness of low-dose pioglitazone in delaying onset of MCI-AD. Mindful of sources of dropouts in longitudinal neurocognitive designs, we adopted several diverse approaches to participant retention in this international clinical trial. The TOMMORROW study closely monitors site performance, which includes monthly metrics of early termination (ET). With the aid of a retention-focused vendor company, the study works with the sites to develop approaches to mitigate preventable ETs in a way that is responsive, flexible, and site specific. Methods that focus on both the subjects and their project partners include newsletters, phone calls, transportation facilitation, web site, and others. Additionally, coordinators, raters, site principal investigators, and neuropsychologists are involved in regular group calls, face to face meetings, and encouraged to share best practices to aid retention. All current TOMMORROW subjects have passed the one-year study milestone with many now in years 2 and 3. ET is highest in the first year with overall rates remaining low and on track with initial statistical projections. Reasons for drop-out are consistent across the study interval, with most ET due to voluntary withdrawals (49%), development of medical conditions (28%), loss to follow-up (4%), protocol deviation (4%), and a variety of other reasons (15%). The TOMMORROW study has adopted a multifaceted approach to enhance subject retention that is site-specific, focuses on both the subjects and their project partners, and provides site investigators with tools necessary to keep participants engaged in a long clinical trial. Specifics to be discussed may prove useful to future clinical trials aiming to identify interventions that ameliorate the cognitive decline of AD.

INTRODUCTION:The study investigated the role of neuropathologies in the relationship between TOMM40 '523 genotype and late-life cognitive decline.METHODS:Participants were community-dwelling older persons who had annual cognitive assessments and brain autopsies after death. Genotyping used DNA from peripheral blood or postmortem brain tissue. Linear mixed models assessed the extent to which the association of '523 genotype with cognitive decline is attributable to neuropathologies.RESULTS:Relative to ε3/ε3 homozygotes with '523-S/VL or '523-VL/VL genotype, both '523-L carriers and ε3/ε3 homozygotes with '523-S/S genotype had faster cognitive decline. The association of '523-L with cognitive decline was attenuated and no longer significant after controlling for Alzheimer's and other neuropathologies. By contrast, the association of '523-S/S was unchanged.DISCUSSION:There are two distinct TOMM40 '523 signals in relation to late-life cognitive decline. One signal primarily acts through AD and other common neuropathologies, whereas the other operates through a different mechanism.

INTRODUCTION:Dementia is one of the major health threats to our aging society, and Alzheimer's disease (AD) is the leading cause. In Japan, ∼15% of the elderly population has dementia. The apolipoprotein E (APOE) genotype and a polymorphism (rs10524523) in the translocase of outer mitochondrial membrane 40 (TOMM40) gene have been associated with the age of onset of AD. However, differences in allele frequencies of these markers in different ethnic populations are not well known.METHODS:Whole blood samples were collected from 300 Japanese subjects, and genomic DNA was extracted to determine APOE alleles and TOMM40 rs10524523 genotypes.RESULTS:Our results indicated that the APOE ε3-TOMM40'523 short haplotype is less frequent in Japanese subjects than in Caucasians, whereas the APOE ε3-TOMM40'523 long and APOE ε3-TOMM40'523 very long haplotypes are more frequent in Japanese subjects than in Caucasians. We also showed that the APOE ε4-TOMM40'523 short haplotype, which was noted to be frequently observed in African Americans, was also found in the Japanese population, although it is extremely rare in the Caucasian population.DISCUSSION:A biomarker risk assignment algorithm, using a combination of APOE, TOMM40'523 genotype, and age, has been developed to assign near-term risk for developing the onset of mild cognitive impairment due to AD and is being used as an enrichment tool in an ongoing delay-of-onset clinical trial. Understanding the characterization of APOE and TOMM40 allele frequencies in the Japanese population is the first step in developing a risk algorithm for AD research and clinical applications for AD prevention in Japan.