The pattern of cortical thickness associated with executive dysfunction in MCI and SCC: The MEMENTO cohort.

BACKGROUND: The association between the pattern of cortical thickness (CT) and executive dysfunction (ED) in mild cognitive impairment (MCI) and subjective cognitive complaints (SCC) is still poorly understood. We aimed to investigate the association between CT and ED in a large French cohort (MEMENTO) of 2323 participants with MCI or SCC. METHODS: All participants with available CT and executive function data (verbal fluency and Trail Making Test [TMT]) were selected (n=1924). Linear regressions were performed to determine relationships between executive performance and the brain parenchymal fraction (BPF) and CT using FreeSurfer. RESULTS: The global executive function score was related to the BPF (sß: 0.091, P<0.001) and CT in the right supramarginal (sß: 0.060, P=0.041) and right isthmus cingulate (sß: 0.062, P=0.011) regions. Literal verbal fluency was related to the BPF (sß: 0.125, P<0.001) and CT in the left parsorbitalis region (sß: 0.045, P=0.045). Semantic verbal fluency was related to the BPF (sß: 0.101, P<0.001) and CT in the right supramarginal region (sß: 0.061, P=0.042). The time difference between the TMT parts B and A was related to the BPF (sß: 0.048, P=0.045) and CT in the right precuneus (sß: 0.073, P=0.019) and right isthmus cingulate region (sß: 0.054, P=0.032). CONCLUSIONS: In a large clinically based cohort of participants presenting with either MCI or SCC (a potential early stage of Alzheimer's disease [AD]), ED was related to the BPF and CT in the left pars orbitalis, right precuneus, right supramarginal, and right isthmus cingulate regions. This pattern of lesions adds knowledge to the conventional anatomy of ED and could contribute to the early diagnosis of AD.

Somatic Variants: New Kids on the Block in Human Immunogenetics.

Somatic variants are not inherited but acquired during an individual's lifetime, and individuals are increasingly considered as complex mosaics of genetically distinct cells. Whereas this concept is long-recognized in cancer, this review focuses on the growing role of somatic variants in immune cells in nonmalignant immune-related disorders, such as primary immunodeficiency and autoimmune diseases. Older case reports described somatic variants early in development, leading to large numbers of affected cells and severe phenotypes. Thanks to technological evolution, it is now feasible to detect somatic variants occurring later in life and affecting fewer cells. Hence, only recently is the scale at which somatic variants contribute to monogenic diseases being uncovered and is their contribution to complex diseases being explored systematically.

[Diagnostic approach to chronic kidney disease]. / Vignette diagnostique de l'étudiant. Approche diagnostique de la maladie rénale chronique.

Chronic kidney disease (CKD) affects ~7 % of the general population and is burdened with significant morbidity and mortality, especially cardiovascular disease. At the terminal stage, CKD requires demanding and costly treatments for the patient and the society, such as dialysis or kidney transplantation. The symptomatology of CKD is poor and unspecific, which complicates the identification and early management of patients with CKD. Diagnostic criteria for CKD include (1) renal morphological abnormality; and/or (2) proteinuria superior to150 mg/g creatinine; and/or (3) glomerular filtration rate (GFR) inferior to 60 ml/min/ 1.73 m². The persistence of these abnormalities for more than 3 months indicates the chronicity of the renal damage. Starting from an exemplary clinical case, we detail the diagnostic steps when faced with a suspicion of CKD.

: La maladie rénale chronique (MRC) touche ~7 % de la population générale et est grevée d'une morbi-mortalité, notamment cardiovasculaire, significative. à son stade terminal, la MRC nécessite des traitements lourds et coûteux pour le patient et pour la société, tels que la dialyse ou la transplantation rénale. La symptomatologie de la MRC est frustre et aspécifique, ce qui complique l'identification et la prise en charge précoce des patients insuffisants rénaux chroniques. Les critères diagnostiques de la MRC incluent (1) une anomalie morphologique rénale, et/ou (2) une protéinurie sup�rieur a 150 mg/g créatininurie, et/ou (3) un débit de filtration glomérulaire (DFG) inf�rieur a 60 ml/min/1,73 m². La persistance de ces anomalies pendant plus de 3 mois signe la chronicité de l'atteinte rénale. Au départ d'une vignette clinique paradigmatique, nous détaillons les étapes diagnostiques face à une suspicion de MRC.

[After the COVID crisis, what solutions for the future nursing home?] / Rapport 22-02. Après la crise COVID, quelles solutions pour l'EHPAD de demain ?

The ageing of the population induces situations of large vulnerability and dependence. Home care usually remains the best response to comply with the person's wish, the family's desire, and the civil society's interest. However, there are circumstances where patient management in a nursing home (EHPAD) is the only solution. The present pandemic of coronavirus COVID-19 has highlighted the issue of EHPAD and their limitations to provide high quality care. To analyze the current position of EHPAD into the care chain and to understand difficulties to their functioning, it seems essential to seek out accelerated changes in the EHPAD since their establishment in 1999 and then in the light of the current crisis, propose possible solutions with a positive view of the role which each EHPAD will have to ensure for future.

Modeling Stripe Formation on Growing Zebrafish Tailfins.

As zebrafish develop, black and gold stripes form across their skin due to the interactions of brightly colored pigment cells. These characteristic patterns emerge on the growing fish body, as well as on the anal and caudal fins. While wild-type stripes form parallel to a horizontal marker on the body, patterns on the tailfin gradually extend distally outward. Interestingly, several mutations lead to altered body patterns without affecting fin stripes. Through an exploratory modeling approach, our goal is to help better understand these differences between body and fin patterns. By adapting a prior agent-based model of cell interactions on the fish body, we present an in silico study of stripe development on tailfins. Our main result is a demonstration that two cell types can produce stripes on the caudal fin. We highlight several ways that bone rays, growth, and the body-fin interface may be involved in patterning, and we raise questions for future work related to pattern robustness.

[COVID-19 inside dialysis units]. / La dialyse chronique face à la COVID-19.

COVID-19 has been the center of global attention and concern for the last months. Patients undergoing dialysis and especially those treated at the hospital are likely to be infected, due to their mandatory presence at the hospital several times a week and due to their intrinsic fragility in regard of chronic kidney disease, often an older age, and the presence of many associated comorbidities. Thereby, patients with chonic kidney disease treated by haemodialysis have higher odds of a more severe COVID-19 infection with a high mortality rate. Prevention is thus a high priority for these patients.

Au cours des derniers mois, la COVID-19 a été au centre des préoccupations et de l'attention de chacun. Les patients dialysés, et surtout ceux hémodialysés en centre, représentent une population particulièrement à risque de contamination vu la nécessité de se rendre à l'hôpital plusieurs fois par semaine et compte tenu de leur fragilité intrinsèque liée au statut de malade rénal chronique, un âge souvent plus avancé, et de nombreuses comorbidités. Ils ont donc un risque de développer une infection grave et potentiellement mortelle. Dès lors, la stratégie de prévention est d'une importance capitale pour ces patients.

[Toward a preventive management Alzheimer's disease]. / Pour une prise en charge préventive de la maladie d'Alzheimer.

Dementias, and Alzheimer's disease (AD) in particular, will increasingly become a public health issue. However, three major data may change the severity of these pathologies: in young adults, simple measures of healthy lifestyle (control of vascular risk factors, physical activity and cognitive stimulation), have an impact on a future cognitive decline; the same lifestyle interventions may delay the start of the disease for elderly people potentially at-risk; finally, and for the first time, a monoclonal antibody directed against amyloid lesions has just shown a significant effect on the progression of AD in patients at an early stage of the disease. According to these results, we will have to reconsider the strategy for managing minor or severe cognitive disorders and particularly AD. Nowadays, patients start the care process too late. The solution is to act earlier, even preventively. It is necessary to improve a care offer adapted to this new situation in order to impact on the disease as soon as possible, even before the onset of symptoms, based on: 1) predictive algorithms aimed at establishing whose cognitively unimpaired individuals may further develop the disease; these algorithms will be based on demographic, family, cognitive, genomic and biological data, such as in the "Santé Cerveau" project developed in partnership with the Health Regional Agency (ARS) and the general practitioners; 2)and on some expert centers which must become "dementia prevention clinics" to test prevention measures, initiate and validate multi-domain therapeutic education programs; to disclose about the risk in response to the request of worried patients; and to propose early pharmacological treatments if these individuals are on the way to declare AD in the coming months, taking into account competition between risks. This will allow to prepare to make use of new pharmacological treatments that might be discovered.

A Precision Medicine Initiative for Alzheimer's disease: the road ahead to biomarker-guided integrative disease modeling.

After intense scientific exploration and more than a decade of failed trials, Alzheimer's disease (AD) remains a fatal global epidemic. A traditional research and drug development paradigm continues to target heterogeneous late-stage clinically phenotyped patients with single 'magic bullet' drugs. Here, we propose that it is time for a paradigm shift towards the implementation of precision medicine (PM) for enhanced risk screening, detection, treatment, and prevention of AD. The overarching structure of how PM for AD can be achieved will be provided through the convergence of breakthrough technological advances, including big data science, systems biology, genomic sequencing, blood-based biomarkers, integrated disease modeling and P4 medicine. It is hypothesized that deconstructing AD into multiple genetic and biological subsets existing within this heterogeneous target population will provide an effective PM strategy for treating individual patients with the specific agent(s) that are likely to work best based on the specific individual biological make-up. The Alzheimer's Precision Medicine Initiative (APMI) is an international collaboration of leading interdisciplinary clinicians and scientists devoted towards the implementation of PM in Neurology, Psychiatry and Neuroscience. It is hypothesized that successful realization of PM in AD and other neurodegenerative diseases will result in breakthrough therapies, such as in oncology, with optimized safety profiles, better responder rates and treatment responses, particularly through biomarker-guided early preclinical disease-stage clinical trials.

French consensus procedure for assessing cognitive function in Parkinson's disease.

INTRODUCTION: One of the objectives of the French expert centers for Parkinson's disease (NS-Park) network was to determine a consensus procedure for assessing cognitive function in patients with Parkinson's. This article presents this procedure and briefly describes the selected tests. METHODS: A group of 13 experts used the Delphi method for consensus building to define the overall structure and components of the assessment procedure. For inclusion in the battery, tests had to be validated in the French language, require little motor participation, have normative data and be recognized by the international community. Experimental tasks and tests requiring specific devices were excluded. RESULTS: Two possibilities were identified, depending on whether an abbreviated or comprehensive assessment of cognitive function was necessary. For an abbreviated assessment, the experts recommended the Montreal Cognitive Assessment (MoCA) as a screening test for cognitive impairment or dementia. For a comprehensive neuropsychological assessment, the experts recommended assessing global efficiency plus the five main cognitive domains (attention and working memory, executive function, episodic memory, visuospatial function and language) that may be impaired in Parkinson's disease, using two tests for each domain. DISCUSSION AND CONCLUSION: A common procedure for assessing cognitive function is now available across the French network dedicated to Parkinson's disease, and is recommended for both research and clinical practice. It will also help to promote standardization of the neuropsychological assessment of Parkinson's disease.

[Management of hypophosphatemia: a case report]. / Le cas clinique du mois. Prise en charge d'une hypophosphatemia.

Hypophosphatemia is defined by a serum phosphate level lower than 0.8 mmol/l. If hypophosphatemia is chronically maintained, it is associated with muscular, osteous, neurological or cardio-respiratory disorders. We describe a patient with isolated hypophosphatemia, detail the mechanisms of phosphate homeostasis, and envisage the differential diagnosis of hypophosphatemia. Furthermore, we propose a sequential decisional algorithm based on basic biological tests and few complementary investigations. Treatment options are reviewed.

Testing the model of caudo-rostral organization of cognitive control in the human with frontal lesions.

The cascade model of cognitive control, mostly relying on functional neuroimaging studies, stipulates that the lateral frontal cortex (LFC) is organized as a cascade of executive processes involving three levels of cognitive control, implemented in distinct LFC areas from the premotor to the anterior prefrontal regions. The present experiment tested this model in patients with LFC lesions and studied the hierarchy of executive functions along the caudo-rostral axis, i.e. the respective roles of the different LFC areas in the control of behavior. Voxel-based lesion-symptom mapping and region of interest group analyses were conducted in 32 patients with focal LFC lesions who performed cognitive tasks assessing the cascade model. We first showed that three different LFC areas along the caudo-rostral axis subserved three distinct control levels, whose integrity is necessary for adaptive behavior. Second, we found that prefrontal cognitive control has an asymmetric organization: higher control processes involving more anterior prefrontal regions rely on the integrity of lower control processes in more posterior regions, while lower control processes can operate irrespective of the integrity of higher control processes. Altogether, these findings support a caudo-rostral cascade of executive processes from premotor to anterior prefrontal regions.

Harmonized diagnostic criteria for Alzheimer's disease: recommendations.

BACKGROUND: Two major sets of criteria for the clinical diagnosis of Alzheimer's disease (AD) recently have been published, one from an International Working Group (IWG) and the other from working groups convened by the National Institute on Aging (NIA) and the Alzheimer's Association (AA) in the United States. These criteria both aim to support a clinical diagnosis with in vivo evidence of AD pathology, using imaging methods and detection of biofluid biomarkers, and emphasize an aetiological diagnosis even in the prodromal stages of the disorder. Nonetheless, there are substantial differences in these two sets of criteria. METHODS: An international group of investigators with experience in the clinical diagnosis of AD met at the Key Symposium in Stockholm, Sweden on 6 & 7 December 2012, to develop recommendations to harmonize these criteria. The group was led by individuals who were integral to the development of both the IWG and the NIA-AA criteria. The similarities and differences between the two sets of criteria were identified and open discussion focused on ways to resolve the differences and thus yield a harmonized set of criteria. RESULTS: Based on both published evidence as well as the group's collective clinical experience, the group was tasked with achieving consensus, if not unanimity, as it developed recommendations for harmonized clinical diagnostic criteria for AD. CONCLUSION: The recommendations are to: (i) define AD as a brain disorder, regardless of clinical status; (ii) refer to the clinically expressed disorder, including its prodromal stages, as symptomatic AD; (iii) after the successful completion of standardization efforts, consider incorporating biomarkers into diagnostic algorithms for AD; and (iv) allow nonamnestic, atypical presentations to be included as symptomatic AD, especially when there is supportive biomarker evidence.

Measuring cognitive change in subjects with prodromal Alzheimer's disease.

OBJECTIVE: To investigate the sensitivity of a large set of neuropsychological tests to detect cognitive changes due to prodromal Alzheimer's disease(AD); to compare their metrological properties in order to select a restricted number of these tests for the longitudinal follow-up of subjects with prodromal AD. PARTICIPANTS: 212 patients with mild cognitive impairment were tested at baseline by a standardised neuropsychological battery, which included: the Free and Cued Selective Reminding test (FCSRT), the Benton Visual Retention test, the Deno100, verbal fluency, a serial digit learning test, the double task of Baddeley, the Wechsler Adult Intelligence Scale (WAIS) similarities, the Trail-Making Test and the WAIS digit symbol test. Patients were monitored every 6 months for up to 3 years in order to identify those who converted to AD (retrospectively classified as prodromal AD). Statistical analyses were performed using a nonlinear multivariate mixed model involving a latent process. This model assumes that the psychometric tests are nonlinear transformations of a common latent cognitive process, and it captures the metrological properties of tests. RESULTS: 57 patients converted to AD. The most sensitive tests in the detection of cognitive changes due to prodromal AD were the FCSRT, the semantic verbal fluency and the Deno100. Some tests exhibited a higher sensitivity to cognitive changes for subjects with high levels of cognition, such as the free recall, delayed free recall scores of the FCSRT and the semantic verbal fluency, whereas others showed a higher sensitivity at low levels of cognition, such as the total recall score of the FCSRT. CONCLUSIONS: Tests used for the follow-up of prodromal AD subjects should be chosen among those that actually decline in this stage of the disease and should be selected according to the subject's initial scores.

"Time Saved" Calculations to Improve Decision-Making in Progressive Disease Studies.

BACKGROUND: Disease modifying therapies (DMTs) may be most beneficial in early disease, when progression is slow and changes small, with clinical relevance difficult to interpret. OBJECTIVES: Time component tests (TCTs) translate differences between treatments from mean change, vertical distance between longitudinal trajectories, into intuitively understood time saved, horizontal distance between trajectories, which can be readily combined across endpoints in a global TCT (gTCT). DESIGN: The value of composites, time savings estimates, and combination scores to optimize measurement and interpretation of DMTs are demonstrated, along with construction details and simulation studies. SETTING: TCT methods were applied to a randomized phase II clinical trial. PARTICIPANTS: Patients with early Alzheimer's disease (N=332). INTERVENTION: Three treatment groups with AFFITOPE® AD02 and two control groups with aluminum oxyhydroxide, AD04. MEASUREMENTS: The co-primary efficacy outcomes were an adapted ADAS-Cog (aADAS) and adapted ADCS-ADL (aADL), which were optimized composite scales specific to cognitive and functional domains. A composite based on these two scores was the study's prespecified primary outcome. The CDR-sb and standard non-adapted ADCS-ADL and ADAS-Cog scales were prespecified secondary outcomes. RESULTS: The AD04 2 mg group showed some statistically significant effects compared with other study arms. It is unclear whether the observed 3.8-point difference on the composite is clinically meaningful. TCT results show a time savings of 11 months in an 18-month study with AD04 2 mg. CONCLUSION: The relevance of 11 months saved is more universally understood than a mean difference of 3.8 points in the composite outcome. These results suggest that a combination of a composite approach and a time savings interpretation offers a powerful approach for detecting and interpreting disease modifying effects.

Dominantly Inherited Alzheimer Network Trials Unit (DIAN-TU): Trial Satisfaction and Attitudes towards Future Clinical Trials.

BACKGROUND: Clinical trial satisfaction is increasingly important for future trial designs and is associated with treatment adherence and willingness to enroll in future research studies or to recommend trial participation. In this post-trial survey, we examined participant satisfaction and attitudes toward future clinical trials in the Dominantly Inherited Alzheimer Network Trials Unit (DIAN-TU). METHODS: We developed an anonymous, participant satisfaction survey tailored to participants enrolled in the DIAN-TU-001 double-blind clinical trial of solanezumab or gantenerumab and requested that all study sites share the survey with their trial participants. A total of 194 participants enrolled in the trial at 24 study sites. We utilized regression analysis to explore the link between participants' clinical trial experiences, their satisfaction, and their willingness to participate in upcoming trials. RESULTS: Survey responses were received over a sixteen-month window during 2020-2021 from 58 participants representing 15 study sites. Notably, 96.5% of the survey respondents expressed high levels of satisfaction with the trial, 91.4% would recommend trial participation, and 96.5% were willing to enroll again. Age, gender, and education did not influence satisfaction levels. Participants reported enhanced medical care (70.7%) and pride in contributing to the DIAN-TU trial (84.5%). Satisfaction with personnel and procedures was high (98.3%). Respondents had a mean age of 48.7 years, with most being from North America and Western Europe, matching the trial's demographic distribution. Participants' decisions to learn their genetic status increased during the trial, and most participants endorsed considering future trial participation regardless of the DIAN-TU-001 trial outcome. CONCLUSION: Results suggest that DIAN-TU-001 participants who responded to the survey exhibited high motivation to participate in research, overall satisfaction with the clinical trial, and willingness to participate in research in the future, despite a long trial duration of 4-7 years with detailed annual clinical, cognitive, PET, MRI, and lumbar puncture assessments. Implementation of features that alleviate barriers and challenges to trial participation is like to have a high impact on trial satisfaction and reduce participant burden.

A trans-specific polymorphism in ZC3HAV1 is maintained by long-standing balancing selection and may confer susceptibility to multiple sclerosis.

The human ZC3HAV1 gene encodes an antiviral protein. The longest splicing isoform of ZC3HAV1 contains a C-terminal PARP-like domain, which has evolved under positive selection in primates. We analyzed the evolutionary history of this same domain in humans and in Pan troglodytes. We identified two variants that segregate in both humans and chimpanzees; one of them (rs3735007) does not occur at a hypermutable site and accounts for a nonsynonymous substitution (Thr851Ile). The probability that the two trans-specific polymorphisms have occurred independently in the two lineages was estimated to be low (P = 0.0054), suggesting that at least one of them has arisen before speciation and has been maintained by selection. Population genetic analyses in humans indicated that the region surrounding the shared variants displays strong evidences of long-standing balancing selection. Selection signatures were also observed in a chimpanzee population sample. Inspection of 1000 Genomes data confirmed these findings but indicated that search for selection signatures using low-coverage whole-genome data may need masking of repetitive sequences. A case-control study of more than 1,000 individuals from mainland Italy indicated that the Thr851Ile SNP is significantly associated with susceptibility to multiple sclerosis (MS) (odds ratio [OR] = 1.47, 95% confidence intervals [CI]: 1.08-1.99, P = 0.011). This finding was confirmed in a larger sample of 4,416 Sardinians cases/controls (OR = 1.18, 95% CI: 1.037-1.344, P = 0.011), but not in a population from Belgium. We provide one of the first instances of human/chimpanzee trans-specific coding variant located outside the major histocompatibility complex region. The selective pressure is likely to be virus driven; in modern populations, this variant associates with susceptibility to MS, possibly via the interaction with environmental factors.

[The Goblets test: Norms in the elderly population and properties in the detection of cognitive impairment in elderly individuals selected from the general population]. / Le test des gobelets : normes et propriétés de détection d'un trouble cognitif chez des sujets sélectionnés en population générale.

INTRODUCTION: Most current tools exploring visuospatial memory abilities are poorly adapted to the elderly population. The Goblets test allows a brief evaluation of visuospatial memory abilities through an encoding phase in which the participant has to learn a particular sequence and a further delayed recall phase. The aim of the present work was to produce normative scores for this test and to study its properties in the detection of dementia. METHODS: Data were collected in a sample of 1002 agricultural retirees aged 65 years and over included in the AMI study, a population-based cohort study conducted in Gironde (southwestern France). The sample analyzed to establish normative data included 795 non-institutionalized and non-demented participants. Regarding the validity study, the sample analyzed included 912 participants of whom 76 subjects with a diagnosis of Alzheimer's disease. RESULTS: Normative scores were calculated according to age (65-74 years and 75 years and over) and educational level (primary school level not validated by a diploma, primary school level validated by a diploma and more than a primary school level). The normative scores of the learning phase were described using the percentiles while rates of success were reported for the delayed recall. Regarding the properties of the test, the Goblets test seemed to be more specific than sensitive and presented high negative predictive values. The Youden index showed that the better cut-off score was two trials (with 75.0% sensitivity and 83.0% specificity). CONCLUSION: The Goblets test can be a helpful tool in screening for dementia. Nevertheless, like many other simple and quick cognitive tests, it cannot be used alone to establish the diagnosis of dementia. This test has the advantage to be easy to administer in clinical situations; the normative scores presented in this study could be used as an aid to interpret a patient's performance.

Alzheimer disease: from biomarkers to diagnosis.

The discovery of biomarkers, considered as surrogate markers of the underlying pathological changes, led an international work group (IWG) to propose a new conceptual framework for AD in 2007 Dubois et al. (2007). According to the IWG, AD is now defined as a dual clinico-biological entity that can be recognized in vivo, prior to the onset of the dementia syndrome, on the basis of: i) a specific core clinical phenotype comprised of an amnestic syndrome of the hippocampal type and ii) supportive evidence from biomarkers reflecting the location or the nature of Alzheimer-type changes. Therefore, AD is diagnosed with the same criteria throughout all symptomatic phases of the disease based on the biologically-based approach to diagnosis independent of clinical expression of disease severity. The definitions were further clarified in 2010 (Dubois et al., 2010). Although the new criteria are proposed for research purposes, we encourage expert centres with adequate resources to begin to use the proposed algorithm in order to move the field forward and facilitate translation into clinical practice.

APOE and Alzheimer disease: a major gene with semi-dominant inheritance.

Apolipoprotein E (APOE) dependent lifetime risks (LTRs) for Alzheimer Disease (AD) are currently not accurately known and odds ratios alone are insufficient to assess these risks. We calculated AD LTR in 7351 cases and 10 132 controls from Caucasian ancestry using Rochester (USA) incidence data. At the age of 85 the LTR of AD without reference to APOE genotype was 11% in males and 14% in females. At the same age, this risk ranged from 51% for APOE44 male carriers to 60% for APOE44 female carriers, and from 23% for APOE34 male carriers to 30% for APOE34 female carriers, consistent with semi-dominant inheritance of a moderately penetrant gene. Using PAQUID (France) incidence data, estimates were globally similar except that at age 85 the LTRs reached 68 and 35% for APOE 44 and APOE 34 female carriers, respectively. These risks are more similar to those of major genes in Mendelian diseases, such as BRCA1 in breast cancer, than those of low-risk common alleles identified by recent GWAS in complex diseases. In addition, stratification of our data by age groups clearly demonstrates that APOE4 is a risk factor not only for late-onset but for early-onset AD as well. Together, these results urge a reappraisal of the impact of APOE in Alzheimer disease.