Ten Years after the National Alzheimer's Plan: Dementia Remains a Hidden Syndrome in France.

Ten years after the implementation of the French Plan on Alzheimer's Disease (2008-2012), the present study aimed at describing the situation of the persons living with dementia in terms of diagnosis and high-risk situations (living alone, continuing driving, inability to handle budget and to manage medication). Among the 115 dementia cases followed-up in the AMI population-based cohort on aging in 2018 (i.e. ten years after the launch of the Plan), the prevalence of under-diagnosis was similar to the one estimated ten years earlier (53.0% vs. 55.6%). Almost all cases (95.3%) were concerned by high-risk situations (61.2% were unable to handle finances, 48.2% were living alone, 27.1% continued driving). Being diagnosed as demented was not associated with a lower frequency of high-risk situations, excepting for driving (16.7% vs. 37.2%). Ten years after the beginning of the French Alzheimer's Plan, dementia remains a hidden syndrome, with a frequent inadequate management of high-risk situations.

Social Vulnerability Predicts Frailty: Towards a Distinction between Fragility and Frailty?

BACKGROUND: All definitions of frailty converge in two aspects: the notion of loss or decline and the ability to predict negative health outcomes. Numerous factors were reported to be associated with frailty among which biological, psychological, economic and social factors. Whether the latter contribute at the same level is a relevant question, as social vulnerability does not refer to an ongoing process of decline leading a person to become frail but rather to a relativity stable state making the person fragile. Thus, social vulnerability should increase the risk of frailty. OBJECTIVES: This study aims at assessing whether social vulnerability increases the risk of incident frailty. METHODS: 1531 participants aged 65 or older from the PAQUID cohort study were included. Cox regression models tested the association between social vulnerability index (SVI, based on 28 social items) and frailty index (FI, based on 25 health-related items) over the 27 years of follow-up. RESULTS: Adjusted for age and sex, higher SVI was associated with increased risk of incident frailty (HR=3.85, 95% CI=1.87-7.94, p<.001). After additional control for IADL disability and comorbidities, higher SVI was associated with increased risk of frailty (HR=3.40, 95% CI=1.63-7.07, p<.05). The association remained significant after controlling for MMSE (HR=2.34, 95% CI=1.08-5.07, p<.05). DISCUSSION: Poor social status is a risk factor of frailty. From a conceptual point of view, our results claim for a distinction between the concepts of frailty and fragility, the first one being the consequence of an ongoing decline, the other one related to a relatively stable condition of fragility, mainly explained by unfavorable social conditions.

Co-Occurrence of Geriatric Syndromes and Diseases in the General Population: Assessment of the Dimensions of Aging.

OBJECTIVES: The co-occurrence of multiple medical or psycho-social conditions (geriatric syndromes (GS) and age-related diseases) is a growing concern in older people. Given the diversity of these conditions and their complex interactions, our aim was to determine whether they could be structured into synthetic dimensions in order to facilitate the management of multimorbidity. DESIGN: The underlying structure of 10 GSs and 8 age-related diseases was identified using a multiple correspondence analysis (MCA), and confronted to subjective and objective health outcomes. SETTING: community residents from Bordeaux City (France) older than 75 years in 2010. PARTICIPANTS: 630 adults aged 75+ years who lived in Bordeaux and participated in the 10-year follow-up of the Three-City study. MEASUREMENTS: GSs included physical frailty, cognitive impairment and dementia, dependency, depressive symptoms, polymedication, thinness, falls, sensory deficit, social isolation, incontinence. Age-related diseases were cancer, cardiac diseases, peripheral vascular diseases, diabetes, hypertension, pulmonary diseases, osteoporosis, other chronic diseases. Association of the MCA-derived independent dimensions was assessed with 10-year visit subjective health and well-being, and with incident death and entry into institution during the remaining cohort follow-up. RESULTS: Most of the participants (82%) had at least two age-related syndromes or diseases. The MCA structured the 18 conditions into three major dimensions: Degradation (D) driven by GS, Vascular (V), and Psychosocial (P) representing 68.7%, 7.4%, and 5.7% of the total variance, respectively. Dimension D was a strong predictor of future death and institutionalization. Dimensions D and P were strongly associated with current well-being. CONCLUSIONS: This work confirmed that multimorbidity is very common among older adults, and demonstrated the essential role of GS as manifestations of aging, even more than age-related diseases.

A Literature Review of Healthy Aging Trajectories through Quantitative and Qualitative Studies: A Psycho-epidemiological Approach on Community-dwelling Older Adults.

The population of older adults over 60 years is growing faster than any other age group and will more than double between 2020 and 2050. This increase has led to clinical, public health, and policy interest in how to age "successfully". Before the Rowe and Kahn's model proposed thirty years ago, aging was seen as a process of losses associated with diseases and disability. However, since the emergence of this model, there has been a shift towards a more positive view, serving for promoting diverse medical or psychosocial models, and personal perspectives. Several technical terms of "success" (e.g. "successful aging", "healthy aging", "active aging", "aging well"…) coexist and compete for the meaning of the concept in the absence of a consensual definition. Our literature review article aims to study discrepancies and similarities between the main technical terms through quantitative or qualitative studies. A literature review using PubMed, SCOPUS, PsycINFO, Psycarticles, Psychology, and Behavioral Sciences Collection, Cochrane database, and clinicaltrials.gov databases was conducted. A total of 1057 articles were found and finally, 43 papers were selected for full extraction. We identified several components in these definitions, which reveal considerable inconsistency. The results particularly suggest that lay personals perspectives could bridge the gap between biomedical and psychosocial models in successful aging. In conclusion, an optimal definition would be a multidimensional one that could combine functional capacities, psychosocial abilities, environmental factors and subjective assessments of one's own criteria to discriminate older adults at potential risk of "unsuccessful" aging to healthy aging trajectories.

Effects of Age, Level of Education and HIV Status on Cognitive Performance in West African Older Adults: The West Africa IeDEA Cohort Collaboration.

An in-depth understanding of the impact of aging, cognitive reserve, and HIV status on cognitive function is needed in older West African adults. Ninety-nine HIV-negative and 334 HIV-positive adults aged ≥ 50 years were enrolled in three clinics (Senegal and Côte d'Ivoire) participating in the IeDEA West Africa collaboration. All subjects underwent the Free and Cued Selective Reminding Test (FCSRT) and the Isaacs Set Test (IST). Age (both linear and quadratic), education level, and HIV status effects on Z-scores were assessed using multivariate linear regression models. Interactions between HIV status and age or educational level were tested. In the present cohort of older West African adults, the role of age and educational level on episodic memory and verbal fluency was observed without revealing an interaction between HIV status and age effect. As age had quadratic effects, older HIV-positive adults should not be considered as a unique group irrespective of their age. Low-educated HIV-positive patients had the lowest verbal fluency performance compared to others. Further studies are needed to duplicate these results. In clinical settings, screening and adapted programs focusing on improving cognition in those patients are needed.

Older People Facing the Crisis of COVID-19: Between Fragility and Resilience.

The health crisis we are facing is challenging seniors' resources and capacities for adaptation and resilience. The PACOVID survey, set up a few days after containment, investigates their psychological and social experiences with regard to the COVID-19 crisis and to what extent these characteristics, representations and attitudes have an impact on health and mortality. A telephone survey is being carried out on 935 people already followed up in the framework of ongoing epidemiological studies. As we are writing this article, the interviews conducted during the containment have just ended. Even though we will have to wait for the analysis of the results to draw conclusions, words collected by the psychologists during the interviews already illustrate a great heterogeneity in the way older adults lived this experience: social isolation, anxiety, the importance of family and the difficulty of being deprived of it, but also remarkable coping skills and resilience capacities.

Frailty Index, Hospital Admission and Number of Days Spent in Hospital in Nursing Home Residents: Results from the Incur Study.

OBJECTIVES: To investigate the predictive capacity of an age-related deficit accumulation index (the so-called Frailty Index [FI] proposed by Rockwood) for hospital admission (HA) and number of days spent in hospital (DSH) among nursing home residents. DESIGN, SETTING AND PARTICIPANTS: Data are from a longitudinal cohort study, the Incidence of pNeumonia and related ConseqUences in nursing home Residents (INCUR), of 768 elder people (75.4% women) living in 13 nursing homes in France. MEASUREMENTS: The FI was computed taking into account 30 possible deficits at the baseline visit. Hospital admissions were defined as all urgent and involuntary admissions including unplanned readmissions. The length of stay was the total number of days spent by the resident in the hospital. Cox proportional hazard models in the presence of competing risks (death) were performed to study the relationship between the FI and HA over a 12-month follow-up. A Zero-inflated negative binomial regression was performed to study the association between the FI and DSH. RESULTS: Mean age of participants was 86.7 (standard deviation [SD] 6.9) years, with a mean FI of 0.37 (SD 0.11). At the end of the follow-up, 238 (30.9%) HA events were recorded. Positive associations of the FI with DSH and HA were reported (per 0.01 FI increment: age- and gender-adjusted hazard ratio 1.15, 95% confidence interval 1.020-1.297, p=0.02 and OR 1.209 (1.075 - 1.359, p<0.001, respectively). CONCLUSIONS AND IMPLICATIONS: The FI is a strong predictor of negative health-related outcomes as HA and DSH events, even with very old and complex nursing home residents.

Cerebral alterations in West African HIV and non-HIV adults aged ≥50: An MRI study.

OBJECTIVES: To cross-sectionally describe brain alterations in PLHIV aged above 50 years old, receiving antiretroviral treatment (ART) and living in Senegal compared to HIV-negative subjects. METHODS: Twenty PLHIV and 26 HIV-negative subjects with comparable socio-demographic and clinical characteristics underwent an MRI exam (3D-T1 and FLAIR sequences). Global atrophy and White Matter Hyperintensities (WMH) were evaluated. After assessing the feasibility and acceptability of MRI scans in this population, we described atrophy and WHM prevalence and associated factors using logistic regressions. RESULTS: Overall, 43.5% of the study sample were aged ≥60 years, 58.7% were women, and 28.3% had hypertension. The overall prevalence of atrophy and WMH was 19.6% [95% CI: 8.1-31.1] and 30.4% [95% CI: 17.1-43.7]. HIV status had no significant effect on atrophy or WMH. Unemployment and hypertension were significantly associated with atrophy, whereas women were less likely to present atrophy. Aged ≥60 years was the only factor associated with WMH. CONCLUSIONS: A high prevalence of atrophy and WMH was observed in West African adults aged over 50 years without a clear HIV impact. As brain MRI studies are critical to better understand cognitive and emotional outcomes, we encourage those studies in older PLHIV in West Africa.

Important oral care needs of older French people: A cross-sectional study.

BACKGROUND: Older persons comprise a growing proportion of the European population and may have a distinct epidemiological oral profile requiring specific preventive and curative care poorly documented. The objectives of this study were to assess the oral health status of people ≥90 years of age in France, to compare their perceived and observed oral care needs and to investigate the oral problems associated with a low oral health-related quality-of-life (OHRQoL). METHODS: An oral cross-sectional study was performed during the 25th follow-up of a cohort of older persons being followed up prospectively for screening of dementia over a 15-year period in Gironde and Dordogne, France. Clinical oral indices were determined by oral examinations conducted at the participants' place of living. Cohen's Kappa coefficient was used to assess the agreement between perceived and observed oral care needs. Oral problems associated with a low OHRQoL, measured with the Geriatric Oral Health Assessment Index (GOHAI<50) were investigated with logistic regression. Odds ratios (OR) were estimated with their 95% confidence intervals (CI). RESULTS: Data from 90 persons were analysed (76% female; median age=93 years; 20% living in an institution). Plaque and calculus were present in 93% and 58% respectively, of the 74 dentate participants. The mean number of decayed, missing, and filled teeth was 26.5 (±5.3); 66% of the participants had at least one untreated decayed tooth. Among the 85 participants with tooth loss not replaced by a fixed denture, two thirds had a removable dental prosthesis; 84% of these prostheses were considered to be maladapted. Among the 39 participants who felt unable to consult a dentist (43%), lack of transportation was the most frequently cited reason. Although 88% of the participants needed oral care, only 26% perceived that they had such a need (Kappa=0.06). Oral problems associated with a GOHAI<50 were the absence of posterior occluding teeth (OR=7.15; 95%CI=1.53-33.35; P=0.012), feeling of dry mouth (OR=11.94; 95%CI=3.21-44.39; P=0.0002) and oral pain (OR=9.06; 95%CI=1.91-69.00; P=0.033). CONCLUSIONS: Persons ≥90 years of age have considerable preventive and curative dental care needs that impact their quality-of-life but they are rarely aware and lack transportation. NCT04065828.

Psychosocioeconomic Precariousness and Frailty: The Respective Contribution in Predicting Mortality.

BACKGROUND: Low socioeconomic status and frailty are factors of vulnerability in old age. They are both well-known risk factors of death. On the other hand, low socioeconomic status has been reported as a predictor of frailty, which questions the relationship between socioeconomic status, frailty and death. OBJECTIVES: The aim of this work was to explore the respective contribution of psychosocioeconomic precariousness - which covers socioeconomic status and also psychosocial vulnerability - and frailty in predicting mortality. DESIGN: Prospective population-based study. SETTING: Three-City (3C) Bordeaux study, France. PARTICIPANTS: The sample consisted of 1586 subjects aged 65 or older. MEASUREMENTS: Psychosocioeconomic precariousness was assessed utilizing a structured instrument which assessed poor socioeconomic status, and psychosocial vulnerability. Frailty status was defined by Fried's phenotype. RESULTS: After 14 years of follow-up, 665 deaths (42%) occurred. Psychosocioeconomic precariousness and frailty had both an independent contribution to mortality prediction (hazard ratio (HR) 1.51 (95% confidence interval (CI) 1.11-2.07)) and (HR 1.68 (95% CI 1.19-2.38)), respectively. Such relationships were adjusted for age, sex, disability, and comorbidities. No interaction term was found between precariousness and frailty. CONCLUSIONS: If psychosocioeconomic precariousness and frailty are both aspects of vulnerability in old age, they have a non-overlapping contribution in the prediction of mortality. These findings emphasize the importance of considering both psychosocioeconomic precariousness and frailty when identifying elderly people at risk of death.

Effect of Multidomain Intervention, Omega-3 Polyunsaturated Fatty Acids Supplementation or their Combinaison on Cognitive Function in Non-Demented Older Adults According to Frail Status: Results from the MAPT Study.

BACKGROUND: Aim: The aim of this study was to explore whether multidomain intervention (MI) and Omega-3 Polyunsaturated Fatty Acids supplementation can modify the cognitive function on elderly according to frail status. METHOD: Data are from a secondary exploratory analysis of the Multidomain Alzheimer Preventive Trial (MAPT), a French community-dwellers aged 70 or over reporting subjective memory complaints, but free from clinical dementia. The multidomain intervention consisted of 2 hours group sessions focusing on three domains (cognitive stimulation, physical activity, and nutrition) and a preventive consultation (at baseline, 12 months, and 24 months). For Omega-3 Polyunsaturated Fatty Acids supplementation, participants took two capsules of either placebo or polyunsaturated fatty acids daily. Linear mixed-model repeated-measures analyses were used including baseline, 6, 12, 24 and 36-month follow-up data to assess between-group differences in the change in cognitive tests over 36 months. RESULTS: The overall mean age of the MAPT study population was 75.25(±4.38). A tend toward significant differences in TMT-A were found for the effect of the multidomain intervention on the prefrail group compared to non-frail group. The MI and n3 PUFA program could not significantly have reduced cognitive function in a sample of pre-frailty elders. CONCLUSION: This population-based study in community-dwellers aged 70 years or over suggested that multidomain intervention and n3 PUFA supplementation have not significant effects on cognitive function change in frail older adults with memory complaints. The beneficial effect of multidomain intervention and n3 PUFA supplementation on cognitive function did not differ between frail and nonfrail participants.

Ginkgo Biloba Extract Consumption and Long-Term Occurrence of Death and Dementia.

OBJECTIVES: To study the benefit of Ginkgo Biloba Extract (GBe) consumption on the long term risk of dementia and death in elderly people. DESIGN: The Paquid study is a population-based cohort with regular follow-up screenings up to twenty-two years and systematic detection of incident cases of dementia. Statistical analysis was conducted with an illness-death model dealing with interval censoring of dementia and competing risk of death. SETTING: The sample was randomly selected from electoral rolls in two administrative areas of southwestern France in 1988-1989. PARTICIPANTS: 3,777 subjects aged 65 years or older at baseline who were living at home. MEASUREMENT: Participants were visited at home by a trained psychologist at baseline in 1988/1989, and then again approximately every two years. Drug consumption for the treatment of cognitive or neurosensory impairment was collected at baseline. Participants were classified as GBe consumers, other drug (OD) consumers and untreated controls (UC) for this motive. RESULTS: After adjustment for sociodemographic factors and cognitive measures at baseline the risk for dementia was not significantly different in GBe consumers and UC (Hazard Ratio (HR)=1.21, 95% Confidence Interval (95% CI)=0.95-1.55, p=0.42) and it was of the same magnitude but significantly increased in the OD group versus UC (HR=1.25, 95% CI=1.06-1.46, p=0.004). With the same adjustment, the risk of dying in non-demented subjects was reduced in GBe consumers versus UC (HR=0.67, 95% CI=0.49-0.93, p=0.02) while it was the same as the reference group in OD consumers. The mean lifetimes without dementia was of 11.2 years in the UC group (95% CI=10.9-11.5), 11.1 years in the GBe group (10.2-11.9) and 9.1 years for the OD group (8.7-9.6). CONCLUSION: GBe consumers have a lower risk of dying before dementia and a longer lifetime without dementia than participants taking other drugs for the same indication.

The impact of chronic psychiatric disorders on cognitive decline.

OBJECTIVES: Based on seemingly contradictory results in the existing literature, the objective of our study was to investigate whether older individuals suffering from chronic psychiatric disorders show a more rapid decline in cognitive performances than their non-psychiatric counterparts, or if the pattern of decline through older age is similar in both groups. METHOD: A total of 820 older adults were selected from the Ageing Multidisciplinary Investigation (AMI) cohort study, which studies health-related issues of people over 65 years old living in rural areas. Among them, 30 suffer from chronic psychiatric disorders. Cognition was assessed with four neuropsychological tests: the Mini-Mental State Examination, the Digit Symbol Substitution Test, the Free and Cued Selective Reminding test and the Isaacs Set Test. Linear mixed models were used to compare the evolution of cognitive performances in the two groups between baseline and the four-year follow-up. RESULTS: Despite lower performances at baseline, the pattern of cognitive decline of the psychiatric group is similar to that of the control group. CONCLUSION: As suggested by this study conducted in rural communities, community-dwelling people suffering from chronic psychiatric disorders should not be considered at greater risk of age-related accelerated cognitive decline than the non-psychiatric older population.

17q21.31 duplication causes prominent tau-related dementia with increased MAPT expression.

To assess the role of rare copy number variations in Alzheimer's disease (AD), we conducted a case-control study using whole-exome sequencing data from 522 early-onset cases and 584 controls. The most recurrent rearrangement was a 17q21.31 microduplication, overlapping the CRHR1, MAPT, STH and KANSL1 genes that was found in four cases, including one de novo rearrangement, and was absent in controls. The increased MAPT gene dosage led to a 1.6-1.9-fold expression of the MAPT messenger RNA. Clinical signs, neuroimaging and cerebrospinal fluid biomarker profiles were consistent with an AD diagnosis in MAPT duplication carriers. However, amyloid positon emission tomography (PET) imaging, performed in three patients, was negative. Analysis of an additional case with neuropathological examination confirmed that the MAPT duplication causes a complex tauopathy, including prominent neurofibrillary tangle pathology in the medial temporal lobe without amyloid-ß deposits. 17q21.31 duplication is the genetic basis of a novel entity marked by prominent tauopathy, leading to early-onset dementia with an AD clinical phenotype. This entity could account for a proportion of probable AD cases with negative amyloid PET imaging recently identified in large clinical series.

Effect size for the main cognitive function determinants in a large cross-sectional study.

BACKGROUND AND PURPOSE: The aim of our study was to examine the effect sizes of different cognitive function determinants in middle and early old age. METHODS: Cognitive functions were assessed in 11 711 volunteers (45 to 75 years old), included in the French CONSTANCES cohort between January 2012 and May 2014, using the free and cued selective reminding test (FCSRT), verbal fluency tasks, digit-symbol substitution test (DSST) and trail making test (TMT), parts A and B. The effect sizes of socio-demographic (age, sex, education), lifestyle (alcohol, tobacco, physical activity), cardiovascular (diabetes, blood pressure) and psychological (depressive symptomatology) variables were computed as omega-squared coefficients (ω2 ; part of the variation of a neuropsychological score that is independently explained by a given variable). RESULTS: These sets of variables explained from R2 = 10% (semantic fluency) to R2 = 26% (DSST) of the total variance. In all tests, socio-demographic variables accounted for the greatest part of the explained variance. Age explained from ω2 = 0.5% (semantic fluency) to ω2 = 7.5% (DSST) of the total score variance, gender from ω2 = 5.2% (FCSRT) to a negligible part (semantic fluency or TMT) and education from ω2 = 7.2% (DSST) to ω2 = 1.4% (TMT-A). Behavioral, cardiovascular and psychological variables only slightly influenced the cognitive test results (all ω2 < 0.8%, most ω2 < 0.1%). CONCLUSION: Socio-demographic variables (age, gender and education) are the main variables associated with cognitive performance variations between 45 and 75 years of age in the general population.

Why Is Later Age at Retirement Beneficial for Cognition? Results from a French Population-based Study.

OBJECTIVE: To determine whether and how age at retirement influences the risk of dementia. The association between the age at retirement, the number of working years and the risk of dementia was evaluated over 12 years of follow-up. DESIGN: A prospective population-based study. SETTING: Three-City cohort, a French population-based study of community-dwelling individuals aged 65 to 95. PARTICIPANTS: The sample consisted of 1,658 non-demented participants at baseline. MEASUREMENTS: All participants were evaluated at home at the initial visit and at two years interval for a period of 12 years. An active research of dementia was conducted at each follow-up; all suspected cases were analysed by an independent committee of neurologists. Information regarding retirement age and number of working years was collected at baseline using a structured questionnaire. RESULTS: The multivariate Cox model, including both the age at retirement and the number of working years and adjusted for potential confounders, revealed that the risk of dementia was independently associated with the age at retirement (p=0.022) but not with the number of working years (p=0.296). CONCLUSION: Although our results are in accordance with previous studies (i.e., older age at retirement is associated with decreased risk of dementia), it provides additional information regarding the possible explanation for such results. Given that a longer working life did not reduce the risk of dementia, the age at retirement cannot be considered as a new factor of cognitive reserve but rather seems to be a psycho-social vulnerability factor. Further evidence is necessary to identify work and retirement related factors that influence the association between the age at retirement and the risk of dementia.

SORL1 rare variants: a major risk factor for familial early-onset Alzheimer's disease.

The SORL1 protein plays a protective role against the secretion of the amyloid ß peptide, a key event in the pathogeny of Alzheimer's disease. We assessed the impact of SORL1 rare variants in early-onset Alzheimer's disease (EOAD) in a case-control setting. We conducted a whole exome analysis among 484 French EOAD patients and 498 ethnically matched controls. After collapsing rare variants (minor allele frequency ≤1%), we detected an enrichment of disruptive and predicted damaging missense SORL1 variants in cases (odds radio (OR)=5.03, 95% confidence interval (CI)=(2.02-14.99), P=7.49.10(-5)). This enrichment was even stronger when restricting the analysis to the 205 cases with a positive family history (OR=8.86, 95% CI=(3.35-27.31), P=3.82.10(-7)). We conclude that predicted damaging rare SORL1 variants are a strong risk factor for EOAD and that the association signal is mainly driven by cases with positive family history.

Analysing Time to Event Data in Dementia Prevention Trials: The Example of the GuidAge Study of EGb761.

Time-to-event analysis is frequently used in medical research to investigate potential disease-modifying treatments in neurodegenerative diseases. Potential treatment effects are generally evaluated using the logrank test, which has optimal power and sensitivity when the treatment effect (hazard ratio) is constant over time. However, there is generally no prior information as to how the hazard ratio for the event of interest actually evolves. In these cases, the logrank test is not necessarily the most appropriate to use. When the hazard ratio is expected to decrease or increase over time, alternative statistical tests such as the Fleming-Harrington test, provide a better sensitivity. An example of this comes from a large, five-year randomised, placebo-controlled prevention trial (GuidAge) in 2854 community-based subjects making spontaneous memory complaints to their family physicians, which evaluated whether treatment with EGb761 can modify the risk of developing AD. The primary outcome measure was the time to conversion from memory complaint to Alzheimer's type dementia. Although there was no significant difference in the hazard function of conversion between the two treatment groups according to the preplanned logrank test, a significant treatment-by-time interaction for the incidence of AD was observed in a protocol-specified subgroup analysis, suggesting that the hazard ratio is not constant over time. For this reason, additional post hoc analyses were performed using the Fleming-Harrington test to evaluate whether there was a signal of a late effect of EGb761. Applying the Fleming-Harrington test, the hazard function for conversion to dementia in the placebo group was significantly different from that in the EGb761 treatment group (p = 0.0054), suggesting a late effect of EGb761. Since this was a post hoc analysis, no definitive conclusions can be drawn as to the effectiveness of the treatment. This post hoc analysis illustrates the interest of performing another randomised clinical trial of EGb761 explicitly testing the hypothesis of a late treatment effect, as well as of using of better adapted statistical approaches for long term preventive trials when it is expected that prevention cannot have an immediate effect but rather a delayed effect that increases over time.