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. 2021 May 5;13(1):95.
doi: 10.1186/s13195-021-00833-4.

The role of sex and gender in the selection of Alzheimer patients for clinical trial pre-screening

Maitee Rosende-Roca  1 , Carla Abdelnour  1   2 , Ester Esteban  1 , Juan Pablo Tartari  1 , Emilio Alarcon  1 , Juliana Martínez-Atienza  1 , Antonio González-Pérez  1 , María E Sáez  1 , Asunción Lafuente  1 , Mar Buendía  1 , Ana Pancho  1 , Nuria Aguilera  1 , Marta Ibarria  1 , Susana Diego  1 , Sara Jofresa  1 , Isabel Hernández  1   2 , Rogelio López  1 , Miren Jone Gurruchaga  1 , Lluís Tárraga  1   2 , Sergi Valero  1   2 , Agustín Ruiz  1   2 , Marta Marquié  1   2 , Mercè Boada  3   4
Affiliations

The role of sex and gender in the selection of Alzheimer patients for clinical trial pre-screening

Maitee Rosende-Roca et al. Alzheimers Res Ther. .

Abstract

Background: Alzheimer disease (AD) is a progressive neurodegenerative disorder affecting the elderly with a prevalence of 7.1% in women and 3.3% in men. Sex-related patterns have been reported in prognosis, biomarker status, and risk factors. Despite this, the interaction of sex has received limited attention, with AD trials persistently recruiting lower numbers of women than the population distribution and a lack of information on the sex-disaggregated effects of anti-dementia therapies. This is the first study aiming to identify the role of sex in the selection for screening in AD clinical trials.

Methods: This cross-sectional study provides a comprehensive analysis of screening eligibility according to a set of pre-selection criteria currently applied at Fundació ACE memory clinic for a more efficient trial screening process. A cohort of 6667 women and 2926 men diagnosed with AD dementia (55%) or mild cognitive impairment (45%) was analyzed. We also assessed the frequencies of men and women effectively screened for trial enrolment over a period of 10 years. Additionally, data from AddNeuroMed study was used to explore trends in eligibility based on the education criteria.

Results: Women showed a significantly lower chance of being eligible for screening than men (OR = 1.26; p < 0.01). This imbalance was confirmed by a lower frequency of women screened for enrolment compared to the study population (63.0% vs. 69.5%). Education was revealed as the key criterion contributing to this unbalance, with men showing over twice the chance of being screened compared with women (OR = 2.25, p < 0.01). Education-based differences were greater in earlier born patients, but the gap narrowed and achieved balance with increasing year of birth. This observation was replicated using data from other European populations included in AddNeuroMed study. Comorbidity was the most limiting criterion with sex differences in frequencies and significant discrimination against the selection of men (OR = 0.86, p < 0.01).

Conclusions: The large number of low-educated elderly women with AD demands for a sex-focused approach in clinical research. New assessment tools insensitive to education level should be developed to enable a proportional representation of women. Although this gender education gap is mostly inexistent in developed countries, economic or cultural factors may lead to different scenarios in other regions. Overlooking the impact of sex may lead to a handicap in AD research with a direct adverse impact on women's health.

Keywords: Aging; Alzheimer’s disease; Dementia; Education; Elderly; Gender; Mild cognitive impairment; Sex; Women.

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Conflict of interest statement

The author(s) declare no potential competing interests.

Figures

Fig. 1
Fig. 1
Cohort selection flow diagram. The study cohort was selected among a total population of 23,739 subjects assessed at Fundació ACE clinic according to three selection requisites: (1) assessment performed from 2008 to 2018, (2) confirmed initial diagnosis of AD (either dementia or mild cognitive impairment) and clinical dementia rating (CRD) score of 0.5-2. The resulting study sample comprised a total of 9593 subjects, 2926 men and 6667 women
Fig. 2
Fig. 2
Odds ratio values comparing eligibility in men and women according to pre-screening selection criteria (age, comorbidity, medication, MMSE, education and all criteria) in the study population (ALL), in the patients diagnosed with Alzheimer dementia (AD) and with minor cognitive impairment (MCI). Asterisk (*) indicate p < 0.05 in test comparing eligibility between males and females by multivariable logistic regression (or univariable logistic regression for all criteria). MMSE, mini-mental state examination
Fig. 3
Fig. 3
Frequencies of eligible candidates for trial screening according to education by year of birth, sex, and diagnosis, in the study population (ALL), in the patients diagnosed with Alzheimer dementia (AD) and with minor cognitive impairment (MCI). Asterisk (*) indicates p < 0.05 in multivariable logistic regression test comparing eligibility between males and female
Fig. 4
Fig. 4
Sex distribution in the sample of patients screened at Fundació ACE memory clinic from 2008 to 2018 (a) compared with the distribution in eligible candidates (b) and in the study population (c) for all the patients (ALL), patients with Alzheimer dementia (AD) and patients with minor cognitive impairment (MCI)
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