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  • Systematic Review
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Ethical issues in genomics research in persons with Alzheimer’s Disease/Alzheimer’s Disease-related dementia (AD/ADRD): a systematic review

BMC Medical Ethics volume 25, Article number: 138 (2024) Cite this article

Abstract

Introduction

Given the growing number of Alzheimer’s Disease and Alzheimer’s Disease Related Dementias (AD/ADRD) genomics research projects and the vulnerabilities of study participants, it is critical to evaluate the literature on the ethical challenges in such studies to ensure high ethical standards.

Methods

We conducted a systematic review of the literature on ethical issues in AD/ADRD genomics research. We searched Embase, PsycINFO, CiNAHL, Scopus, and Ovid Medline for empirical and normative papers published in peer-reviewed journals on the ethical issues involved in conducting genomics research among persons with AD/ADRD. We used ethical principles from an existing framework as a priori codes to categorize the ethical issues and adapted another framework of Dementia Research Ethical Issues (DREI) as subcategories for our synthesis. We used the 2021 PRISMA guidelines to guide our study.

Results

We screened 5,509 papers and included 27 of these papers in the systematic review after deduplication, title, and full-text review. The papers contained 109 ethical issues that were mapped against 42 out of 75 relevant DREIs. The highest number of DREIs were mapped to “respect for persons and communities”, “favorable risk-benefit ratio”, “informed consent” and “scientific validity”. The least mapped principles to the DREIs were “fair participant selection”, “independent review”, “social value”, and “collaborative partnership”.

Conclusion

Our review showed that there is a dearth of literature on the ethical principles of “fair participant selection”, “independent review”, “social value” and “collaborative partnership” in genomics research on AD/ADRDs. It is difficult to draw firm conclusions from the distribution of attention paid to specific principles because these may only reflect the concerns of AD/ADRD genomics research ethicists in high-income countries. There is need for more research on the ethics of AD/ADRD genomics research in low and middle-income countries for a more balanced account of the important ethical considerations in this field.

Peer Review reports

Background

Alzheimer’s disease and Alzheimer’s disease-related dementia (AD/ADRD) occur on a spectrum of cognitive impairments, from cognitively unimpaired persons to persons with full AD/ADRD and functional impairment [1, 2]. AD/ADRD is associated with several risk factors, including air pollution, toxic heavy metals, diet, alcohol, smoking, physical activity, and socioeconomic status [3,4,5,6]. Several monogenic and polygenic risk factors for AD/ADRD have also been identified [6,7,8,9,10]. These include variants in apolipoprotein E (APOE), clusterin (CLU), and ABCA7, a member of the ATP-binding cassette gene SORL1 (also known as SorLA and LR11). Genes involved in the immune response, including CR1 (a member of the receptors of complement activation family), CD33, MS4A, ABCA7, EPHA1, and TREM2, and genes involved in endocytosis/vesicle-mediated transport, including BIN1, CD2AP, PICALM, EPHA1, SORL1, HLA-DRB5/HLA-DRB1, INPP5D, MEF2C, CASS4, PTK2B, NME8, ZCWPW1, CELF1, FERMT2, SLC24H4-RIN3, and DSG2, have also been associated with the risk of AD/ADRD [11].

Several ethical concerns arise when persons with AD/ADRDs participate in research. These include concerns about the adequacy of informed consent, when and how the capacity to consent should be assessed, the role of proxies and their decision-making approach – whether they use best interest versus substituted judgment, how to obtain and respect assent, the role of advance directives and the challenges associated with using it [12,13,14,15,16,17,18,19,20]. Additional ethical concerns, particularly within the context of genomic research, include the impact of disclosure of genomic markers of AD/ADRD to participants and its implications for their relatives [21,22,23], stigmatization, and discrimination related to employment, challenges with obtaining health insurance, social engagement, and risk of suicide [21, 24, 25].

There have been few systematic reviews of ethical issues in research involving persons with AD/ADRDs and no previous systematic reviews of ethical issues in genomics research in this population [12, 21, 26, 27]. In this study, we plan to identify and synthesize the literature on ethical issues related to the conduct of genomics research among persons at all stages of AD/ADRD. We will identify, categorize, and synthesize the implications of these issues based on existing ethical frameworks and highlight the areas that need further research.

Methods

We used the guidance for the review of the empirical and normative bioethics literature from Strech, Synofzik, & Marckmann (2008), and Daniel & Neema (2012) respectively to inform our study design [28, 29]. We also used items that support a mixed-methods systematic review, and the updated PRISMA 2020 guidelines for reporting this study [30]. We did not publish or register the protocol for this review beforehand.

The eligibility criteria

We included only papers published in peer-reviewed journals that addressed, to some degree, the following broad question:

"What are the ethical issues involved in conducting research that involves genomic analysis and/or genomic testing among persons with AD?"

We included both normative and empirical literature. For this review, we adopted Mertz et al.’s definition of normative literature as one that “(i) aims to evaluate judgments, decisions, acts, (social) practices, technologies, institutions, organizations and general states of the world from a moral or legal point of view and/or to define/set out which decision or course of action is or should be morally or legally necessary, prohibited or permitted; or that (ii) aims to develop, interpret or criticize the evaluative or prescriptive concepts required for aim (i)” [31]. We defined the empirical bioethics literature as that which uses data obtained using social science research methods to examine bioethical issues and inform ethical reasoning and theoretical analysis [28, 32, 33]. We relied on the integrity of the peer review mechanism of the journals in which the papers included in our review were published as a criterion of quality [34, 35]. We excluded systematic reviews, editorials, book chapters, commentaries, and consensus statements because we sought to review primary source articles reporting empirical data and normative arguments in peer reviewed journals only.

Search strategy

In October 2018, we searched five databases— Ovid Medline, Embase, PsycINFO, CiNAHL, and Scopus—and found 4,993 unique items. We refined the search strategy and conducted additional searches on Ovid Medline in August 2021 [28, 29, 36, 37]. This involved the addition of thematic terms, their variations, and truncation to the initial search strategy to improve specificity to the research question. We sourced additional literature by searching the references in the retrieved publications. We limited our search to papers published between 1990 and 2021 because the earliest paper on the ethics of AD/ADRD that we found was published in 1994. For completeness, we decided to go back four years to begin our search in 1990. We restricted our search to research involving human beings, and papers published in the English language only. Table 1 shows our detailed search strategy.

Table 1 Search strategy for the review of literature on ethical issues in Genomics Research in persons with AD/ADRD
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Screening and selection of articles

We stored the papers retrieved in EndNote (™) [38] and imported them into DistillerSR© (Version 2.35. DistillerSR Inc.; 2022. Accessed May-Nov 2022. https://www.distillersr.com/) to screen, select and abstract data. Two researchers, AY and IA independently screened all the retrieved papers. Disagreements in inclusion or exclusion were discussed and resolved through consensus. AJ and CA reviewed a subset of the papers at each stage of the screening for quality assurance and served as arbiters during discussions on disagreements.

Theoretical and conceptual framework

We used two frameworks to analyze the data in this review—Emmanuel et al..’s ethical framework for clinical research and Gotzelmann et al.’s framework of Dementia Research Ethical Issues (DREIs). Emmanuel et al..’s (2008) framework proposed a set of eight principles that need to be evaluated to ensure that a given clinical study is ethical [39]. These principles include respect for persons and communities, scientific value, fair participant selection, a favorable risk-benefit ratio, independent review, social value, informed consent, and collaborative partnership. The ethical issues in different research studies can be identified and specified by using these norms. We used these principles to categorize the ethical issues found in the papers included in our review.

The framework of DREIs described in Götzelmann et al.’s (2021) paper proposed a detailed set of ethical issues in AD/ADRD research, organized according to Emmanuel et al.’s framework [27]. The framework of DREIs provides a systematic way of analyzing ethical issues in AD/ADRD research, allowing for the specification of particular ethical issues for more practical application under each of the eight principles in Emmanuel et al..’s framework. We used this framework to screen for ethical issues in the papers we reviewed. We used information from the literature to create additional DREIs using Gotzelmann et al..’s framework as a guide.

Data analysis and synthesis

We categorized the ethical issues discussed in the 27 papers included in our review using the eight principles for ethical research proposed by Emmanuel et al.. (2008) as a priori codes [39]. Initially, all ethical issues were mapped by AY and OM. The issues were then reviewed by IA, AJ, and CA, and any reassignments were discussed and agreed upon between these researchers.

For synthesis, we adapted the DREIs developed by Götzelmann et al. as subcategories to further classify the ethical issues we extracted [27]. Two researchers, AY and OM, reviewed and narrowed down the 105 DREIs to only those DREIs that were more likely to apply to genomics research. DREIs focused on general research ethics issues such as informed consent, capacity assessment, and competence, unless specifically discussed in the context of genomics research, were excluded.

We also derived new DREIs, which we considered important in genomics research but were not explicitly identified by Götzelmann et al.. We adopted a multi-stage approach to derive these new DREIs. One reviewer, AY, coded these ‘unmapped’ ethical issues against each of the eight Emmanuel et al.’s ethical principles. These were reviewed by a second reviewer, OM. Where there were disagreements, a third reviewer, CA, arbitrated on a consensus. The phrasing for the ethical issue as a DREI then followed this same process, adapting the process described by Götzelmann et al. in their paper. Overall, the synthesis of the ethical issues from our review was guided by 47 DREIs from Götzelmann et al..’s framework and 28 new DREIs created inductively from readings during our review. We presented the DREIs according to Emmanuel et al..’s principles using heatmaps. We further categorized the issues into ethical outcomes as ethical recommendations or ethical reflections with practical, normative, or theoretical implications as defined by Mertz et al. [31], as shown in Table 2.

Table 2 Types of ethical outcomes deducible from the bioethics literature [31]
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Results

The PRISMA diagram in Fig. 1 provides details of the papers reviewed, screened, and included in our review, with reasons for exclusion at each stage of the review. The completed PRISMA checklist is available as a supplementary file (supplementary file 1). We identified 5,509 papers through a database search and an additional four papers through citation snowballing and manual searching. After removing 498 duplicates and screening the titles and abstracts of 5,015 unique papers, 60 studies underwent full-text review. Only 27 papers were included in the analysis and synthesis, as reported in Table 3.

Fig. 1
figure 1

PRISMA flow diagram for the identification, screening, eligibility assessment, and selection of papers included in the review

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Table 3 Detailed characteristics of papers on the ethical issues in genomics research in persons with AD/ADRD reviewed
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Characteristics of the included studies

As shown in Table 4, the 27 papers included in this review were published between 1994 and 2021, with 20 (74%) of the papers written between 2010 and 2021. All the papers were led by authors from institutions based in high-income countries—the most being from the United States (41%; n = 11) and the least from Spain (4%; n = 1). Eight (30%) of the papers used data collected from an empirical study to discuss ethical issues, while the rest (19; 70%) were argument-based, discussing ethical issues based on reports by other experts or put forward in some guidelines on ethical issues in AD/ADRD genomics research. Most of the papers (19/27) provided recommendations on ways to address the ethical issues they raised, while 23 were ethical reflections on the issues raised, with implications for practice. Nine papers were ethical reflections that described arguments for or against a normative claim. None of the papers proposed new ethical theories or modifications of existing ones. See supplementary file 2, for the chart of all the ethical outcomes in the papers reviewed.

Table 4 Summary characteristics of papers on ethical issues in genomics research in persons with AD/ADRDs reviewed
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DREIs related to AD/ADRD Genomics Research

We identified 109 ethical issues in the 27 papers reviewed. The issues were mapped against 75 DREIs in the 27 papers reviewed. Most of the DREIs (47, 63%) aligned with those described by Götzelmann et al., while 28 DREIs (37%) were newly developed during our analyses. The full details of the extracted texts and their categorization according to the DREIs are provided in supplementary file 3.

Figure 2 shows a heatmap of the reported DREIs categorized according to Emmanuel et al.’s principles for ethical research. The principles with the highest number of reported DREIs were “respect for persons and communities” (37 DREIs) and “favorable risk-benefit ratio” (31 DREIs). “Informed consent” and “scientific validity” had 19 and 13 DREIs, respectively. The lowest number of reported DREIs were for “fair participant selection” (6 DREIs), “independent review” (2 DREIs), “social value” (2 DREIs), and “collaborative partnership” (0 DREIs).

Fig. 2
figure 2

Heatmap showing the summary of reported DREIs by research ethics principles

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Looking at the DREIs reported for all the principles over the years, the highest peaks were reported in 2017 and 2021, with 22 and 18 DREIs, respectively. We also identified two trends in the DREIs reported over time per principle. DREIs related to the principles of respect for participants and communities and of favorable risk-benefit ratios were reported almost every year between 1994 and 2021. For all the other principles, we see a chequered reporting on their related DREIs.

DREIs related to “respect for recruited participants and study communities”

Figure 3 shows that the most common DREI under “respect for persons and community” is the risk of harming AD/ADRD research participants due to the disclosure of their research results [22, 24, 25, 40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55]. The core issues under this DREI include concerns about the psychological, social, and behavioral harms of disclosure [40, 45, 48, 49, 54], including harm related to discrimination by insurers and others [25, 41, 44, 45], suicide [40, 42, 47, 52, 53, 55], anxiety [40, 50, 52], stigmatization [24, 25, 40, 45, 46, 51, 54, 55], and discrimination [24, 25, 46, 51]. Other concerns under this norm were related to inadequate legal protections for persons with AD/ADRD against various forms of discrimination [25, 41, 44, 49, 54] and the harms that the disclosure of genomics research results may cause to study partners, carers, and relatives of persons with AD/ADRD [22, 24, 25, 55,56,57].

Fig. 3
figure 3

DREIs related to the principle of respect for participants and communities

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DREIs related to this principle were generally published yearly. DREIs related to the harm of disclosure of genomics risks for AD/ADRDs were reported every year except in 2003 and 2008, with two peaks in 2017 and 2021. Concerns about the lack of guidance on disclosure for professionals and the inadequacy of legal protections against genomic discrimination were only raised recently, in 2015 and 2016, respectively. Two new topics – AD/ADRD readiness cohorts and registries using genomic data – were initially raised in 2017, and no more than two papers have raised these concerns since.

DREIs related to “independent review”

The only DREI relevant to this principle is the capacity of research ethics committees (RECs) to review complex and data-centric research studies, which is a characteristic of genomic research [23, 58], as shown in Fig. 4. These concerns were raised only once each in 2008 and 2017.

Fig. 4
figure 4

DREIs related to the principles of independent review and fair participant selection

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DREIs related to “fair selection/recruitment of study participants”

Figure 4 also shows that the risk of unfair recruitment practices when using genomic markers as a requirement for inclusion or exclusion in a given study is the major DREI under the principle of fair participant selection [22, 43, 51, 57]. For example, researchers may allow a subgroup of persons with AD/ADRD “selected based on genotyping to enroll in clinical trials and incur all the associated risks” [57]. There are also concerns related to the validity of informed consent when using a transparent enrollment approach (requiring genomic risk status disclosure before inclusion) [45] and of researchers enrolling low-risk AD/ADRD participants as a means of avoiding disclosure [48]. Overall, none of the DREIs under this principle were consistently reported in the papers we reviewed. For example, the DREI on unfair participant recruitment due to genomic marker-based enrollment, which had the highest number of reports under this principle, was only reported in 1999 initially and most recently in 2017, with reports in four papers overall.

DREIs related to “favorable risk-benefit ratio”

The principle of favorable risk benefit ratio had three additional subcategories—“determining risk adequately”, “considering risk adequately” and “managing risk adequately”, as shown in Fig. 5. The “managing risk adequately” subprinciple had the most DREIs (10 DREIs). Among these DREIs, discrimination by insurers and employers was the most commonly reported [23,24,25, 41, 43, 46, 55, 59]. There were two other important DREIs under this subprinciple. The first is discrimination risks that positive genomic marker status poses to affected persons, largely by insurers and employers [23,24,25, 46, 55, 59]. The second is the risk of disclosure of risk marker status, leading affected persons to misinterpret the state of their cognitive capacity (assuming they already have AD and hence question their cognitive ability even though the risk marker is only predictive of the risk of AD-related cognitive decline) [24, 47, 49, 50, 60].

Fig. 5
figure 5

DREIs related to the principle of “favorable risk-benefit ratio”

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Except for the year 1994, DREIs related to this principle were reported every other year, including 2021, which was the last year in our review and one with the most DREIs (8). The risk of discrimination under the “managing risks appropriately” subcategory had the most consistent reports over the years, with eight papers between 1994 and 2021 out of the 24 ethical issues under this subcategory and 31 overall under the principle.

DREIs related to “social value”

Concerning the social value principle, Fig. 6 shows that two key DREIs were reported. One was concerned with genomic screening and counseling for family members of persons diagnosed with AD/ADRD [57], and the other was concerned with the risk of harm due to the incorrect perception of the utility of AD/ADRD results (Fig. 6). The latter DREI is specifically concerned with the risk that participants may ascribe some degree of clinical validity to their genomic test results and take actions, some of which may be negative, whereas such results are only risk-predictive [61]. Only two papers, one each in the year 2000 and the other in the year 2018, addressed these two DREIs.

Fig. 6
figure 6

DREIs related to the principle of “social value”

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DREIs related to “scientific validity”

The principle of scientific validity had five additional subcategories—“research design and planning”, “recruiting bias”, “informant bias”, “drop out”, and “agenda setting”—with two DREIs that were most commonly reported, as shown in Fig. 7. The first most reported DREI is under the “research design and planning” subcategory and is concerned with balancing standards against personal methodological preferences [41, 45, 49]. This relates to researchers’ choice for a methodological preference, such as blinded enrollment (in which genomic risk marker status is not disclosed to participants at enrollment), for example, against the need to have enough eligible research participants enrolled in a study [45]. The second is the DREI under the “agenda setting” subcategory and is concerned with bias in genomics research in AD/ADRD because most studies are conducted among European populations [24, 25, 46, 54]. Four other DREIs related to the risk of stigmatization concerns leading to low participation rates [23], the risk that the equipoise may not be satisfied when enrollment is based on genotype [62], and the risk of biased cognitive judgment due to risk status disclosure [60] were reported only once each between 2003 and 2014. Overall, the DREIs related to the scientific validity principle were sparingly and inconsistently raised over our review period.

Fig. 7
figure 7

DREIs related to the principle of “scientific validity”

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DREIs related to “informed consent”

According to this principle, we identified twelve relevant subcategories (Fig. 8). In the years covered by our review, DREIs related to this principle were reported approximately two-thirds of the time. The most reported DREIs were about two subcategories: “consent understanding” and “proxy/substitute consent”. For “consent understanding”, the challenge of ensuring that research participants understand some of the complex languages used in genomics research (e.g., exome sequencing) is the most reported DREI [51,52,53, 61]. Concerning proxy/substitute consent, two DREIs were prominent. The first concerns the potential of bias in the decision of proxies because they share genotype with the AD/ADRD person [22, 58]. The other DREI is concerned with the risk that proxy consent in large family AD/ADRD genomics studies may violate the right not to know of other family members if they are not part of the consenting process [22, 23]. The remaining DREIs for which there were publications were referred to by at most one paper, except for the DREI on the risk of compromising the integrity of informed consent because researchers lacked the skills to adequately administer AD/ADRD consent due to related complexities [51, 54]. Overall, there were no more than two reports for 16 out of the 19 DREIs under this principle, showing room for further research related to this principle.

Fig. 8
figure 8

DREIs related to the principle of “informed consent”

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For “collaborative partnership”, no DREI relevant to genomics research in AD/ADRD was identified from the studies included in this review.

Discussion

In this systematic review, we identified 75 DREIs related specifically to genomics research involving persons with AD/ADRD. The majority of these DREIs center around the principles of respect for persons/communities, favorable risk-benefit ratios, informed consent, and scientific validity, while fewer DREIs are related to fair participant selection, independent review, social value, and collaborative partnerships.

Capturing DREIs according to the eight principles of Emanuel et al. and characterizing them by using heatmaps is a practical approach that would enable researchers to identify trends and potential saturation of discussions on specific DREIs. It would also enable researchers and policy makers to identify gaps within and across each principle, which would inform future research, policy reviews, or development plans. Our review is also likely to be of value to research ethics committees in providing adequate oversight and to persons with or affected by AD/ADRD as they consider participating in AD/ADRD studies.

To demonstrate within-principle gaps in DREIs, we identified a preponderance of DREIs related to the principle of “respect for participants and communities”. This finding contrasts with the most common DREIs identified in a report on the ethics of general dementia research by Gotzelmann et al. [27]. Our findings suggest that there is a greater concern for individual, family, and community harms that could result from genomic risk marker status disclosure, which is more relevant in genomics studies of AD/ADRD [63, 64]. Studies suggest an indirect relationship between genomic risk maker status and stigma; such markers only increase stigma risks for health conditions that are already stigmatized by other factors such as culture and religion [65, 66]. Collectively, these observations suggest that further research on the impact of genomic marker risk status disclosure in AD/ADRD patients is needed [24, 25].

We also observed that DREIs on the principle of informed consent are more focused on “understanding the consent process” and “proxy/substitute consent” in diagnostic research, which are only a fraction of the DREIs under this principle. Nevertheless, focusing on these issues is important in research on genomic biomarkers of AD/ADRD, particularly among underrepresented populations such as Africans [67]. The complexity of explaining to participants that they are taking part in a study that is solely for the validation of biomarker tests is of significant concern. The unwillingness of underrepresented populations to participate in AD/ADRD research has been attributed to social factors such as a low level of education [68]. This suggests a need to adequately consider these social determinants that facilitate the comprehension of consent among different populations [55]. Additionally, proxies’ conflicts of interest may affect how their wards participate in AD/ADRD genomics research, especially when research includes diverse populations that are characterized by ‘paternalistic’ cultures [69]. Although paternalism could be justified, it is certainly a problem when the justification is based solely or predominantly on the interests of the proxy. Therefore, supported decision-making is being promoted as a more ethical approach compared to pure proxy/substitute consent [70, 71]. These concerns call for closer consideration of the appropriate informed consent process for diverse populations participating in genomics research in AD/ADRD. This will also address other DREIs of concern under this principle, such as respecting participants’ refusal to use their stored genomic data and the use of advance research directives due to a lack of adequate guidelines.

Another practical application of our findings is related to the risk of stigma and discrimination of persons with AD/ADRDs participating in genomics research. This is associated with gaps in legislation against the disclosure of genomic risk marker status, which is a favorable risk-benefit ratio principle. Whereas in the United States, the Genetic Information Nondiscrimination Act (GINA) protects persons with known genomic predispositions to diseases such as AD/ADRD from discrimination by health insurers or employers [72], research participants are still afraid of discrimination and are not willing to share their genomic risk marker status in the workplace [24, 25]. In the European Union (EU), AD/ADRD genomic marker-based insurance and employment discrimination are regulated under Directive 95/46/CE [73]. However, privacy is regulated differently in member states, with some EU countries regulating privacy as a constitutional right [49]. In African countries, only Malawi has legislation against discrimination based on genomic information [74, 75]. Similarly, in Asia, a seven-country (China, India, Japan, the Philippines, South Korea, Singapore, and Taiwan) study showed that only South Korea has specific legislation preventing genomic discrimination [76]. These observations highlight a global gap in protections for persons involved in genomics research, including genomics research in AD/ADRD, which policymakers and researchers may find useful in strengthening systems to protect participants in such research studies.

Across the principles, we found that few papers focused on DREIs related to the principles of “fair participant recruitment”, “independent review”, “social value”, and “collaborative partnership”. Regarding “fair participant recruitment”, for instance, Fry (1999) questioned how equity would affect research conducted using specific populations, such as those with the APOE gene [43], which affects AD in different populations differently [77, 78]. With independent reviews, RECs face challenges in providing oversight for genomics research, including in AD/ADRD [23, 58, 79]. In African countries, the inadequate capacity of RECs has become a major concern [79]. In the US and EU, some RECs reported facing challenges in conducting risk-based reviews and reviews for data-centric research in AD/ADRD [23, 58]. These challenges highlight the need for more work to understand how best to empower RECs to provide adequate oversight for research on the genomics of AD/ADRD. Last, the discussion on the social value of genomics research in AD/ADRD should extend beyond the personal utility argument. This is not only because some researchers have counter-argued the case for personal utility as a value for disclosing results of genomics research in AD/ADRD [61] but also because the concept of social value often includes discussions about providing benefits to stakeholders at various levels in the research enterprise [80].

Between 1994 and 2021, there was no discernible trend in academic scholarship on most DREIs related to the genomics of AD/ADRD research, except for DREIs related to principles of respect for persons and communities and favorable risk–benefit ratios. This suggests that there has been limited academic discourse in this area. We observed spikes in DREIs reported in 2017 and 2021 related to the principles of respect for persons and communities and favorable risk-benefit ratio, respectively. These included DREIs on topics not discussed in the literature before 2017, including concerns about readiness cohorts and AD/ADRD registries and the use of genomic markers in the process. We also observed that of the 17 DREIs raised regarding informed consent, seven were raised in 2017, five of which had not been raised previously. These newly discussed DREIs include concerns about the experience and skills of researchers to sensibly include and address ethical issues in the informed consent process, the risk of substitute decision-makers not providing adequate protection for data sharing, and reconsenting for longitudinal AD/ADRD genomics research. The spikes seen in DREIs reported in 2017 and 2021 may be related to the heightened attention given to AD/ADRD research arising from the WHO’s publications calling for more research on AD/ADRD, among other measures, to curtail the global estimated increases in its prevalence [81, 82]. Another interesting new topic, discussed only in 2008, has to do with the concept of family consent in family studies, which is likely of even greater interest when conducting genomics studies in AD/ADRD [83].

Furthermore, categorizing our results into ‘ethical outcomes’ (Tables 2 and 3) has added value for different stakeholder groups. Researchers seeking to address specific ethical issues in AD/ADRDs looking at best practice recommendations can refer to specific articles that we have grouped under the “ethical reflection recommendation” to find suggested approaches that they could adopt in their proposed studies. For instance, with the proliferation of AD/ADRD prevention trials, selecting an ethically appropriate enrollment approach is an important consideration. Our detailed table of ethical outcomes (Additional file 3) provides a quick overview of the ethical arguments for and against the use of blinded vs transparent enrollment approaches, as argued by Porteri et al. (2017) and Kim et al. (2015), which can serve as a guide for researchers to determine the appropriate enrollment approach given their context [45, 51].

This study has several limitations. First, we limited the review to papers published in English, and we may have missed relevant papers in other languages, however, we note that some authors of the papers we reviewed were from non-English-speaking countries, including Germany, Mexico, and Spain. The framework we adopted may have resulted in some overlaps among the DREIs. However, this allowed us to document DREIs at broad and more specific levels which is helpful for emphasis and actionability.

All the articles we reviewed were from high-income countries (HICs). Future research from low and middle-income countries (LMICs) may change the priority accorded to different DREIs. Future research should explore the DREIs in more detail thereby allowing sponsors, researchers, or policymakers to make decisions on the need for further research or adequacy of current evidence to inform policy. While some of the issues covered in our review apply broadly to genomics research, the focus on AD/ADRD genomics research would enable identification of unique issues at the intersection of AD/ADRD and genomics research. Similar discourses are applicable to other diseases characterized by cognitive impairment. We focused on AD/ADRD specifically because of concerns that current guidelines and regulations do not provide adequate protection for persons with AD/ADRD undergoing genomics and other research [12, 84]. The upcoming surge in incidence of AD/ADRD in LMICs with cultural, social, and legal perspectives that are different from those of HICs also justify the focus of our review.

Conclusion and recommendations

Our review showed that only a subset of the ethical issues in genomics research involving AD/ADRD global genomics research have garnered the most attention in the literature. These are mostly issues related to the principles of “respect for persons and communities”, “favorable risk-benefit ratio”, “informed consent” and “scientific validity”. There is a dearth of papers on the principles of “fair participant selection”, “independent review”, “social value” and “collaborative partnership”. While this pattern may reflect the areas of most concern for AD/ADRD genomics research ethicists in HICs, we cannot draw firm conclusions that the hitherto underreported areas were being systematically overlooked.

Because most of the articles in our review were from HICs, deeper reflections, research, and scholarly discourse on the ethics of AD/ADRD genomics research in the LMICs is necessary. This would broaden the global discourse and may lead to novel research in currently understudied areas and areas of most concern to LMIC AD/ADRD genomics research participants. Additional empirical and normative research on issues such as the applications and limits of family consent within the evolving clinical spectrum of AD/ADRD is required.

Data availability

Data is provided within the manuscript or supplementary information files.

Abbreviations

AD/ADRD:

Alzheimer’s Disease and Alzheimer’s Disease Related Dementias

DREIs:

Dementia Related Ethical Issues

HIC:

High Income Countries

LMIC:

Low- and middle-income countries

PRISMA:

Preferred Reporting Items for Systematic reviews and Meta-Analyses

RECs:

Research Ethics Committees

References

  1. Jack CR Jr, Bennett DA, Blennow K, Carrillo MC, Dunn B, Haeberlein SB, et al. NIA-AA research framework: toward a biological definition of Alzheimer’s disease. Alzheimers Dement. 2018;14(4):535–62. https://doi.org/10.1016/j.jalz.2018.02.018.

    Article  Google Scholar 

  2. Aisen PS, Cummings J, Jack CR Jr, Morris JC, Sperling R, Frolich L, et al. On the path to 2025: understanding the Alzheimer’s disease continuum. Alzheimers Res Ther. 2017;9(1):60. https://doi.org/10.1186/s13195-017-0283-5. Epub 2017/08/11.

    Article  Google Scholar 

  3. Killin LO, Starr JM, Shiue IJ, Russ TC. Environmental risk factors for dementia: a systematic review. BMC Geriatr. 2016;16(1):175. https://doi.org/10.1186/s12877-016-0342-y. Epub 2016/10/13.

    Article  Google Scholar 

  4. Eid A, Mhatre I, Richardson JR. Gene-environment interactions in Alzheimer’s disease: a potential path to precision medicine. Pharmacol Ther. 2019;199:173–87. https://doi.org/10.1016/j.pharmthera.2019.03.005. Epub 2019/03/17. PubMed PMID: 30877021; PubMed Central PMCID: PMCPMC6827882.

    Article  Google Scholar 

  5. Bird TD. Genetic factors in Alzheimer’s disease. N Engl J Med. 2005;352(9):862–4. https://doi.org/10.1056/NEJMp058027. Epub 2005/03/05. PubMed PMID: 15745976.

    Article  Google Scholar 

  6. Gatz M, Reynolds CA, Fratiglioni L, Johansson B, Mortimer JA, Berg S, et al. Role of genes and environments for explaining Alzheimer disease. Arch Gen Psychiatry. 2006;63(2):168–74. https://doi.org/10.1001/archpsyc.63.2.168. Epub 2006/02/08.

    Article  Google Scholar 

  7. Sims R, Hill M, Williams J. The multiplex model of the genetics of Alzheimer’s disease. Nat Neurosci. 2020;23(3):311–22. https://doi.org/10.1038/s41593-020-0599-5. Epub 2020/03/01.

    Article  Google Scholar 

  8. Bellenguez C, Küçükali F, Jansen IE, Kleineidam L, Moreno-Grau S, Amin N, et al. New insights into the genetic etiology of Alzheimer’s disease and related dementias. Nat Genet. 2022;54(4):412–36. https://doi.org/10.1038/s41588-022-01024-z.

    Article  Google Scholar 

  9. Strittmatter WJ, Saunders AM, Schmechel D, Pericak-Vance M, Enghild J, Salvesen GS, et al. Apolipoprotein E: high-avidity binding to beta-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease. Proc Natl Acad Sci U S A. 1993;90(5):1977–81 PubMed PMID: 8446617; PubMed Central PMCID: PMCPMC46003.

    Article  Google Scholar 

  10. Goldberg TE, Huey ED, Devanand DP. Association of APOE e2 genotype with Alzheimer’s and non-Alzheimer’s neurodegenerative pathologies. Nat Commun. 2020;11(1):4727. https://doi.org/10.1038/s41467-020-18198-x. Epub 2020/09/20. PubMed PMID: 32948752; PubMed Central PMCID: PMCPMC7501268 trials and was supported by NIA grant R01AG051346. E.D.H. has acted as a consultant to Biogen and Ionis. D.P.D. is a consultant for Acadia, Eisai, Avanir, Genentech, Neuronix, and Grifols.

    Article  Google Scholar 

  11. Giri M, Zhang M, Lu Y. Genes associated with Alzheimer’s disease: an overview and current status. Clin Interv Aging. 2016;11:665–81. https://doi.org/10.2147/CIA.S105769. Epub 2016/06/09. PubMed PMID: 27274215; PubMed Central PMCID: PMCPMC4876682.

    Article  Google Scholar 

  12. West E, Stuckelberger A, Pautex S, Staaks J, Gysels M. Operationalizing ethical challenges in dementia research-a systematic review of current evidence. Age Aging. 2017;46(4):678–87. https://doi.org/10.1093/aging/afw250. Epub 2017/01/21.

    Article  Google Scholar 

  13. Kim SYH. The ethics of informed consent in Alzheimer disease research. Nat Rev Neurol. 2011;7. doi: 10.1038/nrneurol.2011.76.

    Article  Google Scholar 

  14. Pennington C, Davey K, Ter Meulen R, Coulthard E, Kehoe PG. Tools for testing decision-making capacity in dementia. Age Aging. 2018;47(6):778–84. https://doi.org/10.1093/aging/afy096. Epub 2018/07/17.

    Article  Google Scholar 

  15. Dubois MF, Bravo G, Graham J, Wildeman S, Cohen C, Painter K. Comfort with proxy consent to research involving decisionally impaired older adults: do type of proxy and risk–benefit profile matter? Int Psychogeriatr. 2011;23. doi: 10.1017/S1041610211000433.

    Article  Google Scholar 

  16. Karlawish J, Kim SYH, Knopman D, Dyck CH, James BD, Marson D. The views of Alzheimer disease patients and their study partners on proxy consent for clinical trial enrollment. Am J Geriatr Psychiatry. 2008;16:240. https://doi.org/10.1097/JGP.0b013e318162992d.

    Article  Google Scholar 

  17. Birchley G. The theorization of ‘best interests’ in bioethical accounts of decision-making. BMC Med Ethics. 2021;22(1):68. https://doi.org/10.1186/s12910-021-00636-0. Epub 2021/06/03.

    Article  Google Scholar 

  18. Torke AM, Alexander GC, Lantos J. Substituted judgment: the limitations of autonomy in surrogate decision making. J Gen Intern Med. 2008;23(9):1514–7. https://doi.org/10.1007/s11606-008-0688-8. Epub 2008/07/12.

    Article  Google Scholar 

  19. Black BS, Rabins PV, Sugarman J, Karlawish JH. Seeking assent and respecting dissent in dementia research. Am J Geriatr Psychiatry. 2010;18. https://doi.org/10.1097/JGP.0b013e3181bd1de2.

  20. Jongsma K, van de Vathorst S. Advance directives in dementia research: the opinions and arguments of clinical researchers – an empirical study. Res Ethics. 2015;11(1):4–14. https://doi.org/10.1177/1747016114523422.

    Article  Google Scholar 

  21. Bemelmans SA, Tromp K, Bunnik EM, Milne RJ, Badger S, Brayne C, et al. Psychological, behavioral and social effects of disclosing Alzheimer’s disease biomarkers to research participants: a systematic review. Alzheimers Res Ther. 2016;8(1):46. https://doi.org/10.1186/s13195-016-0212-z. Epub 2016/11/12.

  22. van der Vorm A, Vernooij-Dassen MJFJ, Kehoe PG, Rikkert MGMO, van Leeuwen E, Dekkers WJM. Ethical aspects of research into Alzheimer disease A European Delphi Study focused on genetic and nongenetic research. J Med Ethics. 2009;35(2):140–2.

    Article  Google Scholar 

  23. van der Vorm A, Rikkert MO, Vernooij-Dassen M, Dekkers W. Genetic research into Alzheimer’s disease: a European focus group study on ethical issues. Int J Geriatr Psychiatry. 2008;23(1):11–5. https://doi.org/10.1002/gps.1825. Epub 2007/05/05.

    Article  Google Scholar 

  24. Largent EA, Bhardwaj T, Abera M, Stites SD, Harkins K, Lerner AJ, et al. Disclosing genetic risk of Alzheimer’s disease to cognitively unimpaired older adults: findings from the study of knowledge and reactions to APOE testing (SOKRATES II). J Alzheimers Dis. 2021;84(3):1015–28. https://doi.org/10.3233/JAD-210675. Epub 2021/10/05.

    Article  Google Scholar 

  25. Largent EA, Stites SD, Harkins K, Karlawish J. That would be dreadful’: the ethical, legal, and social challenges of sharing your Alzheimer’s disease biomarker and genetic testing results with others. J Law Biosci. 2021;8(1):lsab004. https://doi.org/10.1093/jlb/lsab004. Epub 2021/05/28.

    Article  Google Scholar 

  26. Chandra M, Harbishettar V, Sawhney H, Amanullah S. Ethical issues in dementia research. Indian J Psychol Med. 2021;43(5 Suppl):S25–30. https://doi.org/10.1177/02537176211022224. Epub 2021/11/05. PubMed PMID: 34732951; PubMed Central PMCID: PMCPMC8543611.

    Article  Google Scholar 

  27. Gotzelmann TG, Strech D, Kahrass H. The full spectrum of ethical issues in dementia research: findings of a systematic qualitative review. BMC Med Ethics. 2021;22(1):32. https://doi.org/10.1186/s12910-020-00572-5. Epub 2021/03/28.

    Article  Google Scholar 

  28. Strech D, Synofzik M, Marckmann G. Systematic reviews of empirical bioethics. J Med Ethics. 2008;34(6):472–7. https://doi.org/10.1136/jme.2007.021709. Epub 2008/05/31. PubMed PMID: 18511623.

    Article  Google Scholar 

  29. Daniel S, Neema S. How to write a systematic review of reasons. J Med Ethics. 2012;38(2):121. https://doi.org/10.1136/medethics-2011-100096.

    Article  Google Scholar 

  30. Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. 2021;372:n71. https://doi.org/10.1136/bmj.n71. Epub 2021/03/31. PubMed PMID: 33782057.

    Article  Google Scholar 

  31. Mertz M. How to tackle the conundrum of quality appraisal in systematic reviews of normative literature/information? Analyzing the problems of three possible strategies (translation of a German paper). BMC Med Ethics. 2019;20(1):81. https://doi.org/10.1186/s12910-019-0423-5.

    Article  Google Scholar 

  32. Davies R, Ives J, Dunn M. A systematic review of empirical bioethics methodologies. BMC Med Ethics. 2015;16:15. https://doi.org/10.1186/s12910-015-0010-3. Epub 2015/04/18.

    Article  Google Scholar 

  33. Sugarman J, Sulmasy DP. Methods in medical ethics. 2nd ed. Washington, D.C.: Georgetown University Press; 2010. p. xiii, 353.

    Google Scholar 

  34. Strech D, Mertz M, Knuppel H, Neitzke G, Schmidhuber M. The full spectrum of ethical issues in dementia care: systematic qualitative review. Br J Psychiatry. 2013;202. https://doi.org/10.1192/bjp.bp.112.116335.

  35. McDougall R. Reviewing literature in bioethics research: increasing Rigour in non-systematic reviews. Bioethics. 2015;29(7):523–8. https://doi.org/10.1111/bioe.12149. Epub 2015/02/07.

    Article  Google Scholar 

  36. Mertz M, Nobile H, Kahrass H. Systematic reviews of empirical literature on bioethical topics: results from a meta-review. Nurs Ethics. 2020;27(4):960–78 Epub 2020/04/03. doi: 10.1177/0969733020907935. PubMed PMID: 32238039; PubMed Central PMCID: PMCPMC7323745.

    Article  Google Scholar 

  37. Mertz M, Strech D, Kahrass H. What methods do reviews of normative ethics literature use for search, selection, analysis, and synthesis? In-depth results from a systematic review of reviews. Syst Reviews. 2017;6(1):261. https://doi.org/10.1186/s13643-017-0661-x.

    Article  Google Scholar 

  38. The EndNote Team. EndNote. EndNote X9 ed. Philadelphia: Clarivate Analytics; 2013.

    Google Scholar 

  39. Emanuel EJ, Wendler DD, Grady CC. An ethical framework for biomedical research. In: Emanuel EJ, Grady CC, Crouch RA, Lie RK, Miller FG, Wendler DD, editors. The Oxford textbook of clinical research ethics. Oxford: Oxford University Press; 2008. p. 123–35.

    Chapter  Google Scholar 

  40. Alpinar-Sencan Z, Schicktanz S. Addressing ethical challenges of disclosure in dementia prediction: limitations of current guidelines and suggestions to proceed. BMC Med Ethics. 2020;21(1):33. https://doi.org/10.1186/s12910-020-00476-4. Epub 2020/05/13.

    Article  Google Scholar 

  41. Davis DS. Ethical issues in Alzheimer’s disease research involving human subjects. J Med Ethics. 2017;43(12):852–6. https://doi.org/10.1136/medethics-2016-103392. Epub 2017/08/12.

    Article  Google Scholar 

  42. Davis DS. Alzheimer disease and preemptive suicide. J Med Ethics. 2014;40(8):543–9. https://doi.org/10.1136/medethics-2012-101022. Epub 2013/07/12. PubMed PMID: 23842079.

    Article  Google Scholar 

  43. Fry ST. Ethical issues in Alzheimer disease research. Alzheimer Dis Assoc Disord. 1999;13(Suppl 1):S54–58. https://doi.org/10.1097/00002093-199904001-00013. Epub 1999/06/16.

    Article  Google Scholar 

  44. Grill JD. Recruiting to preclinical Alzheimer’s disease clinical trials through registries. Alzheimers Dement (N Y). 2017;3(2):205–12. https://doi.org/10.1016/j.trci.2017.02.004. Epub 2017/04/26.

    Article  Google Scholar 

  45. Kim SY, Karlawish J, Berkman BE. Ethics of genetic and biomarker test disclosures in neurodegenerative disease prevention trials. Neurology. 2015;84(14):1488–94 Epub 2015/03/13. doi: 10.1212/WNL.0000000000001451. PubMed PMID: 25762713; PubMed Central PMCID: PMCPMC4395889.

    Article  Google Scholar 

  46. Manrique de Lara A, Soto-Gomez L, Nunez-Acosta E, Saruwatari-Zavala G, Renteria ME. Ethical issues in susceptibility genetic testing for late-onset neurodegenerative diseases. Am J Med Genet B Neuropsychiatr Genet. 2019;180(8):609–21. https://doi.org/10.1002/ajmg.b.32699. Epub 2018/12/14. PubMed PMID: 30525300.

    Article  Google Scholar 

  47. Milne R, Bunnik E, Diaz A, Richard E, Badger S, Gove D, et al. Perspectives on communicating biomarker-based assessments of Alzheimer’s disease to cognitively healthy individuals. J Alzheimers Dis. 2018;62(2):487–98. https://doi.org/10.3233/JAD-170813. Epub 2018/02/27.

    Article  Google Scholar 

  48. Milne R, Bunnik E, Tromp K, Bemelmans S, Badger S, Gove D, et al. Ethical issues in the development of readiness cohorts in Alzheimer’s disease research. J Prev Alzheimers Dis. 2017;4(2):125–31. https://doi.org/10.14283/jpad.2017.5. Epub 2017/12/01.

    Article  Google Scholar 

  49. Molinuevo JL, Cami J, Carné X, Carrillo MC, Georges J, Isaac MB, et al. Ethical challenges in preclinical Alzheimer’s disease observational studies and trials: results of the Barcelona summit. Alzheimers Dement. 2016;12(5):614–22. https://doi.org/10.1016/j.jalz.2016.01.009. Epub 2016/03/19.

    Article  Google Scholar 

  50. Mozersky J, Hartz S, Linnenbringer E, Levin L, Streitz M, Stock K, et al. Communicating 5-year risk of Alzheimer’s disease dementia: development and evaluation of materials that incorporate multiple genetic and biomarker research results. J Alzheimers Dis. 2021;79(2):559–72. https://doi.org/10.3233/jad-200993. Epub 2020/12/19.

    Article  Google Scholar 

  51. Porteri C, Albanese E, Scerri C, Carrillo MC, Snyder HM, Martensson B, et al. The biomarker-based diagnosis of Alzheimer’s disease. 1-ethical and societal issues. Neurobiol Aging. 2017;52:132–40. https://doi.org/10.1016/j.neurobiolaging.2016.07.011. Epub 2017/03/21. PubMed PMID: 28317644.

    Article  Google Scholar 

  52. Porteri C, Frisoni GB. Biomarker-based diagnosis of mild cognitive impairment due to Alzheimer’s disease: how and what to tell. A kickstart to an ethical discussion. Front Aging Neurosci. 2014;6: 41. https://doi.org/10.3389/fnagi.2014.00041. Epub 2014/03/29.

    Article  Google Scholar 

  53. Post SG. Genetics, ethics, and Alzheimer disease. J Am Geriatr Soc. 1994;42(7):782–6. https://doi.org/10.1111/j.1532-5415.1994.tb06542.x. Epub 1994/07/01. PubMed PMID: 8014357.

    Article  Google Scholar 

  54. Renteria ME, Mitchell BL, de Lara AM. Genetic testing for Alzheimer’s disease: trends, challenges and ethical considerations. Curr Opin Psychiatry. 2020;33(2):136–40 .0000000000000573. PubMed PMID: 31770136.

    Article  Google Scholar 

  55. Schicktanz S, Schweda M, Ballenger JF, Fox PJ, Halpern J, Kramer JH. Before it is too late: professional responsibilities in late-onset Alzheimer’s research and presymptomatic prediction. Front Hum Neurosci. 2014;8:8. https://doi.org/10.3389/fnhum.2014.00921.

    Article  Google Scholar 

  56. Burgess MM. Ethical issues in genetic testing for Alzheimer’s disease: lessons from Huntington’s disease. Alzheimer Dis Assoc Disord. 1994;8(2):71–8. https://doi.org/10.1097/00002093-199408020-00004. Epub 1994/01/01.

    Article  Google Scholar 

  57. Issa AM, Keyserlingk EW. Apolipoprotein E genotyping for pharmacogenetic purposes in Alzheimer’s disease: emerging ethical issues. Can J Psychiatry. 2000;45(10):917–22 Epub 2001/02/24. doi: 10.1177/070674370004501007. PubMed PMID: 11190361.

    Article  Google Scholar 

  58. Thorogood A, Deschenes St-Pierre C, Knoppers BM. Substitute consent to data sharing: a way forward for international dementia research? J Law Biosci. 2017;4(1):133–58. https://doi.org/10.1093/jlb/lsw063. Epub 2017/08/31.

    Article  Google Scholar 

  59. Sevick MA, McConnell T, Muender M. Conducting research related to treatment of Alzheimer’s disease. Ethical issues. J Gerontol Nurs. 2003;29(2):6–12. https://doi.org/10.3928/0098-9134-20030201-05. Epub 2003/03/19.

    Article  Google Scholar 

  60. Lineweaver TT, Bondi MW, Galasko D, Salmon DP. Effect of knowledge of APOE genotype on subjective and objective memory performance in healthy older adults. Am J Psychiatry. 2014;171(2):201–8. https://doi.org/10.1176/appi.ajp.2013.12121590. Epub 2013/10/31.

    Article  Google Scholar 

  61. Bunnik EM, Richard E, Milne R, Schermer MHN. On the personal utility of Alzheimer’s disease-related biomarker testing in the research context. J Med Ethics. 2018;44(12):830–4. https://doi.org/10.1136/medethics-2018-104772. Epub 2018/08/30.

    Article  Google Scholar 

  62. Issa AM, Keyserlingk EW. Current and future clinical trials for Alzheimer’s disease: evolving ethical concerns. Prog Neuropsychopharmacol Biol Psychiatry. 2000;24(8):1229–49. https://doi.org/10.1016/s0278-5846(00. Epub 2000/12/28.

    Article  Google Scholar 

  63. Wauters A, Van Hoyweghen I. Global trends on fears and concerns of genetic discrimination: a systematic literature review. J Hum Genet. 2016;61(4):275–82. https://doi.org/10.1038/jhg.2015.151.

    Article  Google Scholar 

  64. Palk AC, Stein DJ. Ethical implications of genomic research on dementia in Sub-Saharan Africa: addressing the risk of stigma. In: Dubljević V, Bottenberg F, editors. Living with Dementia: Neuroethical Issues and International Perspectives. Cham: Springer International Publishing; 2021. p. 199–221.

    Chapter  Google Scholar 

  65. de Vries J, Landouré G, Wonkam A. Stigma in African genomics research: gendered blame, polygamy, ancestry and disease causal beliefs impact on the risk of harm. Soc Sci Med. 2020. https://doi.org/10.1016/j.socscimed.2020.113091. 258:113091. Epub 2020/06/11.

    Article  Google Scholar 

  66. Matshabane OP, Campbell MM, Faure MC, Appelbaum PS, Marshall PA, Stein DJ, et al. The role of causal knowledge in stigma considerations in African genomics research: views of South African xhosa people. Soc Sci Med. 2021;277:113902. https://doi.org/10.1016/j.socscimed.2021.113902. Epub 2021/04/18.

    Article  Google Scholar 

  67. Klyucherev TO, Olszewski P, Shalimova AA, Chubarev VN, Tarasov VV, Attwood MM, et al. Advances in the development of new biomarkers for Alzheimer’s disease. Transl Neurodegener. 2022;11(1):25. https://doi.org/10.1186/s40035-022-00296-z. Epub 2022/04/23.

    Article  Google Scholar 

  68. Gleason CE, Zuelsdorff M, Gooding DC, Kind AJH, Johnson AL, James TT, et al. Alzheimer’s disease biomarkers in Black and non-hispanic White cohorts: a contextualized review of the evidence. Alzheimers Dement. 2022;18(8):1545–64. https://doi.org/10.1002/alz.12511. Epub 2021/12/07. PubMed PMID: 34870885; PubMed Central PMCID: PMCPMC9543531.

    Article  Google Scholar 

  69. Andoh CT. African communitarian bioethics and the question of paternalism. J Educ Soc Behav Sci. 2016;15(4):1–16. https://doi.org/10.9734/BJESBS/2016/25131.

    Article  Google Scholar 

  70. Dworkin G. Paternalism. Monist. 1972;56(1):64–84.

    Article  Google Scholar 

  71. Devi N, Bickenbach J, Stucki G. Moving toward substituted or supported decision-making? Article 12 of the convention on the rights of persons with disabilities. Alter. 2011;5(4):249–64. https://doi.org/10.1016/j.alter.2011.07.002.

    Article  Google Scholar 

  72. Arias JJ, Karlawish J. Confidentiality in preclinical Alzheimer disease studies: when research and medical records meet. Neurology. 2014;82(8):725–9. https://doi.org/10.1212/wnl.0000000000000153. Epub 2014/01/31.

    Article  Google Scholar 

  73. Coppieters Y, Leveque A. Ethics, privacy and the legal framework governing medical data: opportunities or threats for biomedical and public health research? Arch Public Health. 2013;71(1): 15. https://doi.org/10.1186/0778-7367-71-15. Epub 2013/06/27.

    Article  Google Scholar 

  74. Joly Y, Feze IN, Song L, Knoppers BM. Comparative approaches to genetic discrimination: chasing shadows? Trends Genet. 2017;33(5):299–302. https://doi.org/10.1016/j.tig.2017.02. Epub 2017/04/04.

    Article  Google Scholar 

  75. Nmehielle VO. Genomics, insurance and human rights: is there a place for regulatory frameworks in Africa? Afr J Legal Stud. 2006;2(1):20–34. https://doi.org/10.1163/221097312X13397499736381.

    Article  Google Scholar 

  76. Kim H, Ho CWL, Ho CH, Athira PS, Kato K, De Castro L, et al. Genetic discrimination: introducing the Asian perspective to the debate. NPJ Genom Med. 2021;6(1):54. https://doi.org/10.1038/s41525-021-00218-4. Epub 2021/07/03.

    Article  Google Scholar 

  77. Hendrie HC, Murrell J, Baiyewu O, Lane KA, Purnell C, Ogunniyi A, et al. APOE ε4 and the risk for Alzheimer disease and cognitive decline in African americans and Yoruba. Int Psychogeriatr. 2014;26(6):977–85. https://doi.org/10.1017/s1041610214000167. Epub 2014/02/26.

    Article  Google Scholar 

  78. Gao S, Ogunniyi A, Hall KS, Baiyewu O, Unverzagt FW, Lane KA, et al. Dementia incidence declined in African-Americans but not in Yoruba. Alzheimer’s & dementia : the journal of the Alzheimer’s Association. 2016;12(3):244–51 Epub 2015/07/29. PubMed PMID: 26218444; PubMed Central PMCID: PMCPMC4728056.

    Article  Google Scholar 

  79. de Vries J, Abayomi A, Littler K, Madden E, McCurdy S, Ouwe M, Oukem-Boyer O, et al. Addressing ethical issues in H3Africa research – the views of research ethics committee members. HUGO J. 2015;9(1):1. https://doi.org/10.1186/s11568-015-0006-6.

    Article  Google Scholar 

  80. Anja B, Michelle N, Taryn A, Tsaone T, van Peter H, Olorunyomi O, et al. A framework for the promotion of ethical benefit sharing in health research. BMJ Global Health. 2022;7(2):e008096. https://doi.org/10.1136/bmjgh-2021-008096.

    Article  Google Scholar 

  81. WHO. Global status report on the public health response to dementia. Geneva: World Health Organization; 2021.

    Google Scholar 

  82. WHO. Global action plan on the public health response to dementia 2017–2025. Geneva: World Health Organization; 2017. p. 9241513489.

    Google Scholar 

  83. Al P. The value of communities and their consent: a communitarian justification of community consent in medical research. Bioethics. 2021;35(3):255–61. https://doi.org/10.1111/bioe.12820. Epub 2020/10/21.

    Article  Google Scholar 

  84. Thorogood A, Mäki-Petäjä-Leinonen A, Brodaty H, Dalpé G, Gastmans C, Gauthier S. Consent recommendations for research and international data sharing involving persons with dementia. Alzheimers Dement. 2018;14:14. https://doi.org/10.1016/j.jalz.2018.05.011.

    Article  Google Scholar 

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Acknowledgements

Not applicable.

Funding

Research reported in this publication was supported by grant funding for the “Entrenching Training and Capacity in Research Ethics in Nigeria (ENTRENCH)” Program from the Fogarty International Center (FIC) of the National Institutes of Health under Award Number R25TW010514. Additional support was provided by funds through the “Maryland Department of Health’s Cigarette Restitution Fund Program (CH-649-CRF); the University of Maryland Greenebaum Cancer Center Support Grant (P30CA134274) and the “Bridging Gaps in the ELSI of Data Science Health Research in Nigeria (BridgELSI) under Award number U01MH127693. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or the Maryland Department of Health.

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Authors and Affiliations

  1. Center for Bioethics and Research, 102 Basorun Rd, Akobo, Ibadan, Oyo State, 200285, Nigeria

    Aminu Yakubu, Isaac Adedeji, Oluchi C. Maduka, Ayodele Jegede & Clement Adebamowo

  2. Department of Bioethics, Faculty of Multi-Disciplinary Studies, University of Ibadan, Ibadan, Oyo State, Nigeria

    Aminu Yakubu & Oluchi C. Maduka

  3. Department of Sociology, Olabisi Onabanjo University, Ago-Iwoye, Ogun State, Nigeria

    Isaac Adedeji

  4. Department of Sociology, Faculty of the Social Sciences, University of Ibadan, Ibadan, Oyo State, Nigeria

    Ayodele Jegede

  5. Greenbaum Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, MD, USA

    Clement Adebamowo

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Contributions

CA and AY conceptualized and designed the review. AY and AI screened and selected the papers for inclusion. AJ and CA reviewed the screening, selection and categorization of papers and oversaw the resolution of any discordance in the process. AY and OM categorized the studies for synthesis and analysis. CA and AY analyzed the data and drafted the manuscript. All authors read, read, reviewed, and approved the final manuscript.

Corresponding author

Correspondence to Clement Adebamowo.

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Ethics approval and consent to participate

This review was approved by the National Health Research Ethics Committee of Nigeria (NHREC/01/01/2007-09/01/2019), and the University of Ibadan/University College Hospital Joint Ethics Committee (UI/EC/19/0121) as part of the “Research ethics of Alzheimer’s disease and Alzheimer’s disease-related dementias (AD/ADRD) in Nigeria (READING Project)”.

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Yakubu, A., Adedeji, I., Maduka, O.C. et al. Ethical issues in genomics research in persons with Alzheimer’s Disease/Alzheimer’s Disease-related dementia (AD/ADRD): a systematic review. BMC Med Ethics 25, 138 (2024). https://doi.org/10.1186/s12910-024-01141-w

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BMC Medical Ethics

ISSN: 1472-6939

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