Table 1 Clinical, personal, and societal considerations

1

Validity

[14,15,16,17,18,19,20,21,22,23,24,25,26,27,28]

• Clinical criteria have limited validity

• Biomarkers enhance diagnostic certainty and accuracy

• Validity is strong or sufficient (in selected cohorts)

• Predictive value for progression is demonstrated (in selected cohorts)

2

Lack of validity

[14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39]

• Validity is uncertain and insufficient or needs further research

• Predictive value is uncertain and limited or needs further research

• Discerning normal aging from latent disease is difficult or impossible

• Many individuals with AD biomarkers never develop dementia

• Abnormal biomarkers are not the sole cause of AD

• Procedures may be burdensome or risky

• Consequences of misdiagnosis are severe

3

Utility

[14, 16,17,18,19, 21,22,23,24, 26,27,28,29,30,31,32, 34,35,36, 40]

• Drugs can suppress symptoms in some patients

• Lifestyle changes or interventions may be beneficial

• Early diagnosis may lead to better healthcare

4

Lack of utility

[14,15,16,17,18, 20,21,22,23,24, 26,27,28,29,30,31,32, 34,35,36, 38, 40]

• Utility is absent and uncertain or needs further research

• There is no disease-modifying therapy

• Lifestyle changes or interventions have uncertain or modest effect at best

• Lifestyle changes should be done regardless

5

Protocols and training

[14, 16,17,18, 20,21,22,23, 25, 26, 28, 30,31,32, 36,37,38,39,40]

• Protocols, methods, and materials are scarce or required

• Knowledge of genetic or oncological markers may offer a starting point

• Healthcare professionals need to develop knowledge and skills

6

Disclosure

[14,15,16,17,18,19,20,21,22,23,24,25, 27,28,29,30,31,32, 34,35,36,37,38,39,40]

• There is growing consensus toward the use of biomarkers and sharing of results

• Disclosure is difficult, especially to a person with (full) insight

• Safety may be improved by informed consent, pre-test counseling, post-disclosure support, take-home materials, time for reflection, involvement of a relative, and tailoring the approach to the individual’s needs

• Research into the impact of disclosure is scarce or required

7

Certainty

[14, 16, 17, 20, 23, 24, 28, 34, 37, 39]

• An in vivo (biomarker) diagnosis of AD is inherently uncertain

• Individuals may appreciate an uncertain risk prediction

• Individuals may understand uncertainty

8

Uncertainty

[14, 15, 17, 20, 22,23,24,25, 28, 31, 32, 34,35,36]

• Early detection may lead to more or longer uncertainty

• Individuals may expect a certain diagnosis

• Individuals may misinterpret test results

• It is hard to deal and live with uncertainty

9

Actionability (personal utility)

[14,15,16,17,18,19,20,21,22,23,24,25, 27, 28, 31, 32, 34,35,36,37,38,39]

• Individuals and relatives can prepare for the future

• Individuals can advance plans or improve quality of life

• Individuals can contribute to or profit from prevention trials

10

Lack of actionability (personal utility)

[15, 16, 23, 25, 28, 32, 34]

• There is no actionability

• Results may be too uncertain for decisions

• Preparing for the future should be done regardless

11

Positive psychological impact

[14,15,16,17,18,19,20, 22,23,24, 27, 32, 36]

• Result may lead to positive emotions, e.g., relief, solace, or social exoneration (by providing an explanation for behavior or functioning)

• There is value in knowing, understanding, and accepting the situation

12

Negative psychological impact

[14, 16,17,18, 20,21,22,23,24,25,26,27,28,29,30,31,32, 34,35,36,37,38,39,40]

• Result may lead to negative emotions, e.g., fear, anxiety, and depression

• There is risk of catastrophic reactions (euthanasia or suicide)

• Negative reactions may be over-rated, limited, or preventable

• Early detection may increase (subjective) cognitive decline (stereotype threat)

13

Right to (not) know

[14, 15, 17, 19,20,21,22,23,24,25, 27,28,29,30,31,32,33,34,35, 39]

• Individuals have a right to know their status in research and the clinic

• Individuals have a right to not know their status in research and the clinic

• Right to (not) know may be overruled by the principle of primum non nocere (first, do no harm)

14

Wish to (not) know

[14,15,16,17,18,19,20,21,22, 24, 25, 28, 29, 31, 32, 35, 36, 38, 39]

• Many individuals wish to know

• Some individuals do not wish to know

• Individual’s preference should be included in the informed consent

15

Share

[14, 16, 19,20,21, 23, 24, 28, 30,31,32,33, 35, 37,38,39]

• Patients have the right to privacy and confidentiality

• Fear of stigma and discrimination may prevent individuals from seeking help

• A predementia diagnosis may lead to support

16

Support

[14, 20, 22, 28, 30, 32, 37]

• Services are needed to help individuals cope with predementia AD

17

Stigma

[14, 16, 20,21,22,23,24,25,26, 28,29,30, 32, 34, 35, 37, 38, 40]

• Label of AD may lead to loss of status, identity, or personhood

• Label of AD may lead to public stigma, e.g., pity, patronizing, and distancing

• Label of AD may lead to self-stigma

• Label of AD may lead to spillover stigma (extends to relatives)

• Predementia detection may increase the stigma of AD

• Predementia detection may decrease the stigma of AD

18

Discrimination

[14, 16, 17, 20,21,22,23,24, 27,28,29,30,31,32,33, 35, 37,38,39,40]

• Predementia detection may lead to discrimination in employment, insurance, rights (voting and driving), health care, legal status

19

Policy and law

[14, 20,21,22,23,24,25, 28, 30,31,32,33, 35, 37,38,39]

• Current laws do not protect individuals from biomarker discrimination

• Regulation and law should regulate confidentiality and privacy

• Regulation and law should regulate obligation to (not) disclose

• Regulation and law should regulate forced screening or testing

20

Misconception

[14,15,16,17, 19,20,21,22,23,24,25, 27,28,29,30,31,32, 34,35,36,37,38]

• The concept of predementia AD is difficult to explain and understand

• (Re) conceptualization of AD may lead to misconceptions

• At-risk individuals are prone to (therapeutic) misconceptions

• Healthcare professionals are prone to misinterpretation

• The general public is prone to misconceptions

21

Engagement and education

[14, 16, 20,21,22, 24,25,26, 28, 30,31,32, 35, 37,38,39]

• Patients and the public should be involved in the design of protocols and policy

• Education may improve awareness, acceptance, and attitudes

22

Advance research

[14,15,16, 18, 20, 22, 23, 27,28,29,30,31,32,33,34,35, 37, 38, 40]

• Therapies are more likely to prevent than cure AD

• Predementia phase offer opportunities to stop, delay, or slow symptom onset

• Potential interventions will target patients in early stages of the disease

23

Medicalization

[14, 20, 23, 28, 32, 34, 35, 37]

• Predementia detection may lead to medicalization and overdiagnosis

• Predementia detection may increase urgency or treating AD

• Predementia detection may decrease urgency or treating AD

24

Resources

[14, 16,17,18, 20, 22,23,24, 27, 28, 30,31,32,33, 35, 37, 39]

• Tests and treatment may not be affordable or accessible for all

• Predementia detection may exhaust healthcare and overwhelm current systems

• Predementia detection may prioritize prevention over care or other research

• Early detection may lead to higher cost

• Early detection may lead to lower cost

25

Hope

[23, 28, 34]

• Research (participation) should not be motivated by false hope

26

Fear

[14, 16, 23, 24, 26, 29, 31, 32, 34, 35, 37, 39]

• There is a lot of fear for (the implications) of AD

• Predementia detection may increase fear