Direct-to-Consumer AD Test

FYI -

Pat & Dennis Bender Early Dementia Diagnosis & Prognosis Fund

Dennis & Pat 07-84 $C:\Users\jdenb\AppData\Local\Microsoft\Windows\INetCacheContent.Word\Dennis.jpg$ $C:\Users\jdenb\AppData\Local\Microsoft\Windows\INetCacheContent.Word\DSCN2587.jpg$

J. Dennis Bender

Office, Home & Cell Phone: 859-391-5226

5726 La Jolla Blvd. – Suite 311

La Jolla, CA 92037-7345

Office - 100 Riverside Pl. - Suite 303

Covington, KY 41011-5711

We support the development of improved diagnostic methods for the early detection and diagnosis of MCI, Alzheimer’s, vascular and other dementias, their likely prognosis, and best treatment options. We focus on the development of Bayesian-based medical-decision-support systems, comparative-effectiveness research, and the better utilization of these for the above. (After incorporating in KY as a 501(c)(3) in 2002, we dissolved that entity for a simplified form of two entirely self-financed, private philanthropies utilizing a Vanguard Charitable Trust for making annual-research-grants for early-dementia-detection and its correct differential-diagnosis and likely-prognosis. They will continue on, after I am gone, either mentally or physically. Prof. Randall Bateman is the first of our fund’s research advisors.

See: https://www.alz.org/alzheimers-dementia/research_progress/earlier-diagnosis )

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www.JDBender.com – EMS/eVTOL Experimental Aviation Fund (Vanguard Charitable Trust)

www.JDBender.org – Dementia Diagnosis Fund (Vanguard Charitable Trust)

September 2, 2023

“The ‘AD-Detect Test’ is available on the Quest website for $399 to anyone-over-18. . . Based on the available empirical-data on the impact of sharing-results, these authors found that interest among personal-stakeholders was high, and sharing-test-results did not cause significant short-term psychological-harm, yet offered actionability. . . C₂N Diagnostics also sells a CLIA-approved mass-spec-plasma-test using the Aβ42/Aβ40-ratio, [plus tau-ratios,] but their test has extensive development and validation data behind it, and the Company is not marketing directly-to-consumers.

Quest Diagnostics is selling an AD-blood-test directly-to-consumers.
No peer-reviewed data are published on that test.
It has low-specificity, potentially generating many false-positive-results.
Experts fear it will do more harm than good.” [Wrong!]

“Included 35-publications. Most personal stakeholders expressed interest in biomarker-assessment. Learning negative-biomarker results led to relief and sometimes frustration, while positive-biomarkers induced anxiety but also clarity. Meta-analysis of 5 studies including 2,012 participants (elevated-amyloid = 1,324 [66%], asymptomatic = 1,855 [92%]) showed short-term psychological-impact was-not-significant (random-effect-estimate = 0.10, standard-error = 0.23, P = 0.65). Most professional-stakeholders valued biomarker-testing, although attitudes and practices varied considerably. . . Disclosing amyloid-PET-results does not pose immediate psychological-harm to asymptomatic-research-participants, but little is known about social and behavioral implications and the impact in cognitively-impaired-populations.^{24, 25} . . . Compared to those with normal-biomarkers, they [those with MCI] were more-likely to make lifestyle-changes to improve physical and cognitive-health;^{49, 54} adapt-future-plans, including practical, medical, financial, and legal affairs;^{49, 52-54, 59, 63} and reevaluate-priorities to enjoy-time-left and optimize-quality-of-life,^{53-55, 59}” [just as I have!]

Now that I’ve completed my long, frustrating, first-step of a complex-project intended to donate an ultralight-eVTOL to the San Diego Air & Space Museum (see: www.JDBender.com ), I can finally return this Fall to my other, and more-important, long-term project of developing a simple combination of a blood-based, plus other, tests for the early-detection and proper-diagnosis of dementia as to type and its likely prognosis (see: www.JDBender.org )

Having a simple blood-test is a huge improvement over the of little-value, simplistic, quickie, annual mental-health-checklist now used at the annual-wellness-visit. At least that one is better-than-having-nothing but could easily be made so much better. Better education and a better set of more-cost-effective, multiple-bioindicators are what is needed, not resisting their use until some perfect-combo, inexpensive, gold-standard test is ultimately developed. Using these newly-developed, less-expensive, bioindicators now would certainly be a major-step-forward in the right-direction!

I have been funding and actively participating in this sort of dementia diagnostic-biomarker research effort for 22-years now, starting with helping to fund the original development of PiB for amyloid-PET-scans at the U. of Pittsburgh in 2001, being an FDA-volunteer for their approval a decade-ago, along with building-up a Vanguard Trust of now $15.47M (as of 8/31/23) for a dementia-research-grant endowment-fund to further this effort, long after I am gone, now at the age of 81.

My effort is focused on exactly the issue of developing a better combination of biomarkers for the early-detection of dementia and its proper diagnosis, plus determining its most-likely-prognosis; such as by using these newly-developed, blood-plasma tests, now finally being offered by C₂N and others. They are a key component, but only just one component. The optimal, most-cost-effective, combination is what we have been seeking for the past-two-decades.

C₂N offers a similar but likely superior test than the one now being offered by Quest. It too is now available to everyone in the U.S. through their PCP or other healthcare-provider, with just a simple order for a blood-draw for this mass-spec-based test; now readily available at 700+ certified-lab locations in the U.S.

C₂N’s test is a better-researched and more-comprehensive test than the simpler Quest-test, which is limited to just analyzing the amyloid-beta-ratio alone, which C₂N has already been offering for a number of years now. Hopefully, it at least gets folks started with their less-precise, $399 DTC-test; without the hassle I had to go through just to finally get the newly-CLEA-approved and likely-superior C₂N PrecivityAD2 – blood-test-ordered by my own PCP [https://precivityad.com/about-precivityad2-patient.] The following discussion unfortunately skips over that better C₂N-PrecivityAD2 option, with just a brief side-comment, and no further mention of it.

It is time medical-professionals start more-carefully listening to their patients and looking at the actual empirical research data, cited below in detail, instead of just assuming patients are incompetent to understand, or disinterested in participating in, their own mental-health diagnostic and treatment decisions. Given today’s plethora of Internet medical-research resources, that I survey every morning, in addition to having interesting new tools, such as ChatGPT, in addition to now nearly-unlimited medical-research resources, it opens a world-of-opportunity on the near-horizon.

Fortunately, we now have an excellent summary of the actual-empirical-evidence, versus a few misinformed opinions of some healthcare folks, versus we, their patients. Jetske van de Schaar et al. have performed an excellent meta-analysis of 5 published large and well-designed, well-vetted studies, including 2,012-participants of whom 66% had elevated-amyloid-levels, indicative-of-AD, while 92% were asymptomatic. Based on the available empirical-data on the impact of sharing-results, these authors found that interest among personal-stakeholders was high, and that sharing-test-results did not cause significant short-term psychological-harm and offered actionability, just as I have been contending for a very-long-time now.

“Although most healthcare-professionals value-biomarker-testing, attitudes and practices varied considerably. Their results indicate that even in a professional-setting, development and harmonization of testing-guidelines and communication-protocols are required” (van der Schaar et al., 2023). I absolutely agree and totally-support that conclusion.

Better yet, formal, Bayesian-based, medical-decision-analysis is what is sorely needed; based on actual, real-world data, not just on a few medical-professionals’ personal opinions. Talk directly with we geriatric-patients and don’t just make assumptions regarding we seniors being generally incompetent or disinterested in participating in decisions regarding our own mental-healthcare.

All the empirical-evidence is clearly contrary to the proposition that these hypothetical problems might develop and cancel-out the net-gains of widely-providing such tests! We 80+year-old patients are generally smarter than that in dealing with our own healthcare decisions. Don’t try to prevent the majority of us from benefiting from such important new decision-aids, based upon an unproven and undocumented fear that a few might misunderstand and/or misuse them. If one doesn’t want to know one’s results, one always has the easy and obvious option to simply opt-out and ignore them, as some will likely do, but certainly not the majority of us.

The solution is better-education and wider, inexpensive-test availability, not preventing such tests from becoming easily available through PCPs and other healthcare practitioners; such as C₂N’s test now finally is, after many-years-of-delay. The continuing use of extremely-weak, poorly-designed, blunt-instrument tests, such as the very-old, poorly-designed, simplistic, quickie, MMSE or somewhat-improved MoCA test; or worse yet, the current PCP annual-mental-health-checklist; where I scored an honest-score of “0,” indicating no mental problems, what-so-ever; while clearly having amnestic-MCI-of-mixed-etiology, as confirmed with my constantly requested, and now finally obtained, but only after great difficulty, series of comparative, longitudinal-MRI-scans, C₂N’s PrecivityAD2 – blood-test and other related test-results.

[My self-requested donepezil treatment, plus U.K. neurologist-recommended memantine combo has made a noticeable subjective-improvement in my own slowly-deteriorating cognition (see: www.JDBender.org-Memantine, Donepezil, or Combo for details.)]

Direct-to-Consumer Alzheimer’s Blood-Test Opens Pandora’s-Box [or Not]

Madolyn Bowman Rogers – Alzforum - 31 Aug 2023

The first direct-to-consumer Alzheimer’s-disease-blood-test has arrived. Quest Diagnostics, a worldwide diagnostic service headquartered in Secaucus, New Jersey, announced on July 31 that it would market a plasma-Aβ42/ Aβ40 Alzheimer’s-test to the public, [already offered by C₂N but requiring a physician’s order.]

The “AD-Detect Test” is available on the Quest website for $399 to anyone-over-18. After going in for a blood-draw at a Quest-clinic, purchasers will receive a digital-report with the results and be offered the chance to discuss them via telemedicine with an “independent-physician.” The assay uses a mass-spectrometry-methodology similar to blood-tests developed at Washington University in St. Louis, [i.e., C₂N.] Unlike those tests, however, there are no published data on how Quest's test performs, nor on how it was validated.

Alzheimer’s researchers contacted by Alzforum universally decried Quest's decision. In addition to concerns about the test’s-accuracy, they stressed the need for blood-tests to be interpreted by a knowledgeable dementia specialist. “This is clearly not a good idea," Philip Scheltens, who last month retired from VU University, Amsterdam, wrote to Alzforum. “Every diagnostic-test should be used in the context of a proper-workup led by a skilled-clinician,” he added (comment below). Scheltens now heads EQT Life Sciences Dementia Fund.

Suzanne Schindler at WashU noted that people tend to trust blood-tests, and likely will not understand the uncertainty and nuances of being amyloid-positive or -negative. “People will think they have a clear answer, when they do not,” Schindler told Alzforum. More-broadly, lack of clear standards and regulations, combined with high-demand, could lead to many poorly-validated-tests coming on the market.

Scientists have been working on AD-blood-tests for many years, and the topic took on new urgency after the Food and Drug Administration approved the amyloid-immunotherapy lecanemab (Jul 2023 news). More than a dozen such tests are in development at different companies (Hampel et al., 2023). So far, none are FDA-approved. [C₂N’s is CLIA-approved.]

However, diagnostic-tests do not need FDA approval to be marketed to the public. They can clear a lower-bar by becoming CLIA-approved, meaning the assay has good-test-retest-reproducibility. Quest's test cleared this hurdle, but Alzheimer’s-researchers are troubled by the lack-of-information about it. The only publicly available data come from a poster at the 2022 AAIC. In a cohort of 209-people, the test was reported to have a sensitivity of 0.89, specificity of 0.71, and AUC-of-0.82. [Not bad, but C₂N’s is better and based on a much-larger-sample!]

AD researchers said this is not good enough for a consumer-test. Such a test should have greater than 90% sensitivity and specificity, [a purely arbitrary level requirement without formal decision-analysis justification, just his opinion,] said Oskar Hansson at Lund University, Sweden (comment below). Henrik Zetterberg at the University of Gothenburg, Sweden, cautioned that the range-of-Aβ-ratios for amyloid-positive and -negative people overlap significantly. “A direct-to-consumer test has to be super-robust and easy-to-interpret. This is not the case for the plasma Aβ42/Aβ40-ratio, irrespective of which assay is used. The test needs to be interpreted together with additional-biomarkers,” he wrote. [I totally agree, but that is no reason to reject such tests, out-of-hand, without a proper formal Bayesian-based decision-analysis.]

For comparison, the company C₂N Diagnostics also sells a CLIA-approved mass-spec-plasma-test using the Aβ42/Aβ40-ratio, but their test has extensive development and validation data behind it, and the Company is not marketing directly-to-consumers. [Correct!]

How well would Quest's AD-Detect Test work in practice? If it were used in a memory-clinic-population, where 60% of patients have amyloid-plaques, it would misdiagnose 18% of them, Schindler said (Rabinovici et al., 2019). [So what! The current MMSE & MoCA tests are lame but still used because they are quick, easy and cheap, but have terrible test-stats!] However, the test is likely to reach a broader-population, including cognitively-healthy people concerned about their cognition. [So?]

The Company’s website suggests its use for “anyone with a family-history of Alzheimer’s-disease” who is over-50. In this population, where 20% of people have amyloid-plaques, the test would misdiagnose a quarter of them, Schindler calculated based on a recent study (Jansen et al., 2022). In particular, only 43% of positive-results would be true-positives. [Currently available tests have an even higher misdiagnosis-rate than that!] Earlier this month, Quest's website had recommended women take the test regardless-of-age or family-history, but as of August 30, that sentence was no longer there.

Such a large-number of false-positive-test-results would hike demand for follow-up-testing and services from memory-clinics, [just as it should!] This would likely overwhelm them, noted Dennis Selkoe at Brigham and Women’s Hospital, Boston (comment below).

In the absence of expert-guidance, misleading-results could be severely distressing. “In our clinic, we see people in-person to discuss a [possibly] life-changing diagnosis such as Alzheimer’s-disease,” Andrew Budson at the VA Boston Healthcare System wrote to Alzforum. Budson thinks blood-tests are the future but that little good will come of direct-to-consumer-testing. [What actual evidence is there for that opinion? None! Just an opinion. That testing would simply lead to the recommended further testing and evaluation by healthcare professionals using existing CSF and PET-scans, etc.]

Scientists noted many downsides. For one, a cognitively-healthy-person with a positive-test would not qualify for treatment with lecanemab, and insurance would likely not cover follow-up-testing. For another, positive-tests could discourage people from investigating other, treatable, causes for their cognitive-problems, such as medication-side-effects or depression, [no, rather just the opposite,] said Michelle Mielke at Wake Forest University in Winston-Salem, North Carolina. Charlotte Teunissen at Amsterdam UMC fears that inaccurate results will lead people to lose faith in AD-blood-testing. [I very-much doubt that is the case and there is little evidence to support such a contention.] Teunissen cited the Dutch saying, “Trust arrives on foot, but leaves on horseback.” [Is this the best you can offer for demonstrated actual real such issues? Give me a break!]

Mielke and Teunissen are among the world's leading AD-fluid-biomarker-experts. Both are working closely together, with Schindler, Hansson, and many others, in an ongoing effort started by Kaj Blennow, Henrik Zetterberg, [one of my heroes,] and Maria Carrillo in 2011 (Aug 2012 conference news). Called the Global Biomarker Standardization Consortium, aka GBSC, these scientists work to ensure that CSF and blood-tests are being properly-developed, validated, and fully-certified by their respective country's clinical-chemistry agencies, such that they can be robust and trustworthy once they enter-prime-time (e.g. Blennow Q&A;, see also Further Reading below and GBSC page on the Alzheimer's Association website). [A great idea and a worthwhile undertaking!]

In 2022, the Alzheimer’s Association published appropriate-use-recommendations for blood-based-biomarkers. They suggest that, for the time being, these tests be used only in specialty-clinics, with positive-results confirmed by CSF or amyloid-PET (Aug 2022 news). Ultimately, FDA approval will be needed to define a gold-standard-test, Schindler said. [They already have – an autopsy – that frequently, as in my own Father’s case, demonstrate the very high rate of current misdiagnosis! We obviously need something more-useful than that, namely a simple blood-test as a first-step in a sequence of more-elaborate further sequential testing.] She predicted that the longer this takes, the more-chaotic the arena will become in the interim, [so we need to keep improving the available set of bioindicators – not suppress them indefinitely! We already have a long-standing ‘gold-standard’ PET-scan for amyloid and tau, that I helped to fund the develop of way back in 2001, but it is still too expensive for mass-screening, unlike these new plasma-based blood-tests and other biometrics, such as eye-scans, EEG-analysis, etc. that are now being developed.].

Comments

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Philip Scheltens
Alzheimer Center Amsterdam; Head EQT Life Sciences Dementia Fund - Posted: 31 Aug 2023

This is clearly not a good idea. Aside from a far from satisfactory sensitivity and specificity, which leaves far too much room for false-negative and false-positive results, it is also in contrast to what the AD community has always voiced very-clearly: every diagnostic test should be used in the context of a proper-work-up led by a skilled-clinician.

The people who likely seek comfort in ordering such a test are the so-called "worried-well," people who experience memory-problems and worry about incipient-Alzheimer’s-disease. More than 1-out-of-10-of-them will be reassured, falsely, that AD is not present, while an even-larger-percentage will be falsely-suspected-of-AD. This will increase the burden on the healthcare-system, which is already challenged by an increase in patients who want to know whether they are eligible-for-Leqembi.

In a proper-diagnostic-workup, especially in those individuals without dementia, the diagnostic-test results need to be discussed in the context of all other findings, and the diagnostic-and-prognostic-value need to be intensely-discussed. In a recent paper, Jetske van de Schaar et al. performed a meta-analysis of 5-studies, including 2,012-participants of whom 66% had elevated-amyloid-levels indicative-of-AD and 92% were asymptomatic. Based on the available empirical-data on the impact of sharing-results, these authors found that interest among personal-stakeholders was high, and sharing test results did not cause significant short-term psychological harm, yet offered actionability. Although most healthcare professionals valued-biomarker-testing, attitudes and practices varied considerably. Their results indicate that even in a professional-setting, development and harmonization of testing-guidelines and communication-protocols are required (van der Schaar et al., 2023). [Absolutely agree! No problem with that.]

References: van der Schaar J, Visser LN, Ket JC, Groot C, Pijnenburg YA, Scheltens P, Bredenoord AL, van den Hoven MA, van der Flier WM. Impact of sharing Alzheimer’s-disease biomarkers with individuals without dementia: A systematic review and meta-analysis of empirical data. Alzheimers Dement. 2023 Jul 26; PubMed.

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Oskar Hansson
Lund University - Posted: 31 Aug 2023

I am generally against screening of healthy populations, unless rigorous science has shown that such screening approaches result in more good than harm. To do that, large-scale, population-based prospective studies are needed. Such studies should show that the test used for screening must be very-accurate (sensitivity and specificity likely well above 90%). [What is the basis for that purely-arbitrary 90% figure?] That is because the pretest probability of AD will be rather low in the general population, resulting in many false-positive test results. [No reason not to perform the test, along with proper education as to its meaning.]

There must also be a plan in place to detect false-positive results with another test (e.g., amyloid-PET), and the costs for society to do that must be reasonable. Most-importantly, a true, positive test result must be associated with the possibility to initiate a beneficial treatment in all individuals who have received such a result. This is why clinical assessments before testing are vital.

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Dennis Selkoe

Co-Director, Brigham and Women's Hospital's Ann Romney Center for Neurologic Diseases - Posted: 31 Aug 2023

I am against offering a direct-to-consumer Aβ42/40-blood-test for individuals to initiate themselves without oversight by an experienced AD provider, who has formally evaluated the person for AD and other potential neurological conditions in several standard ways. [Specifically which “standard ways?” Don’t tell us just the very-weak MMSE and or MoCA.]

Among several problems with the use of such a consumer-initiated test are the imperfect sensitivity, specificity, and AUC cited by Quest, [all such tests are ‘imperfect,’] a lack of an expert-provider’s guidance about whether to obtain this test, and the lack of expert interpretation of the result in the context of the subject’s fully-documented medical situation. This is a bad idea because it is prone to excessive ordering of a test that would be medically-meaningless for many of those who choose to order it by themselves, including many people younger-than-50, those with exclusionary-medical-conditions-for-AD-treatment, and those without evidence of a cognitive-syndrome-consistent-with-AD.

Moreover, the claim by Quest that this test could enable earlier access to a disease-modifying, amyloid-lowering therapeutic is highly-misleading, because there are strict, detailed, prescribing guidelines as to which patients with definite-signs-of-early-AD should be considered for treatment with lecanemab, the only anti-Aβ-antibody treatment fully approved by FDA at present, [but many-more coming, as we know.]

Further, the AD medical field is already concerned about the lack of sufficient capacity as regards expert-providers familiar with this new class of treatments, and the use of this “over-the-counter” blood-test could lead to many inappropriate subjects coming forward for evaluation of possible AD in a way that may well decrease the access for neurologically appropriate MCI/mild AD patients qualified for lecanemab and for other subsequently approved amyloid-lowering-therapeutics. There are also economic arguments against widespread use of an imperfect, self-initiated-blood-test without full expert guidance on a personal basis. [Again, no citation of published empirical research supporting this contention and opinion.]

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Andrew E. Budson
VA Boston Healthcare System - Posted: 31 Aug 2023

That this test is being marketed directly-to-consumers tells us that people are worried about Alzheimer’s-disease, and that they don’t always want to work through their regular doctor. This is complicated by the fact that many primary-care doctors aren’t knowledgeable about the latest biomarkers or treatments for Alzheimer’s, and by the wait to see dementia specialists being often 6- months-or-longer. I do think that blood tests to diagnose Alzheimer’s-disease are the future, but I worry that the way Quest is going about it is a huge mistake, for two reasons.

First, as many people have pointed-out, the sensitivity isn’t so bad at 89%, but the specificity, at 71%, is terrible, [compared with what? C₂N’s is better than that,] meaning that a lot of people will be told that the biomarker suggests they have Alzheimer’s-disease when they do not.

Second, in our clinic, we don’t give amyloid or tau biomarker results back over-the-phone—we see people in person to discuss a life-changing-diagnosis such as Alzheimer’s-disease. I cannot imagine any good that will come of someone finding-out that they are likely to have Alzheimer’s-disease and then, at some time later, needing to seek out a doctor who can help them understand what the test means and what they should do about it. [Again, the assumption of the average patient being incompetent in decision-making! Most of them are not incompetent and seek-out many sources of information, in addition to their PCPs.]

The bottom-line is that, like it or not, primary-care-physicians will need to become knowledgeable about Alzheimer’s-disease and its biomarkers. There simply aren’t enough specialists out there to evaluate all the older-individuals at-risk for this disease. Blood-tests-for-Alzheimer’s are the future, but they should be done through one’s doctor, and with a test that has higher sensitivity and specificity. [Of course, we all want higher sensitivity and specificity, but seeking perfection cannot become the enemy of the good.]

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Charlotte Teunissen
VU University Medical Center - Posted: 31 Aug 2023

This is a very-worrying development, and may harm the process of implementation of blood-based-biomarkers. As the Dutch saying goes, “Trust arrives on foot, but leaves on horseback.”

The lack of any data is a very-serious problem. [There is plenty of other evidence.] Even if the assay is similar to C₂N’s, that does not imply the same performance characteristics. Not all mass-spectrometry-assays have the same discriminative value, or correlate well with each other. See the global Alzheimer’s Association round-robin study on plasma Aβ methods (Panee et al., 2021).

First of all, data should be disclosed. Did they test prospectively in real-world-settings? And in the wider/general-population, which they seem to target? Which reference-standard was used for evaluation? These are only a few of the questions to address.

Data shown by others, repeatedly, have indicated that only a 10%-15% reduction in plasma-amyloid-ratios is observed in those who are amyloid-positive on a group-level, and in the earlier-stages-of-disease this difference might be smaller even. Therefore, assays must be of extremely high quality to perform well for individual patients. As long as Quest fails to disclose its data, testing cannot be done with this assay.

Next, Alzheimer’s-biomarker-testing should always be done in the clinical-context, taking the patient-history into account and the evaluation of their cognitive-performance by healthcare professionals. [Of couse, but not exclusively.]

I am concerned this commercially-driven announcement by Quest will lead to people obtaining a blood-test result that they cannot interpret or contextualize themselves. They will likely seek medical advice, which will lead to an overload of the healthcare-system. [“Overload” really? What evidence of this is there? PCPs, psychiatric-social-workers, etc. can all deal with it.]

References: Pannee J, Shaw LM, Korecka M, Waligorska T, Teunissen CE, Stoops E, Vanderstichele HM, Mauroo K, Verberk IM, Keshavan A, Pesini P, Sarasa L, Pascual-Lucas M, Fandos N, Allué JA, Portelius E, Andreasson U, Yoda R, Nakamura A, Kaneko N, Yang SY, Liu HC, Palme S, Bittner T, Mawuenyega KG, Ovod V, Bollinger J, Bateman RJ, Li Y, Dage JL, Stomrud E, Hansson O, Schott JM, Blennow K, Zetterberg H. The Global Alzheimer's Association Round Robin Study on Plasma-Amyloid-Β Methods. Alzheimers Dement (Amst). 2021;13(1):e12242. Epub 2021 Oct 14 PubMed.

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Michelle Mielke
Mayo Clinic - Posted: 31 Aug 2023

I do have several concerns about the Quest direct-to-consumer-test. Below are just some of them.

First, there is no published data on the test’s performance or how the cutoffs were determined. Other blood-tests that are currently clinically available, albeit not FDA-approved, have been rigorously researched and the results presented to the public, and for peer review. It cannot be assumed that Quest’s test has good-accuracy just because it is mass-spec-based, which is similar to WashU’s test methodology.

Second, current guidelines for the use of Alzheimer’s-disease-blood-based-biomarkers recommend them for symptomatic-individuals to aid in the diagnosis-of-Alzheimer’s—it is advised that AD-blood-tests not be used for asymptomatic-individuals until more information regarding their prognostic ability can be obtained. The field is currently trying to understand how to best implement blood-markers in primary-care for the diagnosis-of-AD in symptomatic-individuals.

Moreover, an individual’s perceived-cognitive-change could be due to a variety-of-reasons, some of which are modifiable, e.g. medications, chronic-conditions, depression, and a positive-test-result in these individuals could be incidental. Thus, AD-blood-tests should not currently be used in asymptomatic-individuals only, under a physician’s guidance, for those with objective-cognition-changes that may be due to AD.

Lastly, if this test is going to be available direct-to-consumer in the general-population, then a rigorous assessment of this test in a diverse-population-based cohort is necessary first.

[So easy to say all this, after decades of saying so, but then doing little to make it happen! We who have been, have a different point-of-view.]

Review Article - Open Access

Impact of Sharing Alzheimer’s-Disease Biomarkers With Individuals Without Dementia: A Systematic Review and Meta-Analysis of Empirical Data

Jetske van der Schaar, Leonie N. C. Visser, Johannes C. F. Ket, Colin Groot, Yolande A. L. Pijnenburg, Philip Scheltens, Annelien L. Bredenoord, Mariëtte A. van den Hoven, Wiesje M. van der Flier

First published: 26 July 2023 - https://doi.org/10.1002/alz.13410

PDF

Abstract

Introduction We conducted a systematic-literature-review and meta-analysis of empirical-evidence on expected and experienced implications of sharing Alzheimer's-disease (AD) biomarker-results with individuals without dementia.

Methods PubMed, Embase, APA PsycInfo, and Web of Science Core Collection were searched according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Results from included studies were synthesized, and quantitative-data on psychosocial-impact were meta-analyzed using a random-effects-model.

Results We included 35-publications. Most personal stakeholders expressed interest in biomarker assessment. Learning negative biomarker results led to relief and sometimes frustration, while positive biomarkers induced anxiety but also clarity. Meta-analysis of 5 studies including 2,012 participants (elevated-amyloid = 1,324 [66%], asymptomatic = 1,855 [92%]) showed short-term psychological-impact was-not-significant (random-effect estimate = 0.10, standard error = 0.23, P = 0.65). Most professional-stakeholders valued biomarker-testing, although attitudes and practices varied considerably.

Discussion Interest in AD biomarker-testing was high and sharing their results did not cause psychological-harm.

Highlights

Most personal stakeholders expressed interest in Alzheimer's-disease-biomarker-assessment.
Personal motivations included gaining-insight, improving-lifestyle, or preparing-for-the-future.
There was no short-term psychological impact of sharing-biomarker-status, implying it can be safe.
Most professional stakeholders valued-biomarker-testing, believing the benefits outweigh the risk.
Harmonized-guidelines on biomarker-testing and sharing results are required.

1 Background The pathophysiological-hallmarks of Alzheimer’s-disease (AD) start accumulating 20-to-30-years before the onset-of-cognitive-decline.1^-3 Decades of fundamental research and technological innovations have enabled in-vivo detection of these protein-changes in cerebrospinal-fluid (CSF) and using positron-emission-tomography (PET) scans. This has led to a shift toward a biological-definition-of-AD, by characterizing individuals based on the presence of AD-associated-pathology. The “ATN” (amyloid/tau/neurodegeneration) research framework denotes AD as the combination of abnormal-amyloid and abnormal-tau, meaning persons with this profile have the disease, even if they don't fulfill criteria for dementia (yet).4 While the construct was introduced for research purposes, the approval of disease-modifying-therapies,5^,6 increase of prognostic-accuracy,7^-9 and advancements in blood-based-biomarkers10^-13 suggest biomarker-testing may move into clinical-practice to improve-diagnostic-accuracy, and therapeutic-decision-making.14

At the same time, this has fueled a heated and ongoing debate in the field. When patients without substantial cognitive deficits visit a memory-clinic, is it ethically acceptable to conduct AD biomarker assessments and communicate the outcome? Learning whether amyloid or tau pathology is present in the brain may offer a chance to improve one's health, prepare-for-the-future, and optimize-quality-of-life.15^-17 Yet, being aware of living on the AD-continuum may also involve risks of emotional burden, stigma, and discrimination.18^-20 As such, clinicians have a duty-to-do-no-harm, but also to provide good care, whereas individuals have a right to (or not to) know their test results.21^-23 Previous reviews indicate that disclosing amyloid-PET-results does not pose immediate psychological-harm to asymptomatic-research-participants, but little is known about social and behavioral implications and the impact in cognitively-impaired-populations.24^,25

To address these issues, we recently conducted a systematic review of theoretical data, and identified 26 diverse and contradictory considerations related to a clinical, personal, and societal context.26 A next step is to examine how these, and perhaps other, aspects are perceived by stakeholders, including the general public, patients, families, and health-care professionals. In this study, we therefore aimed to provide an overview of empirical data on expected and experienced implications of sharing AD biomarker results with individuals who do not have dementia (yet).

2 Methods A systematic literature search was conducted (by J.C.F.K. and J.v.d.S.) and reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Statement guidelines.27 Our query combined synonyms and spelling variations on the terms “Alzheimer's” AND “disclos*” OR “diagnos*” AND “predementia” AND “biomarkers,” using controlled standardized keywords as well as free-text terms (Material S1 in supporting information). We searched PubMed, Embase, APA PsycInfo, and Web of Science Core Collection from inception up to November 10, 2021. Additional records were identified through other sources, for example, reference-lists.

To be included, publications had to present empirical-data (quantitative or qualitative) on expected or experienced implications of disclosing amyloid and/or tau results to cognitively-normal (CN) individuals or those with subjective-cognitive-decline (SCD) or mild-cognitive-impairment (MCI; corresponding to clinical-stages 1–3 in the ATN-framework).28 Data could be collected from any perspective, including patients, family members, clinicians, and so forth. The scope was limited to scientific articles written in English for which the full-text was available (no editorials, commentaries, conference proceedings or [sections of] books). Studies on later stages and other types of dementia or neurodegenerative-diseases were not included, as well as those primarily focused on trial-design or genetic-risk.

Two authors (J.v.d.S. and W.M.v.d.F.) independently screened all titles and abstracts. Articles marked as potentially relevant were assessed for eligibility based on full-text. In case of discrepancy, arguments for inclusion and exclusion were discussed while re-examining the contents and criteria. In all cases consensus was reached.

Included articles were grouped according to design (qualitative, quantitative), study-population, and timing (i.e., expectations before or experiences after disclosure). Content was analyzed inductively, by identifying and categorizing main findings. We summarized the results narratively by the most common themes emerging from the data.

Studies reporting sufficient quantitative-data on the psychological-impact of biomarker-disclosure were included in a meta-analysis. From these we extracted pre- and post-disclosure measurements and calculated standardized-mean-differences in test-scores of anxiety, depression, stress, or suicidality. A random-effects-model was used to synthesize effect-sizes. In case of multiple follow-up assessments within a single study, we selected the measurement closest to 3-months after disclosure, as this was the most-common follow-up time across publications. Two corresponding authors of studies included in the meta-analysis were contacted for additional information, and both responded. Risk-of-bias was assessed by two authors (J.v.d.S. and C.G.) independently using the Risk of Bias In Non-randomized Studies—of Interventions (ROBINS-I) tool (Material S2 in supporting information).29

3 Results The flow-diagram in Figure 1 shows that our database search, complemented with additional records identified through other sources, and after removing duplicates, yielded 8,046 records. Two reviewers independently screened all titles and abstracts, by consensus excluding 7,853 for not addressing the topic-of-interest. Subsequently, 193 full-text records were examined for eligibility. After applying selection-criteria, we included 35 articles.

Research in Context

Systematic Review: We searched PubMed, Embase, APA PsycInfo, and Web of Science Core Collection for articles on disclosing Alzheimer’s-disease (AD) biomarker results to individuals without dementia. As a biological definition of AD is increasingly used in research, and a small but growing body of evidence has emerged, we conducted a systematic-review of the broad implications of early-biomarker-testing.
Interpretation: Personal-stakeholders’ high-interest in biomarker-assessment was motivated by gaining insight, reducing dementia-risk, or preparing-for-the-future. Those testing-positive reported changing their lifestyle and plans, yet some worried about stigmatization. Most understood the meaning of biomarker results. The majority did not regret being informed. Attitudes among professional-stakeholders were positive, but practices varied.
Future Directions: There is a need of developing guidelines and recommendations for how to incorporate biomarker-testing and sharing results in diagnostic-work-up, particularly considering the imminent advancements in disease-modifying-treatment.

Figure 1

Open in figure-viewer

Flow-Diagram of Study-Selection Of these, 19 presented quantitative data,30^-48 1 mixed-methods research,49 and 15 qualitative data.50^-64 As the designs varied considerably, we classified them in three categories, according to population and timing. 27 articles reported on perspectives of personal stakeholders, that is, members of the general public, research participants, study partners, patients, caregivers, or relatives.32^-34^,36^-38^,40^,41^,44^,46^-57^,59^-64 13 of these assessed expectations before (hypothetical) testing (Table 1),33^,34^,36^,40^,44^,46^,50^,51^,56^,57^,60^-62 and 14 addressed actual experiences after disclosure of results in a research setting (Table 2).32^,37^,38^,41^,47^-49^,52^-55^,59^,63^,64 The remaining 8 represented attitudes and practices of health-care professionals, including general-practitioners, neurologists, and dementia-specialists (Table 3).30^,31^,35^,39^,42^,43^,45^,58

Table 1 - Publications on personal stakeholders’ expectations before (hypothetically) learning-biomarker-results.

Quantitative
Authors (year)	Design (determinants)	Population (cohort)	Scenario	Outcome measures	Results	Conclusion
Stites et al. (2022)46	Randomized controlled survey with vignettes of no/mild/moderate symptoms, ‘positive’/‘negative’ biomarkers, and with/without disease-modifying treatment	1,817 members of general public (national panel, US)	Appraising a hypothetical person with preclinical biomarker diagnosis	Stigma (FS-ADS)	Vignettes with asymptomatic persons evoked weaker reactions of stigma than those with mild/moderate dementia (all P < 0.001). Positive biomarker results yielded harsher judgments on all but one stigma domains, compared to negative outcomes (all P < 0.001). Availability of a disease-modifying treatment had no significant effect (P > 0.05).	Dementia stigma spills over into preclinical AD, regardless of treatment.
Gooblar et al. (2015)36	Randomized controlled survey (educational intervention: n = 119, placebo presentation: n = 100; predictors of interest); survey with vignette	219 CN research participants; 1418 members of general public (KADRC; TAPS, US)	Learning actual biomarker (CSF and amyloid PET), genetic (APOE) and cognitive test results	Interest, implications	*95% of research participants wanted to learn their actual research results*. An education intervention lowered this (81%), except in those with high subjective risk, family history, and low research involvement. “Extreme interest” was lower in members of the general public (55% vs. 13%), yet strongest in those likely to participate in research and with family history (44%).	Interest is increased by AD experience and somewhat tempered by education.
Caselli et al. (2014)33	Survey	4,036 CN visitors of AD prevention website (APR, US)	Taking a hypothetical preclinical biomarker and genetic test	Interest, knowledge, implications	80% would want biomarker-testing. Interest was related to male sex, education level, and family history. 33% did not recognize that results reflect risk or presence of AD. If at high risk, 91% would pursue a healthier lifestyle, 77% would obtain long-term care insurance, and 19% would spend all their money for pleasure, but 10% would also seriously consider suicide.	Interested individuals should be educated and psychologically screened.
Caselli et al. (2015)34	Survey (predictors of high risk for suicidal ideation)	287 CN research participants (Arizona APOE cohort, US)	Taking a hypothetical preclinical biomarker and genetic test	Interest, suicidal ideation	72% would want biomarker-testing. If diagnosed with preclinical AD, 6% thought they would consider suicide. These participants were more likely to feel unsupported but did not differ in cognitive or depression scores. Both interest and endorsement of suicidal ideation were substantially lower in this research cohort than in previously reported website cohort (see publication number 3)33	Suicidal ideation is not associated with depression, or cognitive decline.
Sheffrin et al. (2016)44	Survey (predictors of interest in and completion of advance directives)	874 CN research participants (HRS, US)	Taking a hypothetical free and definite predictive test	Interest, completion of advance directives	75% of respondents would want predictive testing. Those willing had similar race and education levels but were more likely to be ≤75 years old and less likely to have completed an advance directive. Interest did not differ by subjective risk or perceived memory. If certain to develop AD, 87% would discuss health plans with loved ones and 81% would complete an advance directive.	Older adults are very interested to engage in advance care planning.
Ott et al. (2016)40	Survey	164 participants of AD registry, CN or with MCI (RIPR, US)	Taking a hypothetical biomarker (amyloid PET) and genetic (APOE) test	Interest, knowledge, implications	81% would want amyloid testing. Interest was related to perceived risk and inversely related to having an affected parent, but not to knowledge. > 70% answered at least four out of six amyloid PET questions correctly. Motivations included arranging personal affairs (74%), participating in research (73%), preparing family (60%), and ending their life once symptomatic (12%).	Individuals are very interested in amyloid testing to assist in making life plans.
Qualitative
Authors (year)	Design	Population (cohort)	Scenario	Themes	Results	Conclusion
Milne et al. (2018)57	Focus groups	48 CN research participants (PREVENT, UK; BBRC/ALFA, Spain)	Taking a hypothetical biomarker (amyloid PET) and genetic (APOE) test	Interest, implications	Most were interested in testing. Willingness and comprehension were shaped by certainty, actionability, and family history. Participants would take action to reduce risk, improve quality of life, and manage the future, but also expected anxiety, (un)welcome vigilance from themselves and others, and loss of social status. The altered time perspective would also change priorities.	Living with risk is likely to be a complex, long-term, and social phenomenon.
Milne et al. (2018)56	Focus groups	48 CN research participants (PREVENT, UK; BBRC/ALFA, Spain), 6 dementia patients and 4 caregivers (EWGPWD, Europe)	Taking a hypothetical preclinical biomarker test	Interest, implications	Participants were interested in testing, motivated by personal utility. Given family history and perception of high risk, they did not expect additional psychological harm, but some mentioned suicide to avoid suffering. Long-term effects included hypervigilance of their own cognition and being second-guessed by others, which was both perceived as valuable and worrying.	Interest depends on personal utility and more on long- than short-term effects.
Vanderschaeghe et al. (2019)61	Focus groups	40 CN stakeholders (10 healthy elderly, 9 informal caregivers, 6 nursing staff, 8 researchers, and 7 clinicians) (stakeholder group, Belgium)	Taking a hypothetical (amyloid PET) biomarker test	Interest, implications	Most would want to know their own results, to have clarity, inform relatives, make arrangements, change lifestyle, and enjoy life more. Arguments con included fear and anxiety, lack of treatment, and risks of tests. Some consequences were classified as both pro and con. They reported a need for information and support, and anticipated patronization and stigmatization.	Individuals are interested, but reasons are diverse, and views differ.
Vanderschaeghe et al. (2017)60	Semi-structured interviews	38 research participants with MCI (BioAdaptAD, Belgium)	Learning actual (amyloid PET) biomarker results	Interest, implications	All participants wished to know their actual research results, to learn what is going on, make future plans, and optimize their health. Half saw no disadvantages, others mentioned emotional impact and fear of regression. Most indicated elevated results would be unpleasant but preferred to know. Terminology of “positive” and “negative” results was sometimes confusing.	Individuals want to know what is going on and to make informed decisions.
Lingler et al. (2022)62	Semi-structured interviews	30 research participants with MCI, 19 caregivers (ADRC, US)	Learning actual (amyloid PET) biomarker results	Interest, knowledge, implications	Interest was high: 24 patients wished to know their actual research results, 4 were still undecided, 2 declined. Most demonstrated adequate understanding of biomarker limitations. Most dyads were motivated by gaining insight in the etiology and prognosis of MCI, to plan ahead or for knowledge's sake. Mention of drawbacks, including negative psychological impact, was minimal.	Individuals are focused on benefits and should be educated on limitations.
Alpinar-Sencan et al. (2021)50	Focus groups	28 patients with mild neurocognitive disorder, 20 relatives, 40 caregivers (various settings, Germany, Israel)	Taking a hypothetical preclinical biomarker test	Interest, motivation, implications, cultural differences	Participants were evenly split pro or con testing. Moral motivation comprised of personal utility for well-being, prospective responsibility for their families, self-determination to control their future, and personal notions of a good life. German participants tended to be more concerned about test validity, more focused on autonomy and more open about suicide.	Attitudes are related to perceived personal utility of the information.
Arias et al. (2015)51	Semi-structured interviews	17 family members of patients with MCI/dementia (memory clinics, US)	Taking a hypothetical preclinical biomarker test	Interest, implications	Most participants reported a positive perspective on testing. Potential benefits included making lifestyle changes, seeking treatment, and preparing for cognitive decline. Risks comprised psychological burden, adverse life decisions, and social harms. Consequences were reported to depend on an individual's (unspecified) personality or traits.	Individuals are interested and reported non-clinical benefits and harms.

Abbreviations: AD, Alzheimer’s-disease; ADRC, Alzheimer’s-disease Research Center; ALFA, Alzheimer's and Families; APR, Alzheimer's Prevention Registry; BioAdaptAD, Biomarker-Based Adaptive Development in Alzheimer’s-disease; BBRC, BarcelonaBeta Brain Research Centre; CN, cognitively normal; CSF, cerebrospinal fluid; EWGPWD, European Working Group of People with Dementia; FS-ADS, Family Stigma in Alzheimer’s-disease Scale; HRS, Health and Retirement Study; KADRC, Knight Alzheimer Disease Research Center; MCI, mild cognitive impairment; PET, positron emission tomography; RIPR, Rhode Island Alzheimer's Prevention Registry; TAPS, The American Panel Survey; US, United States.

Table 2. Publications on personal stakeholders’ experiences after learning biomarker results.

Quantitative
Authors (year)	Design (determinants)		Population		Determinant		Assessment time points		Scenario		Outcome measures		Results		Conclusion
Ryan et al. (2022)41	Longitudinal study		4,327 CN research participants (A4, US)		Amyloid PET status (elevated: n = 1280, not elevated: n = 3047)		Baseline and after disclosure		Learning actual (amyloid PET) biomarker results		Motivation (VPAI)		Participants rated altruism and contributing to research as most important motivations. Before disclosure those with elevated amyloid endorsed confirming or assuaging perceived risk more strongly, which disappeared after adjusting for subjective memory concerns. After disclosure all scores increased across both groups.		Participants are mostly motivated by altruism and contributing to research.
Grill et al. (2020)37	Longitudinal study		1705 CN research participants (A4, US)		Amyloid PET status (elevated: n = 1167, not elevated: n = 538)		Before, at, 1–3 days, and mean of 42/57 days after disclosure for elevated/non-elevated groups		Learning actual (amyloid PET) biomarker results		Anxiety (STAI), depression (GDS), suicidality (CSSRS), concern (CAADS), future time perspective (FTPS), and impact of events (IES)		Participants with elevated amyloid were no more likely to experience short-term increases in depression, anxiety, or suicidality. They did have increased concern about AD (P < 0.001). Individuals with a negative result experienced a slight increase in future time perspective (P < 0.001).		Participants do not experience short-term negative psychological sequelae.
Burns et al. (2017)32	Longitudinal study		97 CN research participants (APEX, US)		Amyloid PET status (elevated: n = 27, not elevated: n = 70)		Before, at, 6 weeks, and 6 months after disclosure		Learning actual (amyloid PET) biomarker results		Anxiety (BAI), depression (CES-D), test-related distress (IGT-AD)		Depression was stable over time and did not differ between groups. A small increase in anxiety at disclosure (P = 0.03) was not sustained over time. Distress was slightly higher in the elevated group at 6 weeks (P < 0.001) and 6 months (P < 0.015), which was predicted by baseline anxiety and depression.		Disclosure to CN participants appears to be safe and well tolerated.
Wake et al. (2020)48	Longitudinal study		42 research participants with SCD (memory clinic, Japan)		Amyloid PET status (elevated: n = 10, non-elevated: n = 32)		Pre, 6, 24, and 52 weeks post-disclosure		Learning actual (amyloid PET) biomarker results		Anxiety (STAI), depression (BDI-II), impact of events (IES-R)		Anxiety, depression, and distress were well within cut-off scores and did not change over time within or between the groups, except at 52 weeks distress was higher in participants with non-elevated amyloid (P = 0.04). This was correlated with baseline anxiety in individuals with normal (P = 0.02), but not with abnormal results.		Disclosure to SCD individuals does not cause psychological risk.
Lim et al. (2016)49	Mixed methods: longitudinal study; semi-structured interviews		11 research participants with SCD (memory clinics, trials matching service, US)		Amyloid PET status (elevated: n = 4, not elevated: n = 7), psychoeducational intervention (yes: n = 6, no: n = 6)		Baseline and 9 or 18 months after disclosure		Learning actual (amyloid PET) biomarker results		Anxiety, depression, stress (DASS), depression (GDS), impact of events (IES-R), memory complaints (MAC-Q)		Disclosure did not affect mood, subjective memory impairment, or perceived risk of AD, nor caused distress, regardless of status. Those with normal results felt relief, those with elevated amyloid were not surprised, given their family history, and more likely to make lifestyle changes. Education did not alter perceived risk.		Disclosure to SCD individuals appears to be safe and tolerable.
Mattos et al. (2019)38	Longitudinal study		24 patients with MCI (ADRC, US)		Amyloid PET status (elevated: n = 12, not elevated: n = 12)		12 daily contacts over 2 weeks after disclosure		Learning actual (amyloid PET) biomarker results		Anxiety and depression (PHQ-2), mood and suicidal ideation (EMA)		No significant effects of amyloid status, time, or interaction were found. Patients with an elevated result had more variability in anxiety from day to day (P = 0.047), and a trend of more variability in depression (P = 0.056) compared to peers with a normal scan outcome.		Ecological momentary assessment is effective for adverse event monitoring.
Taswell et al. (2018)47	Longitudinal study		99 patients with MCI and 34 with AD (memory clinics, Australia)		Amyloid PET status (elevated: n = 104, not elevated: n = 29), age (< 70: n = 58, > 70: n = 75), diagnosis (MCI: n = 99, AD: n = 34)		Median of 35 before and 57 days after scan		Learning actual (amyloid PET) biomarker results		Anxiety (STAI, HADS-A), depression (HADS-D, CES-D, GDS)		Patients reported no change in anxiety or depression before versus after disclosure, overall or in the subgroups. Those with non-elevated outcomes experienced a slight increase in STAI (P = 0.040) and GDS (P = 0.050) based on the Gosset t test, but not Wilcoxon's, so the authors considered this a Type I error.		Disclosure to patients with MCI/AD causes no short-term psychological harm.
Qualitative
Authors (year)		Design		Population		Amyloid PET status		Assessment time points		Scenario		Themes		Results		Conclusion
Largent et al. (2019)63		Semi-structured interviews		80 CN research participants (A4/LEARN, US)		Elevated: n = 50, not elevated: n = 30		4–12 weeks and 12 months after disclosure		Learning actual (amyloid PET) biomarker results		Implications		Two thirds of participants reported not thinking of physician-assisted death, several were ambivalent, and 1 in 5 stated pursuing this upon deterioration. Proportions were roughly equivalent in those with negative results, when asked to consider being positive.		Learning results does not change attitudes toward physician-assisted death.
Largent et al. (2020)54		Semi-structured interviews		80 CN research participants (SOKRATES [A4/LEARN], US)		Elevated: n = 50, not elevated: n = 30		4–12 weeks and 12 months after disclosure		Learning actual (amyloid PET) biomarker results		Comprehension, implications		Most participants understood their results. Those with elevated amyloid viewed the test as serious, given its implications for sense of self and stigma. They reported more changes in health behavior and future plans than those with normal status, who were relieved and reinterpreted their memory concerns.		Participants with elevated amyloid make more changes to health and future plans.
Largent et al. (2021)55		Semi-structured interviews		80 CN research participants (SOKRATES I [A4/LEARN]/SOKRATES II, US)		Elevated: n = 50, not elevated: n = 30		4–12 weeks and 12 months after disclosure		Learning actual (amyloid PET) biomarker and (APOE ε4) genetic results		Sharing results with others		Participants found it burdensome to decide whom, why, and how to tell others. All with elevated amyloid shared this with at least one person close to them, half with friends, and almost none at work. Reasons pro were receiving emotional and future support. Reasons con were avoiding stigma and discrimination.		Decisions about sharing are complicated by stigma and discrimination.
Largent et al. (2021)53		Semi-structured interviews		70 family members of CN research participants (REVEAL-SCAN, US)		Elevated: n = 27, not elevated: n = 43		1.8–33 months after disclosure		Learning actual (amyloid PET) biomarker results		Motivation, comprehension, implications		Interviewees understood (83%) and valued (75%) the test results. Favorable outcomes evoked happiness and relief; increased risk led to disappointment and sometimes vigilance of memory. While noting a lack of medical utility, a third described changes in health behaviors and future plans.		Family members value information but could take on a pre-caregiver role.
Mozersky et al. 201864		Semi-structured interviews		50 CN research participants (SOKRATES [A4], US)		Elevated: n = 50		4–12 weeks and 12 months after disclosure		Learning actual (amyloid PET) biomarker results		Comprehension		62% interpreted their results as increased but uncertain risk of developing AD. Understanding of the probability varied considerably. Some requested more information on the degree of amyloid elevation. 54% expected their results, due to family history or subjective complaints.		Most participants understand the meaning of elevated results.
Vanderschaeghe et al. (2017)59		Semi-structured interviews		38 patients with MCI (BioAdaptAD, Belgium)		Elevated: n = 8, not elevated: n = 30)		2 weeks and 6 months after disclosure		Learning actual (amyloid PET) biomarker results		Comprehension, implications, regret		Most patients could recall their results, some were confused about “positive”/”negative.” Two (A+) had emotional difficulties, three (A–) questioned their outcome. Reported advantages and disadvantages were modified by expectations, biomarker status, and assessment time. One (A+) doubted her decision.		MCI patients’ reactions are related to expectations, test results, and time.
Grill et al. (2017)52		Semi-structured interviews		10 patients with SCD/MCI/dementia and 23 caregivers (memory clinic, US)		Elevated: n = 18, not elevated: n = 2, no scan: n = 6		234 ± 176 days after scan		Learning actual (amyloid PET) biomarker results		Motivation, comprehension, implications, regret		Participants were mainly motivated by learning the cause of cognitive impairment. They commonly expressed relief upon learning the result, regardless of the scan outcome. Nearly all would make the same decision again, although some had unrealistic expectations of diagnostic confidence.		Participants value information but should be counseled on limitations.

Abbreviations: A4, Anti-Amyloid Treatment in Asymptomatic AD; ADRC, Alzheimer’s-disease Research Center; APEX, Alzheimer's Prevention through Exercise; APOE, apolipoprotein E; CN, cognitively normal; BAI, Beck Anxiety Index; BDI-II, Beck Depression Inventory-II; BioAdaptAD, Biomarker-Based Adaptive Development in Alzheimer’s-disease; CAADS, Concerns About Alzheimer’s-disease Scale; CES-D, Center for Epidemiologic Studies Depression; CSSRS, Columbia Suicide Severity Rating Scale; DASS, Depression; Anxiety, and Stress Scale; EMA, ecological momentary assessment; FTPS, Future Time Perspective Scale; GDS, Geriatric Depression Scale; HADS, Hospital Anxiety and Depression Scales; IES, Impact of Events Scale; IES-R, Impact of Events Scale Revised; IGT-AD, Impact of Genetic Testing for Alzheimer’s-disease; LEARN, Longitudinal Evaluation of Amyloid Risk and Neurodegeneration; MAC-Q, Memory Assessment Clinic questionnaire; MCI, mild cognitive impairment; PET, positron emission tomography; PHQ, Patient Health Questionnaire; REVEAL-SCAN, Risk Evaluation and Education of Alzheimer’s-disease: The Study of Communicating Amyloid Neuroimaging; SCD, subjective cognitive decline; SOKRATES (I), Study of Knowledge and Reactions to Amyloid Testing; SOKRATES II, Study of Knowledge and Reactions to APOE Testing; STAI, State-Trait Anxiety Inventory; US, United States; VPAI, Views and Perceptions of Amyloid Imaging questionnaire.

TABLE 3. Publications on professional stakeholders’ attitudes and practices regarding biomarker-testing.

Quantitative
Authors (year)	Design (determinants)	Population	Scenario	Outcome measures	Results	Conclusion
Armstrong et al. (2019)30	Survey (subgroups)	114 clinicians (dementia specialists, neurologists), 107 patient stakeholders (patients, caregivers, and advocates) (AAN; various settings, US)	Doing (amyloid PET) biomarker-testing in CN persons and patients with MCI or dementia.	Attitudes	Compared to clinicians, patient stakeholders judged it more important to test asymptomatic individuals (P < 0.001). They also placed more value on the quantity of amyloid and prognosis of cognitive decline (P < 0.001). The only topic they rated lower than clinicians was the harm of a false positive diagnoses (P < 0.001). No differences were found between other subgroups.	Patients place more value on a diagnosis and testing asymptomatic individuals.
Bertens et al. (2019)31	Survey	102 clinicians (EAN/EADC, EU)	Doing biomarker-testing for diagnosing AD in patients with MCI	Attitudes, practices	< 25% routinely performed CSF and less than 5% amyloid PET testing. 68% used research criteria for diagnosing prodromal AD, for increased certainty, counseling, and follow-up. 32% did not for lack of standards, treatment, and implications. > 80% agreed diagnosing AD was helpful, these patients were more often counseled on follow-up, risk, and advance planning (P = 0.0001).	Diagnosing AD in MCI patients has clinical utility, but standardization is needed.
Frederiksen et al. (2020)35	Survey	110 physicians (EADC, EU)	Doing biomarker-testing for diagnosing AD in patients with MCI	Attitudes, practices	91.8% had access to CSF and 50.9% to amyloid PET biomarker-testing. 85.7% most found them useful. 85.7% always or usually discussed the decision to test with patients. Pre- and postbiomarker counseling varied across centers, as did practices for referral to support groups and advice on preventive strategies. 47% reported discussing driving and advance care planning.	The variability in practice calls for better counseling and communication.
Mormont et al. (2020)39	Survey	26 clinicians (BeDeCo, Belgium)	Doing biomarker-testing for diagnosing AD in patients with MCI or dementia	Attitudes, practices	> 60% recommended CSF biomarker-testing to patients with MCI, in case of abnormal results, nearly all disclosed a diagnosis of AD. 88% believed benefits outweigh risks for patients, 31% observe it is sometimes harmful and 12% often. 92% rarely or never learn patients regret being informed. 92% would want to know their own diagnosis, regardless of the stage.	Diagnosing AD in patients with MCI and abnormal biomarkers is recommended.
Sannemann et al. (2020)42	Survey	343 general practitioners (MOPEAD, Spain, Sweden, Germany, Slovenia, the Netherlands)	Doing biomarker-testing for diagnosing AD in patients with MCI or early dementia	Attitudes, practices	74% of general practitioners valued an early diagnosis, most thought benefits outweigh risks for patients (58%) and relatives (71%). Barriers included lack of confidence, time, and reimbursement of procedures, with significant differences across countries. If a disease-modifying treatment were available, 59% would change their implementation of early diagnosis.	Early diagnosis requires education and time for diagnostic procedures.
Schweda et al. (2018)43	Survey	108 physicians (hospitals/memory clinics, Germany)	Doing biomarker-testing for diagnosing AD in CN persons and patients with MCI	Attitudes, practices	In case of elevated biomarkers 88% disclosed risk or diagnosis to patients with MCI and 53% to subjects with SCD. Practiced differed between university and general hospitals (P < 0.0001). 75% always communicated biomarker results, most expected benefits for future planning (75%), but also psychological stress (82%) and self-stigmatization (70%). 86% required medical guidelines.	There is considerable heterogeneity, and a need for standards and guidelines.
Shulman et al. (2013)45	Survey	159 investigators (clinicians, physicians, coordinators; ADNI, US)	Disclosing (amyloid PET) biomarker results to CN research participants or those with MCI	Interest, attitudes, practices	Although 60% of respondents received requests from research participants with MCI and 55% from CN subjects, 90% never returned amyloid PET results to participants with MCI and 94% to CN subjects. If the FDA approved florbetapir, the majority would inform participants with MCI (73%) or CN subjects (58%) but emphasized a need for guidance on disclosure and research on the impact.	Returning research results is supported but guidance and research are needed.
Qualitative
Authors (year)	Design (determinants)	Population	Scenario	Outcome measures	Results	Conclusion
Tromp et al. (2020)58	Semi-structured interviews	15 physicians (5 general practitioners, 6 geriatricians, 4 neurologists; various settings, the Netherlands)	Doing biomarker-testing for diagnosing AD in CN persons patients with MCI	Attitudes	There was large variability in knowledge and terminology. Considerations in favor but mostly against diagnosing AD in CN persons or patients with MCI included respecting patients’ characteristics and wish to (not) know; (lack of) diagnostic validity and clinical utility; risk, cost, and burden of testing; changing definition of AD; and fear or medicalization.	Diagnosing AD in CN persons or patients with MCI conflicts with views of good care.

Abbreviations: AAN, American Acedemy of Neurology; AD, Alzheimer’s-disease; ADNI, Alzheimer’s-disease Neuroimaging Initiative; BeDeCo, Belgian Dementia Council; CN, cognitively normal; CSF, cerebrospinal fluid; EADC, European Alzheimer’s-disease Consortium; EAN, European Academy of Neurology; EU, European Union; FDA, Food and Drug Administration; MCI, mild cognitive impairment; MOPEAD, Models of Patient Engagement for Alzheimer’s-disease; PET, positron emission tomography; SCD, subjective cognitive decline; US, United States.

3.1 Personal Stakeholders’ Perspective: Expectations 13 publications featured results from studies on personal stakeholders' expectations regarding (hypothetical) biomarker-testing, before receiving the results (see Table 1).33^,34^,36^,40^,44^,46^,50^,51^,56^,57^,60^-62 Authors reported on (hypothetical) interest, comprehension, and implications regarding various types of biomarker-testing in individuals without dementia. 6 articles described quantitative33^,34^,36^,40^,44^,46 and 7 qualitative data.50^,51^,56^,57^,60^-62

3.1.1 Interest All but one study gauged personal stakeholders’ wish to (not) learn biomarker-levels.33^,34^,36^,40^,44^,50^,51^,56^,57^,60^-62 A randomized-controlled-survey among 219 CN research participants, who had undergone blinded-biomarker-assessments, found that 95% wanted to learn their results.36 When posed as a hypothetical-scenario, 72% to 75% CN research participants expected they would want to take a test,34^,44 versus 80% to 81% of (mostly) CN at-risk-individuals involved with an AD-prevention registry.33^,40 Similarly, most or all research participants with MCI in two semi-structured interview studies opted to receive their predetermined-amyloid-status.60^,62 3 studies in (mostly) CN populations found that a family-history and/or high-perceived-susceptibility predisposed for a higher-desire for testing,33^,36^,40 yet in one, a survey among 164 at-risk participants, having an affected parent was inversely-related40 and according to a fourth-study among 874 community-dwelling older-adults self-rated-risk was irrelevant.44 “Extreme-interest” was lower in a survey among members of the general-population (55.1% vs. 12.5%).36 Likewise, qualitative-studies found the majority of individuals were open to predictive-testing.50^,51^,56^,57^,60^,61

3.1.2 Comprehension 7 studies reported on personal stakeholders’ knowledge and comprehension of biomarker-tests and results.33^,36^,40^,56^,57^,60^,62 In a randomized-controlled-survey among 219 CN research-participants interest decreased after an educational-intervention on benefits and limitations, except in participants with high-subjective-risk, family-history, and low-attendance to research-meetings.36 Another study among 164 (mostly) CN at-risk participants found desire-to-learn test results was not associated with factual knowledge about amyloid-brain-imaging.40 In a survey among 4,036 visitors of a prevention-website 33% of respondents did not recognize that elevated-biomarkers (CSF and amyloid PET) in a mildly-symptomatic-person reflected “either increased risk for or presence of AD.”33 Qualitative studies provided more-insight. According to focus-groups with mainly CN research participants, interpretation of biomarker-status was shaped by family-history.56^,57 In two interview studies, patients with MCI demonstrated adequate understanding,62 but were sometimes confused by the use of contra-intuitive-terminology, mistakenly believing that a “negative” result would be the “unfavorable-scenario” and vice-versa.60

3.1.3 Implications All studies inventoried personal stakeholders’ expected implications of learning their biomarker-status.33^,34^,36^,40^,44^,50^,51^,56^,57^,60^-62

In quantitative and qualitative studies most-frequently anticipated positive-implications among all groups included preparing-for-cognitive-decline by arranging medical, financial, legal, and personal affairs;33^,36^,40^,44^,50^,51^,57^,60^-62 adopting a healthier lifestyle to reduce risk;33^,36^,50^,51^,56^,57^,61 obtaining early access to care or medication;40^,50^,51^,56^,57 contributing to research;36^,40^,51^,62 and revising life plans and priorities to enjoy-the-time-left.33^,40^,50^,51^,56^,57^,60^,61 Studies among patients with MCI of mixed-populations also reported gaining insight or clarity.51^,60^-62 Those more-sceptic doubted the clinical-validity, the prognostic-certainty, and the medical-utility.40^,50^,51^,56^,61 A lack of need or benefit was only reported by studies among (caregivers or family members of) patients with MCI.50^,51^,62

If found to be at high-risk of cognitive-decline, participants anticipated stress, anxiety, and depression.40^,50^,51^,56^,57^,60^-62 Qualitative research among patients with MCI and their caregivers or family-members also reported worry about consequences for their loved-ones.51^,56^,60 Several studies examined thoughts about suicide and euthanasia, which individuals mentioned as both benefit and harm.33^,34^,36^,40^,50^,56^,57^,60^-62 They found 10%-to-12% of individuals involved with a prevention-registry reported expected thoughts of ending-one's-life,33^,40 compared to 6% in AD research participants,34 and <0.01% among those whose biomarkers had been measured but not communicated.36 Focus-groups with participants from Germany and Israel found cultural-variation in openness to discussing assisted-dying.50

Most CN individuals would share the presence of AD-biomarker evidence with their spouse, but only half with their friends,33 and few anticipated feeling comfortable disclosing their risk to their employer or health-insurance company.36 Informing others was perceived both as a benefit and liability.56^,57^,60^,61 Although being monitored by physicians and loved-ones was appreciated, it was also feared to turn into surveillance or second-guessing, loss of social and professional status, or the freedom-to-drive-a-car.56^,57^,60^,61 Indeed, a vignette-based randomized-controlled-trial among members of the general-population suggested the stigma-of-dementia spills-over into preclinical-AD, irrespective of treatment-availability.46

3.2 Personal Stakeholders’ Perspective: Experiences 14 publications presented results from studies on personal stakeholders' actual experiences after receiving biomarker results (see Table 2).32^,37^,38^,41^,47^-49^,52^-55^,59^,63^,64 Authors reported on motivation, comprehension, and implications regarding amyloid-PET-biomarker-testing in individuals without dementia. All biomarker results were disclosed in a trial-setting, to 6,419 CN research participants,32^,37^,41^,54^,55^,63^,64 53 with SCD,48^,49 62 with MCI,38^,59 70 caregivers/family-members,52^,53 and 166 in mixed-groups.37^,47 6 articles described quantitative-studies,32^,37^,38^,41^,47^,48 one mixed-methods research,49 and 7 qualitative-data.52^-55^,59^,63^,64

3.2.1 Motivation 3 studies addressed personal-stakeholders’-motivation to be informed of biomarker-status.41^,52^,53 Despite differences in design, results suggest that individuals at (perceived) risk were primarily driven by the wish to confirm or assuage subjective-memory-concerns. A questionnaire among 4,327 CN participants identified altruism/contributing-to-research as the most-important reasons. However those who (unknowingly) had elevated-amyloid scored-higher on motivations-of-perceived-risk, and this association was mediated by perceived-cognitive-problems.41 Similarly, family-members of CN participants with at least one first-degree-relative with AD were mostly-interested in learning their relatives’-predisposition, either to be reassured or make plans accordingly.53 In addition, semi-structured-interviews with patient-caregiver-dyads in various (pre)dementia-stages showed the majority was compelled by wanting to receive a definite (etiological) diagnosis, learn more about the condition, and follow their physician's recommendation to undergo the scan, while reasons for opting-out-of-testing included costs, insurance-coverage, or lack-of-benefits.52

3.2.2 Comprehension 6 studies evaluated personal stakeholders’ comprehension of the test-results,49^,52^-54^,59^,64 3 of which reported on results from the SOKRATES study (Study of Knowledge and Reactions to Amyloid Testing).53^,54^,64 When sharing-amyloid-status after pre-disclosure-education, most CN participants and most family members understood that elevated-levels implied “an increased but uncertain risk of developing AD dementia,” although their understanding of the probability varied considerably and some requested information on the degree-of-amyloid-elevation.53^,54^,64 Half of those with normal-readings and the majority of family-members knew their chances were decreased.53^,54 Yet overall, some participants felt the information was ambiguous or insufficient.49^,53^,54 Patients with MCI who tested-positive could not recall the exact message after disclosure, like their amyloid-negative peers did, although they were able [to] convey the essence in their own-words.59 A few (mostly-less-involved) family-members misinterpreted the results, and some patients with MCI were confused by the terminology, struggling with the notion that a “positive” outcome was “bad.”59 [No surprise!]

3.2.3 Implications The impact of disclosing-test-results to personal-stakeholders was measured in 11 studies.32^,37^,38^,47^-49^,52^-54^,59^,63 7 of these presented quantitative-data. In the largest study, 1,705 CN and pre-scan-educated-participants were informed of their results according to a specified-protocol, and psychologically-assessed before, at, and after-disclosure.37 Individuals with elevated-amyloid-levels (n = 1,167) were no more likely to experience short-term negative-psychological-consequences than those with normal-results (n = 538). However, the positive-group did have increased concern about AD, whereas the negative reported a slight-improvement in future-time-perspective. [No surprise.] One study among 97 CN participants found distress was slightly-higher in the elevated-group,32 while another with 42 participants with SCD reported higher-distress in those with normal-results,48 both associated with baseline-levels of anxiety or depression. Research with 24 patients with MCI measured more-variability in anxiety from-day-to-day in those with elevated-results compared to those with normal-scan outcomes.38 None of the other studies found sustained-effects or significant-differences between groups or over-time.

5 studies provided sufficient data on pre- and post-disclosure measurements of anxiety, depression, stress, or suicidality to be included in a meta-analysis. These assessed CN participants,32^,37 those with subjective-decline,48^,49 or MCI/mild-AD,47 with follow-up times ranging from 6-weeks to 1.5-years. Meta-analysis of the standardized-mean-outcome-difference (pre-disclosure vs. 3-months-post-disclosure) revealed no significant psychological-impact when considering all participants (random-effect estimate = 0.10, standard-error [SE] = 0.23, P = 0.65), nor when considering individuals with negative-biomarkers (estimate = 0.19, SE = 0.32, P = 0.55), or positive-biomarkers (estimate = 0.01, SE = 0.33, P = 0.97) separately (see Figure 2). These forest-plots further show this is consistent across outcomes and studies. Thus, our synthesis of results across quantitative-studies indicates that disclosure does not infer short-term-psychological-harm.

Figure 2

Open in figure-viewer

Forest-plots of the psychological-impact of sharing-AD-biomarkers-results with individuals who do not have dementia. Forest-plots of the short-term psychological impact of sharing AD biomarker results with individuals who do not have dementia, before versus 3-months-after-disclosure, are shown using a random-effects-model, considering all participants (random-effect estimate = 0.10, SE = 0.23, P = 0.65), only biomarker-negative-individuals (left-plot, magenta: random-effect estimate = 0.19, SE = 0.32, P = 0.55) and only biomarker-positive individuals (right plot, magenta: random-effect estimate = 0.01, SE = 0.33, P = 0.97). AD, Alzheimer’s-disease; BAI, Beck Anxiety Index; BDI-II, Beck Depression Inventory-II; CES-D, Center for Epidemiologic Studies Depression; CSSRS, Columbia Suicide Severity Rating Scale; DASS, Depression; Anxiety, and Stress Scale; GDS, Geriatric Depression Scale; HADS, Hospital Anxiety and Depression Scales; SE, standard error; SMD, Standardised Mean Difference; STAI, State-Trait Anxiety Inventory.

Psychosocial-implications were further examined in 7 interview studies with (a)symptomatic individuals and/or relatives,49^,52^-55^,59^,63 including 3 in the SOKRATES study.53^-55 The majority of participants were reassured, relieved, or happy upon receiving normal-test-outcomes,49^,52^-55^,59 although in patients with MCI this was sometimes tempered by not having an explanation for concerns or symptoms.52^,54^,59 CN individuals tended to reinterpret previous “memory-lapses” as normal-aging,53^,54 those with MCI resumed previously-suspended “normal” activities and plans.59

Conversely, upon learning-amyloid-levels-were-elevated, participants felt sadness, worry, or despair,49^,52^-54^,59 although they also indicated they appreciated knowing the cause of the cognitive complaints, having more certainty, and better follow-up and monitoring of health and symptoms.49^,52^,54^,59 Compared to those with normal-biomarkers, they were more-likely to make lifestyle-changes to improve physical and cognitive-health;49^,54 adapt-future-plans, including practical, medical, financial, and legal affairs;49^,52^-54^,59^,63 and reevaluate-priorities to enjoy-time-left and optimize-quality-of-life.53^-55^,59 One interview study among CN participants found that two-thirds of interviewees with elevated-amyloid reported not thinking of physician-assisted-death, several were ambivalent, and approximately 1-in-5 stated pursuing this upon deterioration. Proportions were roughly-equivalent in those with negative-results, when asked to consider-being-positive.63

Some participants with SCD were satisfied with the level or social support,49 and patient with MCI experienced improved relationships, due to more-openness and understanding.59 Others described uncertainties about the future and becoming aware or paranoid of cognitive-slips.54^,59 Family-members acknowledged watching them more-closely,53 to the point where patients with MCI felt that monitoring turned into patronizing-attitudes.59 In addition, participants struggled to decide whom-to-confide-in, as well as why-and-how-to-tell-others-about-their-test-results, for fear-of-negative-reactions, losing-control of the information, and worries-about-stigma-and-discrimination.55^,59 As such, amyloid-imaging was considered different from other medical-tests,53^,54 partially because of the unique-relationship to their identity as perceived by themselves and others.54

Even so, upon-reflection most-interviewees stated they would make the same decision again,52^,59 but cautioned others to reflect on their desire and capacity to learn such sensitive-information about themselves.53

3.3 Professional Stakeholders’ Perspective: Attitudes and Practices 8 studies presented professional-stakeholders’ perspectives on biomarker-testing (see Table 3).30^,31^,35^,39^,42^,43^,45^,58 Authors reported on attitudes-and-practices regarding amyloid-PET-testing in individuals-without-dementia. 7 described quantitative,30^,31^,35^,39^,42^,43^,45 and one qualitative, data.58 6 queried healthcare providers from Europe,31^,35^,39^,42^,43^,58 and 2 from the United States.30^,45

3.3.1 Attitudes Regarding the quantitative-data, 3 studies among European health professionals found that 58%-to-88% believed the benefits-outweighed-the-risks-of-detecting-AD-in-patients-with-MCI.31^,39^,42 In addition, a survey among 26 European physicians found that 12% often observed harm. Furthermore, 92% rarely-or-never learned their patients regretted-being-informed.39 One survey on attitudes regarding predementia-biomarker-testing in the United States reported that, compared to patient-stakeholders, clinicians placed more-value on the harm-of-false-positive-results, but judged it less-important to test-asymptomatic-individuals.30

In contrast, qualitative- data from an interview-study among 15 Dutch physicians led to the conclusion that a predementia-biomarker-diagnosis did not fit with their views-on-good-care, regardless of the absence-or-presence-of-symptoms, for-lack-of-medical-utility.58 [Interesting cultural differences in physician opinions.]

3.3.2 Practices Data on current-practices were quantitative and mostly from European studies.31^,35^,39^,42^,43^,45 A survey among 110 physicians from 42 centers found that 92% had access to CSF and 51% to amyloid-PET-testing.35 However, another questionnaire revealed that <25% of clinicians routinely performed lumbar-punctures or amyloid-imaging.31 Practices on disclosure and terminology differed. According to two other studies, in the case of abnormal-results nearly all Belgian clinicians disclosed a diagnosis-of-AD to patients-with-MCI,39 whereas 88% of German physicians communicated an increased-risk-for-dementia to patients-with-MCI and 53% to persons with SCD.43

In a survey among 159 Alzheimer’s-disease Neuroimaging Initiative investigators from the United States, most never returned amyloid-PET-results to research-participants-with-MCI (90%) or CN-subjects (94%), although after the US Food and Drug Administration's approval-of-florbetapir, [that I was a participant in,] the majority would return them to those with MCI (73%) or even CN individuals (58%) upon-request.45

Reasons for performing biomarker-testing included increasing-diagnostic-certainty, providing-counseling, starting-medical-intervention, facilitating-follow-up-planning, and selecting-research-participants.31 Barriers were lack of: validity, standards, time, confidence, clinical-utility, knowledge-about-the-impact-on-patients-and-relatives, as well as cost, risk, and burden of the procedures.30^,31^,42^,45^,58

In addition, practices on counseling, disclosure, referral-to-support-groups, and advice-on-preventive-strategies, as well as information-on-driving and advance-care-planning varied across countries and between centers,35^,42^,43 illustrating room for developing, harmonizing, and educating testing-standards and disclosure-protocols.43^,45

4 Discussion In our systematic-review of the impact of sharing AD biomarker results with individuals who do not have dementia, from different stakeholders and perspectives, we found that the vast majority of individuals was interested in biomarker-testing, learning their results was well tolerated, and this information was perceived as actionable. Although most-professional-stakeholders valued-biomarker-assessments, their attitudes and practices varied considerably, illustrating the importance of developing guidelines and recommendations for how to incorporate biomarker-testing in diagnostic work-up.

Upon comparing these results to our previous systematic review of theoretical data on this topic, from which we synthesized 26 diverse and opposing considerations, related to a clinical, personal, or societal context, we noticed three things. First, the empirical-studies almost-exclusively addressed clinical and personal-implications; only one examined a societal-consequence, that is, how biomarker-results affect the stigma-related-to-AD.46 Second, authors of theoretical-literature tended to focus-on-risks, whereas participants-of-empirical-studies-were-prone-to-highlight-benefits. Third, patients and relatives identified new nuances and concepts, which were not addressed as extensively in theoretical-literature, including the influence-of-subjective-risk-and-family-history; the dynamic among monitoring, vigilance, and paranoia; and the impact-on-quality-of-life. These findings identify gaps in knowledge and starting-points for future-research. We believe the discrepancies should not be interpreted as contradictory but rather as complementary, as they capture different aspects: the theoretical-data are more reflective of ethical-acceptability in general, while empirical-data are closer to social-acceptance, and both are relevant.65 It is important to consider how both-perspectives can be integrated in a comprehensive-moral-evaluation.66^,67

Among-personal-stakeholders, interest-in-biomarker-information-was-high. Nearly all (80%–94%) participants who had been tested in a research-setting wished to receive their results,36^,60^,62 the vast-majority (72%–81%) of persons involved with AD-studies would hypothetically want to learn their biomarker-status,33^,34^,40^,44^,51^,56^,57^,61 while diverse-samples more-representative of the general-population were about evenly-split-pro-and-con.36^,50 These results are consistent with public-interest in genetic-testing-for-AD-in-the-general-population, which ranges from 51%-to-75%.68^-70 Interestingly, several surveys in our review found associations with subjective-risk and a family-history,33^,36^,40 but in one, having an affected-parent actually lowered desire for biomarker-assessment,40 and in another no relation with perceived-susceptibility was found.44 An explanation for these contradictory findings could be that persons with substantial concerns about their cognitive-health may be a self-selected-target-population for biomarker-assessment in pursuit of insight and control-of-their-future. However, similar to pre-symptomatic-testing for pathogenic-mutations-of-AD,71^,72 for some a high-likelihood and more-caregiving-experience may deter them from wanting to be confronted with their disposition for an incurable-and-fatal-disease.

One of the main-concerns of sharing-biomarker-results with individuals who do not have substantial-symptoms is the emotional-burden of knowing-one's-status.73^,74 Our meta-analysis found that in a protocol with pre-scan-education the short-term-psychological-impact-of-disclosure was not-significant when considering all participants, nor when examining those with positive or negative biomarker separately. This supports the emerging-consensus that the psychological risk of sharing biomarker results to individuals without dementia does not reach the threshold for clinical-concern.75

Some studies in our review reported a (trend-toward) more-variability,38 or a slight-increase in distress, anxiety, or depression,32^,47^,48 in all subjects or either subgroup, even exclusively in those with normal-biomarkers.47^,48 In addition, qualitative-data indicate that while “clean”-scans generally evoked reactions of relief or reassurance, lack of an explanation for concern also gave disappointment or frustration, and although evidence-of-AD-pathology typically led to stress or anxiety, it provided insight and clarity too. These ambivalent-responses to both “good” and “bad” news suggest that the degree of concerns and symptoms (including those too-subtle to be picked-up by neuropsychological-tests) shapes the expectations of individuals and their families, which may in turn modify their reactions to the test outcomes. This hypothesis is supported by recent findings that when scan-results confirm-care-partners’-suspicions-of-elevated-amyloid, they tend-to-report-relief-and-gratitude-rather-than-distress.76 More personal and contextual factors may influence the nature-of-responses, which emphasizes the importance of pre-test-counseling and psychological-screening.77

Another matter of extensive-debate is the actionability of sharing biomarker data, in terms of personal-utility.78 Several of the included studies in CN-participants or individuals with SCD reported that those with elevated-amyloid were more-likely to actually-make-changes-to-their-lifestyle, by adjusting-their-diet, exercising-more, challenging-their-minds, or considering-trial-participation, to remain-cognitively-healthy and to delay-or-prevent-cognitive-symptoms.49^,53^,54 In addition, they were more-likely to actually-prepare-for-the-future, by changing financial, legal, and medical plans, as well as their living-arrangements. Last, they were more-likely to actually-improve-quality-of-life, by adapting-their-use-of-leisure-time.53^,54 This is consistent with research showing that disclosing-genetic-risk-information to asymptomatic-individuals is associated-with-changes-in-health-behaviors-and-preparations-for-cognitive-decline.69^,79^,80 However, although some participants reported sharing their biomarker status with their significant others improved relationships and social support, others struggled to decide whom to confide in and mentioned patronizing, stigmatizing, and discriminating attitudes.55^,59 More research is needed into these social-aspects, the dynamics between benign and adverse implications, and their development in the longer-term.

We found that the majority of professional-stakeholders value-biomarker-testing, believing the benefits-outweighed-the-risks.31^,39^,42 However, as most studies examined attitudes and practices in European healthcare professionals, and the majority involved patients with MCI, these findings may not be representative for all clinicians and populations. In addition, regional and conceptual variations were found. Differences in opinions on what abnormal biomarkers implied for individuals were strongly-related to the desirability-of-testing and the communication-of-results. Dutch physicians believed such outcomes indicated an uncertain-prospect, rather than the definite presence of a disease.58 Whereas Belgian clinicians shared a diagnosis of AD,39 German physicians disclosed an increased risk for dementia.43 These inconsistencies may compound existing misconceptions in society.81^,82 Little is known about the implications of various framings, although one study reported not the label, but the prognosis, contributed to stigma and discrimination.83 There is an urgent need for testing-guidelines and communication-protocols to be developed and harmonized for the implementation in memory-clinic-practice, especially as recent evidence suggests that biomarker-information not only improves-diagnostic-certainty and patient-management, but also institutionalization and mortality.84^-86 The advance of disease-modifying-treatments will further-increase-medical-utility.5^,6

Notably, empirical-data on stakeholders’-interest in learning their biomarker status were mostly based on CN research engaging individuals or members of the general-public, while results on their experiences tended to include more-patients with SCD or MCI, and findings on professional-stakeholders’-attitudes-and-practices mostly surveyed-dementia-specialists. This suggests a gap-in-data, as these are different-situations. Implications of receiving-amyloid-and/or-tau-test-results may differ depending on individuals’ cognition (i.e., CN, SCD, or MCI), and the context in which this information is shared (i.e., as part of trial-participation or in the memory-clinic). Currently, the absence or presence of cognitive impairment determines whether disclosure of test results is only recommended in research settings or also permissible in clinical-practice, although this may change once a preclinical-diagnosis-of-AD-becomes-medically-actionable. Still, our findings suggest subjective-concerns-and-symptoms affect patients’ anticipation-of-the-results and thus the emotional-impact-of-learning-them, as elevated-biomarkers may confirm or explain suspicions, while those without worries or unaware-of-signs may be less-prepared to receive “bad-news.” Especially for the latter, pre-test-screening, counseling, and education (on topics including uncertainty, stigma, and discrimination) are important. Conversely, to patients-with-MCI, biomarker results provide information on the underlying condition of a syndrome that has already been diagnosed, whereas negative biomarkers may create frustration over lack-of-insight into-the-cause. Furthermore, disclosure in a symptomatic-phase may leave-less-time-and-opportunity-to-benefit-from-disease-modifying-therapies, adopt a risk-reducing-lifestyle, arrange-personal-affairs, and advance-life-plans, whereas the risk of [or] for medicalization, stigmatization, and discrimination may be bigger in a preclinical-stage. More-research is needed to assess the motivation for and impact of biomarker-testing in various-cognitive-stages and different-settings. Previous-research suggests that individuals come to memory-clinics with specific-motivations, which are not always stated and may differ from those of their caregivers.87 As the evaluation-of-the-risk-and-benefits-is-specific-to-the-individual-and-their-situation, this merits-shared-decision-making-and-a-personalized-approach.

4.1 Strengths and Limitations We supplemented our systematic-review with a meta-analysis of several studies evaluating the impact of sharing biomarker results with persons who do not have dementia. Another strength is our extensive search strategy, which enabled us to synthesize data from both the personal and professional perspective, providing a comprehensive-overview. We incorporated both quantitative and qualitative studies, which conveyed complementary information. In addition, there are some limitations which should be addressed in future research. First, there was considerable heterogeneity among study designs and quality, which complicated comparison of results. Some were based on small and specific populations. The concept-of-biomarker-testing had diverse-operationalizations, such as a hypothetical-assessment, a combination-of-both-biological-and-genetic-markers, or amyloid-PET-imaging-alone. Populations consisted of CN individuals or those with SCD or MCI and their relatives, and most were research-participants rather than clinical-patients, for whom biomarker-testing might be most-relevant. Due to the limited-body-of-data and the variety-in-methods-used for analysis in the included-studies, it was not always possible to distinguish between these groups in our synthesis. Second, as few studies were available for meta-analysis and follow-up was relatively-short, careful interpretation of the overall-results is warranted and the long-term-impact remains to be assessed. Third, the vast-majority of studies included US and European participants, predominantly White and well-educated. In most studies, individuals were psychologically-screened and those with elevated levels of anxiety, depression at baseline, or a history-of-suicidal-ideation were excluded. Several publications reported on different aspects of a single-study or included participants from the same cohorts. These limitations severely-constrain generalizability. There is a lack of research into people with more socioeconomic, ethnic, and racial diversity as well as those with lower psychological resources. Future-research should be more-inclusive, involve larger sample sizes, and include patient-centered-outcomes in more-biologically-oriented studies, whether trials or biomarker-validation.

5 Conclusion In conclusion, biomarker-testing in individuals who do not have dementia is a topic of ethical-debate. Based on the available empirical-data on the impact of sharing-results, our systematic-review and meta-analysis found that interest among personal stakeholders is high, and sharing test results does not cause significant short-term-psychological-harm and offers actionability. Although most health-care-professionals value biomarker-testing, attitudes and practices varied considerably. Development and harmonization of testing-guidelines and communication-protocols are required, particularly in view of the imminent advancements in disease-modifying-therapies.

Acknowledgments Research of Alzheimer Center Amsterdam is part of the neurodegeneration research program of Amsterdam Neuroscience. Alzheimer Center Amsterdam is supported by Stichting Alzheimer Nederland and Stichting Steun Alzheimercentrum Amsterdam. The clinical database structure was developed with funding from Stichting Dioraphte. The chair of Dr. Van der Flier is supported by the Pasman stichting. Jetske van der Schaar is appointed at ABOARD, which is a public–private partnership receiving funding from ZonMW (#73305095007) and Health∼Holland, Topsector Life Sciences & Health (PPP-allowance; #LSHM20106). More than 30 partners participate in ABOARD. ABOARD also receives funding from Edwin Bouw Fonds and Gieskes-Strijbisfonds. Yolande Pijnenburg is recipient of YOD-MOLECULAR (NWO #KICH1.GZ02.20.004).

Conflict of Interest Statement Jetske van der Schaar wrote a book for a layman's audience about the personal impact of dominantly inherited AD, for which she received grants or contracts from Aegon Nederland and Alzheimer Nederland and royalties from Uitgeverij Prometheus. She is a member of the advisory board for the National Dementia Strategy of the Dutch Ministry of Health, Welfare and Sport. Leonie Visser has been an invited speaker by the Schwabe Group; fees were paid to her institution. Her research has been funded by ZonMW, Alzheimer Nederland, Health∼Holland, Topsector Life Sciences & Health, and the Amsterdam Public Health research institute. Philip Scheltens is a full-time employee of EQT Life Sciences (formerly LSP) and Professor Emeritus at Amsterdam University Medical Centers. He has received consultancy fees (paid to the university) from Alzheon, Brainstorm Cell, and Green Valley. Within his university affiliation he is global PI of the phase 1b study of AC Immune, phase 2b study with FUJI-film/Toyama, and phase 2 study of UCB. He is past chair of the EU steering committee of the phase 2b program of Vivoryon and the phase 2b study of Novartis Cardiology and presently co-chair of the phase 3 study with NOVO-Nordisk. Research programs of Wiesje van der Flier have been funded by ZonMW, NWO, EU-FP7, EU-JPND, Alzheimer Nederland, Hersenstichting CardioVascular Onderzoek Nederland, Health∼Holland, Topsector Life Sciences & Health, stichting Dioraphte, Gieskes-Strijbis fonds, stichting Equilibrio, Edwin Bouw fonds, Pasman stichting, stichting Alzheimer & Neuropsychiatrie Foundation, Philips, Biogen MA Inc, Novartis-NL, Life-MI, AVID, Roche BV, Fujifilm, Eisai, and Combinostics. She holds the Pasman chair. She is recipient of ABOARD, which is a public–private partnership receiving funding from ZonMW (#73305095007) and Health∼Holland, Topsector Life Sciences & Health (PPP-allowance; #LSHM20106). She has been an invited speaker at Boehringer Ingelheim, Biogen MA Inc, Danone, Eisai, WebMD Neurology (Medscape), NovoNordisk, Springer Healthcare, NovoNordisk, and European Brain Council. She is consultant to Oxford Health Policy Forum CIC, Roche, and Biogen MA Inc. She participated on advisory boards of Biogen MA Inc, Roche, and Eli Lilly. All funding is paid to her institution. She is a member of the steering committee of PAVE and Think Brain Health. She was associate editor of Alzheimer, Research & Therapy in 2020/2021. She is associate editor at Brain. The other authors have no conflicts of interest to declare. Author disclosures are available in the supporting information.

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[Keywords and compound-keywords (tags) are highlighted-and-hyphenated in italic-and-bold; place-names, organizations and titles are in bold; media-names put in italic. Instead of underlining, I’ve been experimenting with hyphenating entire phrases – long-tail-keywords. This odd style was being tried to enhance generative-AI processing and ease-of-spotting items-of-interest in my specific website-achieved documents. Now experimenting with generative-AI to eliminate this time-consuming distraction.]

{Direct-to-Consumer AD Test}