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Predicting Alzheimer’s Disease: Potential Ethical, Legal, and Social Consequences

(This post oriignally appeared, in very slightly different form,  in the Neuroethics Blog on June 17, 2014, here.)

Would you want to know the date and time of your death? Life-Line, the first published fiction by Robert A. Heinlein, one of the giants of 20th century science fiction, explored that question. The story’s protagonist, Hugo Pinero, had invented a machine that could tell precisely when individuals would die, but, as Pinero found to his distress, he could not intervene to change their fates.

Would you want to know whether you would be diagnosed with Alzheimer disease (AD)? This question is rapidly leaving the realm of science fiction; indeed, it already has for some unlucky people. Our ability to predict who will suffer from this evil (and I chose that word carefully) condition is proceeding on several fronts and may already be coming into clinical use.

This post will briefly note the ways in which AD prediction is advancing and what some of the ethical, legal, and social implications of such an ability would be, before asking “should we care?”


Several different techniques are providing information about an individual’s risk of being diagnosed with AD, including genetics, biomarkers, and neuroimaging.

Genetics can predict AD with great confidence for about one person in a thousand. People who carry a mutated version of the PS1 gene (or, much more rarely, mutated versions of the PS2 or APP genes) are nearly certain to be diagnosed with AD, unless they die earlier from something else, and with an early onset version that typically strikes in one’s 40s or 50s. People with two copies of the APOe4 allele, about one to two percent of the population, have a very high risk (at least 50 percent, perhaps as high as 80 percent) of being diagnosed with AD in their sixties or seventies. People with one APOe4 allele and one APOe2 or APOe3 allele – that’s about 20 percent of the population – have two or three times the AD risk of people without an APOe4 allele. Other alleles of other genes have also been found to confer higher risk of AD, and some single nucleotide polymorphisms have been associated with higher risk of the disease.

Other researchers have identified biomarkers that are associated with risk of AD, both in the cerebral spinal fluid (CSF) and in the blood serum. Thus far, the CSF methods have looked for levels of the protein beta amyloid (42), which forms plaques on dead and dying neurons of those with AD, and the protein named “tau,” which forms tangles in the bodies of those neurons. Some of the blood work has looked at those biomarkers; others have looked at a range of different proteins in the blood. None of these methods is ready for clinical use; some of the published research has claimed nearly 90 percent accuracy in predicting relatively near-term AD diagnosis.

Recently, the FDA approved a radio ligand that attaches to the amyloid plaque in the brain and allows the existence of amyloid plaque to be seen by positron emission tomography (PET). The approved labeling is for use in diagnosing AD, not in predicting it, but the off-label use doctrine allows doctors to prescribe it for any purpose. Other researchers have been trying to find ways to image tau tangles, though currently the only method for detecting them is through a brain biopsy (not an easy technique!).

Note: When the original version of this post went on-line, I was at a neuroscience meeting in Washington, D.C. where I  learned that there are now radioligands that allow PET scanning of tau tangles, though only being used for research so far – not approved for clinical use.)  Some early evidence that it may eventually add still more power to diagnosis and prediction of AD.

It is also known that magnetic resonance imaging (MRI) scans of brains can see changes in grey matter density in certain parts of the brains of people with AD; efforts are under way to use that method to predict AD diagnoses.

These various methods need not be used in isolation. They could be used together, in an effort to provide greater accuracy than any one test would do on its own. We are only at the beginning of efforts to assess those possibilities.

The FDA has not approved any of these methods (yet) for clinical use in predicting AD and professional groups have recommended against such use. It remains unclear how good any of these methods are alone or in combination, or at what age or ages they are useful. (A genetic cause may be strongly predictive even before birth; amyloid plaque levels may – or may not – be relevant only for people over 60.) Their accuracy might also vary between completely cognitively normal and those showing some minor signs of cognitive problems (which, for many people, would not progress to AD).

Importantly, these methods were not discovered in order to use them for clinical prediction. They are the results of basic research, of efforts to understand the natural history of the disease, in hopes of ultimately finding preventions or treatments. Their first use in humans has been in AD research, stratifying research subjects into high and low risk groups in the hope of making clinical trials faster and cheaper. But nothing prevents a physician from ordering the tests for a worried patient (with money to pay for tests that insurance will not reimburse).


Let’s assume that people did begin to get fairly accurate tests for their AD risks. What would follow?

If we had good interventions to prevent or treat the disease, much good might come from such testing, but we don’t (beyond “chicken soup” kinds of recommendations like “exercise”.) So how and why will people use these predictions and what non-medical consequences can we expect?

Some people will use the information for financial planning. A friend of mine is an “elder lawyer,” who spends a good amount of his time in financial planning for the elderly. He says that if we had a test that was 90% accurate, he would urge all of his clients to get such a test so they can plan how to use (and preserve) their assets for their struggle with AD.

On the other hand, some will worry about the effects of getting tested. Being at high risk for AD might lead to all the usual discrimination suspects – employment, health, life, and disability, plus one special one, long term care insurance. The relatively old ages at which AD strikes (except for the roughly 1% of cases that are early onset) mitigate, but do not eliminate, the number of people who would risk employment and health insurance discrimination. Most people will not be employed when they are diagnosed with AD. And, at time of diagnosis (and hence of increased health care costs), most of those affected will be over 65, and thus will have Medicare for health coverage (whatever may happen to Obamacare). Ironically, though, whether GINA, the Genetic Information Non-discrimination Act, protects them will depend on whether their risks were predicted using genetic methods or other methods. (The consequences of the use of mixed methods are not clear.)

A few special cases of possible “employment” discrimination might be noted. Every four years Americans “employ” someone as President. Would the public want to know the AD risks of the candidates? Not too long ago, President Ronald Reagan was diagnosed with AD only a few years after the end of his second term. The public, acting largely through the press, might want AD risk information from future candidates. (Teneille Brown has explored these issues in more depth1.)

Similarly, sitting presidents may well want that kind of information about candidates for appointment to jobs with life tenure – federal judges, and particularly Supreme Court justices. In 2009, Judge Karen Williams, Chief Judge of the United States Court of Appeals for the Fourth Circuit, retired from the bench at the age of 57 because of early onset AD. All things being equal, presidents want the judges they appoint to sit, and influence the law, for decades after the president’s term is over.

It is not clear that life insurers would care much about AD risk; the disease process is so long that the age at death, though somewhat reduced, may not be change significantly. But private disability insurers should care, as AD patients who are employed at the time of diagnosis may end up claiming on such policies.

And long-term care insurers, should care, a lot. AD patients will often need years of long-term care. The private long-term care market is relatively new and small. It is a policy initiative to try to deal with the upcoming huge cost of long term care for Baby Boomers, care that is not significantly covered by Medicare or private health insurance. If people were able to test for their AD risk and then, if they test positive, buy long-term care insurance on the same terms, the resulting “adverse selection” will cause insurers either to lose money or to raise their rates. Either outcome, in this young and relatively fragile market, could end long-term care insurance. On the other hand, if insurers can take AD risks into account (at least when the customer knows those risks), people at high risk will often find long term care insurance unaffordable, even though – and especially because – they will need it.

But other, less tangible, consequences may follow. Consider the effects on family dynamics. Will the children take away Dad’s car keys sooner if he has been predicted to be at high risk for AD? Will they take away his checkbook, and control over his finances? How will the relationships within the family change when spouses, partners, and children expect an AD diagnosis?

And, of course, what will be the effects on people predicted to be at high risk? They may face depression or other psychological consequences. They might even make plans for suicide.

These issues, of course, are not new – they occur already with an AD diagnosis. But an AD prediction may move the opening point of these concerns forward several years, years that otherwise might not have been clouded by the knowledge, or fear, of AD.

Should We Care?

In a different sense, none of these issues is new. They already exist with fatal diseases that can be confidently predicted, like Huntington disease, as well as fatal diseases once they are diagnosed. But AD is, in some ways, distinctive. Instead of striking one person in 20,000, like Huntington disease, it will strike an estimated 10% to 15% of the population. And its memory, and ultimately personality, destroying characteristics lead to special challenges, as well as, for some people, to special horror. What, if anything, should we do about it? For now, I will make only two suggestions: assurance of the accuracy of the predictions and a requirement for counseling.

The accuracy of the tests, alone and in combination, needs to be assessed carefully, and for people of different sexes, ethnicities, and other possibly relevant possibilities. I believe some kind of public assessment of accuracy, akin to (and possibly including) FDA approval, should be required before the testing is allowed.

Then, both before the test is taken as well as after any positive results are returned, we should require skilled counseling. The first session will help make sure that the individual understands the advantages and risks of taking the test. The second will help high risk people deal with the shock of the prediction – and with its longer-term consequences.


Pinero’s “life predictor” never existed and never will. That would have been good for the fictional Pinero: in the short story thugs paid by life insurance companies murdered him, on the very date his machine had predicted

Widespread, accurate (or even inaccurate) AD prediction is not yet here. It will be soon. As a common, expensive, and severe disease, its predictability will bring some foreseeable challenges, as well, no doubt, as some unforeseeable ones. We need to work to understand, and cope with, those challenges. And we need to start yesterday.

Hank Greely


1) Teneille Brown, Double Helix Double Standards: Private Matters and Public People, J. Hlth Care L. & Pol. 11:295-376 (2008).


“NeuroRacer” Creator Gazzaley Seeks FDA Blessing for Brain Training Game

Roland Nadler

Three of my favorite topics — cognitive enhancement, administrative law, and video games — have collided in the headlines this weekend, with several games and tech news outlets reporting on a University of California San Francisco professor’s newly announced bid for U.S. Food and Drug Administration recognition that his lab-developed video game, NeuroRacer, is a safe and effective device for the treatment of cognitive decline in the elderly.

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Vermont to Pass GMO Labeling Law

Malia McPherson

Although Ben & Jerry’s, “Vermont’s Finest” ice cream, already committed to GMO labeling by the end of 2014, their state’s law will now be close behind. On April 23, the Vermont House gave final approval to a bill that will require labeling on foods containing genetically modified ingredients. Gov. Peter Shumlin tweeted that he would sign the bill into law, making Vermont the first state in the U.S. to mandate such labeling. Once the bill takes effect July 1, 2016, all Vermont-retailed foods with more than 0.9% of their total weight in genetically modified ingredients must be labeled with language stating, “may be partially produced with genetic engineering.” Although Connecticut and Maine passed labeling laws in 2013, their statutes stipulate that at least four nearby states pass similar laws before the requirements go into effect. The full, amended statute that passed the Vermont House and Senate can be found here.

But as NPR reported, Vermont’s attorney general is “bracing for a battle” — the bill itself established a $1.5 million fund to help defend against anticipated lawsuits. At stake are free speech issues, federal preemption, and agro-business pushback. Although we will have to “wait-and-see” what legal battles ensue, it is interesting to speculate. Who will fire first: General Mills, Monsanto, the FDA??

Malia McPherson is a first year JD student at Stanford Law School and an officer of its BioLaw organization.

A Second Zohydro Update

Last week I posted about Judge Rya Zobel’s order enjoining the Massachusetts Zohydro ban. While writing that post, I was wondering how Massachusetts would respond to the injunction. Now we know the answer. The night before the injunction was to go into effect, Governor Deval Patrick announced that the state would not appeal Judge Zobel’s order, and, instead of an outright ban on the use of Zohydro, Massachusetts would impose certain restrictions on its use similar to what Vermont has done.

The restrictions that Massachusetts has imposed include requiring Zohydro prescribers to complete a risk assessment and pain management agreement with patients, and participate in Massachusetts’s Prescription Drug Monitoring Program, which collects dispensing information on controlled substances to detect misuse.  If Zogenix chooses to challenge these restrictions – and I’m guessing it won’t because it hasn’t yet sued Vermont over its similar restrictions – one legal question would be: Are these restrictions, like the outright ban, preempted by federal law?

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Zohydro Update

Since FDA approved Zohydro in October 2013, the drug has been the subject of quite a bit of controversy.  In short, the concern is that Zohydro will contribute to the serious prescription drug abuse problem in the U.S. because, as an extended-release drug, it contains a higher dose of hydrocodone than other hydrocodone drugs on the market, and it lacks abuse-deterrent properties (see, e.g., this New York Times blog post).  Perhaps the most interesting part of this controversy is that Massachusetts has attempted to ban the use of Zohydro in that state—which I think makes Massachusetts the first state to flat-out ban an FDA-approved drug.

As we discussed in our recently posted April podcast, Zogenix Inc., Zohydro’s sponsor, sued Massachusetts over this ban (here’s the complaint).  When we recorded the podcast, the federal judge – Judge Rya Zobel of the District of Massachusetts – had not yet ruled on Zogenix’s motion for a preliminary injunction, and I predicted that she would not enjoin Massachusetts from enforcing the ban on preemption grounds.  Well, I was wrong.  On April 15th, Judge Zobel enjoined Massachusetts from enforcing or implementing its Zohydro ban because she concluded that Massachusetts “obstructed the FDA’s Congressionally-given charge” when it “interposed its own conclusion about [Zohydro’s] safety and effectiveness” (here’s the order).

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April Podcast

Podcast Listeners: Our April podcast is up! Listen to us talk about Zohydro, Ebola, biosimilars, and the Ninth Circuit’s en banc decision in Haskell v. Harris.

New Podcast: Top 5 Law and Bioscience Events of 2013!

Podcast Listeners: Our long lost December Podcast is up! Listen to us discuss what we think were the top 5 law and bioscience events of 2013.

Final Batch of 2014 CLB Workshop Mini-Podcasts!

The last two of our mini-podcasts with the 2014 CLB Workshop speakers are posted! Listen to Victoria Stodden (Columbia) discuss data transparency, and Ryan Abbott (Southwestern) discuss off-label use of drugs and devices.

Can Genome Editing Cure AIDS?

Hinco Gierman

Yes. At least, in theory. But, theory might soon become practice according to this week’s issue of the prestigious New England Journal of Medicine [1]. It published the first clinical trial of genome editing, in which the DNA of 12 human volunteers was “edited” to make them “genetically resistant” to the HIV virus.

What do I mean by genome editing and is it safe? How is this different from other gene therapies? Why would this cure AIDS? Is it unethical to genetically modify humans? And of course most importantly, should we be worried about “genetically modified super-humans” taking over the planet?

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Breaking News – Ninth Circuit En Banc Opinion “Affirms” Haskell v. Harris

Just released, the Ninth Circuit en banc, has affirmed the ND Ca decision (by Judge Charles Breyer) upholding California’s statute requiring people arrested for [corrected - thanks, Paul!]  any felony to provide DNA samples for inclusion in the state (and ultimately federal) database.

Sort of.

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