What’s Missing From Hillary Clinton’s Plan to Cure Alzheimer’s Disease

Alzheimer’s Disease (AD) could be the sleeper issue of the 2016 presidential campaign. For politicians AD is a perfect storm. The science is complex and uncertain, the stakes are huge, the issue is raw and deeply emotional for families afflicted, and there are no obvious medical or financial solutions. Left uncured, AD could become the greatest threat to American families’ economic and medical security.

Against this daunting backdrop, as America’s families gathered for year-end holidays, Hillary Clinton released her plan to cure AD.

Clinton’s plan is laudable in a couple of areas. First, she is calling for Alzheimer’s to be cured — not managed or controlled, but cured. This matters given the commonly-held view of Alzheimer’s as a disease of old people.

Within the Democratic Party, and especially among some of Clinton’s long-time health policy advisors, AD is seen as an issue of minimizing losses rather than an opportunity for medical science. Advisors like Dr. Ezekiel Emanuel, elevated by Clinton during her early-1990’s health insurance reform efforts, believe cutting edge treatments for age-related disease serve mostly to drive higher profits for hospitals and drug makers. Absent political pressure to help solve AD, scarcitarians — who believe health policies should suppress demand for new treatments — would cut AD research, seeing investment in a disease that afflicts the elderly as a low ROI choice.

Clinton’s emphasis on curing Alzheimer’s is an important repudiation of scarcitarian thinking. It is a timely reminder, as author and commentator Jim Pinkerton has observed, that cures are cheaper than care — that medical and scientific breakthroughs do far more to improve medical outcomes and reduce health costs than tweaking the status quo or manipulating health insurance rules to change behavior.

Second, Clinton is calling for dramatically more funding for Alzheimer’s research. She would triple federally-sponsored AD research, a meaningful increase at a time when overall federal scientific funding is under pressure, and younger researchers face longer odds to getting new ideas funded.

That’s the good news. So, what’s wrong with her plan?

Clinton’s plan is built on a flawed understanding of AD, accepting the commonly-held belief that it is a disease of the elderly. It also assumes AD treatments will be developed as they have been for other illnesses: through a progression of discoveries by scientific and biopharma elites, building on basic science discoveries to develop drugs, which are then tested in mice, and if successful, in humans. As well as this paradigm has worked for many diseases, it has failed, and will continue to fail, in producing effective AD treatments. AD is a qualitatively different kind of disease, requiring a new kind of cure strategy.

To be fair, Clinton is not alone in her assumption that AD can be cured like other illnesses. The National Plan to Address Alzheimer’s required by a 2011 federal law, for example, is essentially Clinton-lite: it sets a goal to develop treatments by 2025, invest more federal research dollars on AD, and help those afflicted manage the disease’s burdens.

Contrary to popular belief, AD Should Not Be Seen As a Disease of the Elderly

The essential mistake of both the Clinton and National plans is to characterize AD as a disease of the elderly. Yes, most people afflicted begin to exhibit symptoms in their sixties or seventies. But this is not the same as saying it is a disease of the elderly. Just because people become symptomatic late in life does not mean they have not had the disease for many years before.

Consider, for example, a particular kind of cancer that appears in women around the age of fifty. We might consider this a cancer of middle age. However, what if we discovered that the source of the illness was an infection that the woman contracted decades earlier in her teens or twenties? That reframes our understanding, and our treatment approach, and that is exactly what happened with cervical cancer. Today we know almost all cases of cervical cancer are driven by an infectious agent, HPV, contracted years — even decades — before cancer becomes detectable.

We have learned that AD is similarly long-lived. AD pathology begins years if not decades before someone is symptomatic. The disease starts with neuronal death in a couple of key brain regions related to long-term memory. From there it spreads to other brain regions, perhaps like an infectious agent traversing existing neuronal networks, perhaps arising spontaneously in multiple regions for other reasons. Perhaps a combination of both. In any event, AD does not begin when symptoms appear, but is a long-lived process starting years earlier.

So we need to reconceptualize AD as a disease of middle-age, defining it based on when it begins rather than when its symptoms become obvious.

AD, When Seen as a Middle-Aged Disease, Is Curable

Reimagining AD as a middle-aged disease is necessary, politically and scientifically, to finding a cure.

If characterized as it is now, as a disease of the elderly, AD is a recipe for inter-generational political strife. Caring for an Alzheimer’s patient devastates a family economically and emotionally. Invariably, one or more adult children have to take time off work to help care for mom or dad. The person afflicted ceases to work along with their primary caregiver. Very quickly — even if the family can afford long-term care insurance — Alzheimer’s drains family savings, wreaking a double whammy on the next generation. Not only will adult children/caregivers earn less, taking time off to help care for a parent, but the parent’s estate will be diminished by the cost of late-stage care.

As the elderly grow as a proportion of the electorate, and the incidence of AD increases, their need for financial and daily living support will grow. Middle aged and younger voters will come to resent the disproportionate amount of resources consumed by the elderly. Both parties will feel pressure to trim benefits for the elderly, either to free up funds to support late-stage AD patients, or to rebalance spending on workers and the young. Democrats may prefer tax increases to spending cuts while Republicans will prefer the opposite. However, neither approach will be politically or practically sustainable. The cacophony between a growing part of the electorate with large demands (the elderly) will check the demands of other interest groups.

Reframing AD as a disease of middle-age changes the political narrative to one of prevention from one of amelioration. The goal of AD research shifts from restoring the lives of afflicted older people to helping Americans in the prime of life from ever needing costly AD care. We may still need to spend large sums to help those already or soon-to-be afflicted while cures are developed. But this is a much more manageable political and economic proposition if medical research is focused on stopping a flood of new cases.

Seeing AD as a middle-age disease is also key to building sustainable political support over time. Even if we develop a workable treatment by 2025, as Clinton would like, we will not have proof that it works for years afterwards. Assuming millions of 50–60 year olds start taking a drug in 2025, we will not know if it is working until a decade has passed, and also if new treatments have any unanticipated side-effects.

The political coalition to cure AD will need to remain intact for decades, beyond a crash program to discover treatments. In fact, history suggests that building this kind of decades-long political consensus is the only way to defeat serious disease from polio to cutting heart attacks to curing childhood and breast cancer, and most recently in fighting HIV/AIDS. In each case, a broad political coalition gave researchers, regulators and drugmakers the political cover to take greater scientific risks, create research frameworks that operated above or outside traditional constraints, and ensure public support withstood often fatal setbacks.

Curing AD Requires a New Deal For Medical Research

The second key error of Clinton’s plan to cure AD is that it, like the National Alzheimer’s Plan, assumes existing approaches to drug discovery will work in AD too. Neuroscientists will deconstruct what’s happening in people’s brains at a molecular and systematic level, aided by genetic studies identifying AD susceptibility. Then translational researchers and drugmakers will use this data to identify potential drug targets, design treatments, and test ideas — first in mice, later in humans.

This “top-down” approach has worked in a number of diseases, and aided by amazing imaging, diagnostic, and computational approaches, seems like it should work in AD too. Unfortunately AD is a unique disease, warranting a new and different kind of strategy.

AD is frustratingly complex, progressing at widely varying rates. Some people progress quickly, suffering a cascade of functional breakdowns; others progress slowly, with symptoms accumulating over years. Some brains seem to compensate for broken circuitry, masking deterioration. Others lack this redundancy. AD progression may even be linked to dysfunctions in the brain’s immune system, suggesting that the ups and downs of symptom severity are the result of a years-long pitched battle between neuro-destructive and neuro-protective forces.

AD — like many neurodevelopmental conditions — seems to be driven by a large number of genetic and environmental factors. There may be a few “driver” genetic breakdowns (beyond the few already known) that decisively influence the pace and severity of AD onset and progression. More likely we will find that a wide range of factors — including traits that regulate the expression of other genes — each have a small impact on AD risk, but in total, tip the balance towards AD onset. Given this variability in causes and trajectories, it may be that AD is not “a” disease, but a constellation of related conditions, deriving from a variety of factors which lead, unfettered, to a similar kind of widespread cognitive collapse.

A third challenge is that AD requires researchers and physicians to work in the brain, the seat of our individuality, intelligence, and personality. It is vexingly difficult to infiltrate the skull, to monitor particular circuits, and to make repairs with risking damage to unaffected regions. There is a high risk that surgical or medical failures are fatal or cause permanent incapacitation.

Finally, conventional drug development relies on animal models, especially rodents. Yet, it appears, mice models of AD are more imprecise than those used in other diseases. Mice can be engineered to exhibit AD-related plaques and behaviors, but their treatment responses do not seem to correspond consistently to how treatment responses in people. This makes the use of mice models unreliable at best.

For all these reasons, a strategy to cure AD must establish a different paradigm of drug research.

Far more than dollars researchers need data. For data, they need people, millions of people young, middle-aged, and old. Creating a broad political movement described above, is a first step, but we will need to do more. We need a new approach to drug research that flips the conventional model of human involvement. Today, a few subjects are involved at the outset of research. Once a treatment is developed it is tested in exclusive clinical trials before being made generally available. It is only then that we learn the full range of drug effects, including side effects, who a drug works well for, and who it does not.

AD researchers need to turn the conventional model upside down. Instead of waiting to involve millions after a drug is approved, we need to enlist those millions as early, and for as long as possible to understand what’s happening before, during, and after AD onset. We need longitudinal data from millions, brain scans or other diagnostics that can be synchronized with genetic and situational information, to help us see which genetic, environmental, and immunological situations lead to which disease trajectories. Over time, we will develop highly segmented AD treatments, customized to typologies based on a person’s age, genetics, metabolism, and immune function.

To do this, we need to make it drastically easier for people to get and give valuable data, and in return, to give every participant a tangible stake in the fruits of AD research.

• First, we need regulatory consistency. Is the Federal government determined to cure AD or not? A couple of years ago, Eli Lilly developed a diagnostic agent to help doctors observe plaque-like accumulations in the brain associated with AD. The FDA approved Lilly’s agent as safe and effective. But the CMS — the agency that oversees Medicare — limited its use to only a few clinical trials. This was a moment that the government could have spurred AD research rather than constraining it. CMS should have encouraged as widespread use of the Lilly agent as possible, preferably even among those not yet eligible for Medicare — recognizing AD’s long gestation period. Expanding the market for imaging agents would have spurred competitors. If price was CMS’s concern, it could have pushed Lilly a volume discount, or an exception from rules seen to limit its ability to negotiate price. Every instinct of federal health regulators where new treatments are concerned is to push for “less” when every impulse to cure AD should be “more.”
• Second, we need to create a new kind of health/life insurance hybrid that encourages people to contribute data from genetic and periodic diagnostic screening throughout their lives in exchange for access to top quality hospital care for life-threatening conditions. Currently, private health insurers are primarily motivated to keep people from getting seriously ill before they are 65, at which point their issues mostly become Medicare’s to bear. Private insurers have little incentive to investigate the full range of diseases someone might get after they are 65, focusing instead on trying to keep costs down to manage any of them. Medicare, however, should have the opposite goal, to understand as much as possible about slow-developing chronic diseases like AD long before someone turns 65. Most people, hopefully, will die of something other than AD, perhaps cancer or heart disease. However, just because these people do not live long enough to exhibit AD symptoms does not mean they do not have valuable data to provide to inform efforts to cure AD. Likewise, just because someone has AD does not mean they do not have valuable data that could benefit cancer or diabetes research. All complex disease research, but especially efforts to cure AD, need much richer longitudinal data to understand how, when, and why AD takes root or is thwarted.
• Third, we need to move beyond our reliance on animal models to validate treatment efficacy. We are fast approaching a point that we can “see” neural circuitry in action in real-time. We should invest much more time and energy to determine if in silico representations can be more reliable in validating how a drug may or may not work. Animal models will still be necessary to prove concepts, but in silico models will be much more malleable and adaptable, and over time, with much greater fidelity to represent the range of potential outcomes in human brains.
• Fourth, work to develop treatments should focus as much on how therapies can be delivered in the brain with pinpoint accuracy, as on designing the active ingredients. Scientists like Karl Deisseroth have developed approaches to activate and monitor individual neurons or neuronal clusters. Might we modify these approaches for drug delivery? New approaches to cancer drug delivery, using nanomaterial wrappers and programmed biochemical triggers to release drug payloads, might be applicable to target delivery of anti-AD drugs. We should not approach drug delivery and drug design sequentially, but in parallel. Both will require breakthrough discoveries.
• Fifth, we need new business models to pay for AD treatments. Long-lived treatments that can be administered earlier will have more value than those used to mitigate symptoms among those with advanced conditions. This suggests that “preventive” treatments — to slow AD progression — will have enormous value, but as we have seen with debates about Hep-C and cancer treatments, will be unaffordable broadly if priced at hundreds of thousands of dollars per treatment. This suggests the need for some kind of annuitized pricing, in which drugmakers are paid some amount when a drug is administered, and some amount annually over time if the drug continues to halt AD progression.

Aside from a lethal global pandemic, Alzheimer’s is humanity’s most formidable medical enemy. It systematically erases a person’s humanity — their memories, their relationships, their identity. It is long-lived and (currently) hard to detect in its earliest stages.

The need to cure Alzheimer’s is acknowledged by leaders across the political spectrum. Hillary Clinton has made a helpful contribution, emphasizing the need to cure the disease and increase investment to find a cure. However, consciousness raising goes only so far. To cure AD, we need to reframe our understanding of the disease as something that starts — and should be stopped — in middle-age, not old age. We need to build a broad political coalition to support the effort to find cures. And, we need to build on this new political awareness to create new approaches to drug development. AD will not be solved by the existing top-down elite approach to science. The clues to solving AD lie within us, all of us. Amassing that data within a new kind of collective, and applying new computational capability to make sense of this information is the surest path to creating cures.