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An editorial inScience Translational Medicineproposes a portfolio approach to fund a broad spectrum of Alzheimer's disease research rather than focusing simply on specific drugs to combat amyloid-beta and tau, and that the US government be the prime investor in the research megafund.

Creating a “megafund” for simultaneous research on Alzheimer's disease (AD) based on a hierarchy of promising translational science approaches would be expensive, but it would offer a better chance of new drug discovery than the narrower approach currently being pursued, according to a team of leading medical economists.

In a commentary in the June 18 issue of Science Translational Medicine, they proposed a portfolio approach to fund a broad spectrum of research rather than focusing simply on specific drugs to combat amyloid-beta (Abeta) and tau, trials of which have yielded disappointing results. Because the cost of such an effort would be too expensive for the private sector, only the US government could underwrite it, they said.

Andrew W. Lo, PhD, the Charles E. and Susan T. Harris professor of finance and director of the Laboratory for Financial Engineering at Massachusetts Institute of Technology in Cambridge and a team of other researchers called for $38.4 billion for multiple distinct and simultaneous drug development projects over a 13-year period.

The fund could plausibly generate double-digit investment returns in the form of savings for US taxpayers, they wrote, and could be underwritten by issuing bonds.

“If no new drugs are discovered that alter the course of this disease, we are looking at more than $1 trillion in paying for an estimated 13 million-plus AD cases by 2050,” Dr. Lo told Neurology Today in a telephone interview. “The war on Alzheimer's has only just begun, and if we do not address this now, we could become bankrupt in the decades ahead just trying to care for AD patients. We simply need to bite the bullet.”

The team developed a list of 64 promising avenues — from 12 pathways and/or potential hypothesized targets — for AD research covering a range of areas, from immunotherapy, neuroinflammatory and tau pathways to a focus on hormones/growth factors, heavy metals, and mitochondrial cascades. Surveying the medical literature, they assigned an estimated “degree of validation” for each of the candidate therapies — from high to low. [See “Potential AD Projects.”]

“We need to focus on a number of potential pathways that might lead to discoveries in therapeutics. We should try and try again by underwriting parallel research in these areas — this is our message,” said Dr. Lo.

The present value of out-of-pocket development costs for each of the projects in the portfolio was projected to cost $600 million, $100 million in basic research funding and $500 million for clinical development over a 13-year period, a duration supported by a recent study commissioned by the New York Academy of Sciences focused on AD therapeutics.

In 1971, Dr. Lo said, President Richard Nixon declared the “war on cancer” and increased funding at the National Cancer Institute by a factor of four.

“This created a lot of basic research, and the results have translated into new drugs for treating a range of cancers. Last year the US Food and Drug Administration approved 13 new cancer drugs, but none for AD. This should tell us something.”


The authors calculated that it would take 13 years to develop an individual drug, including clinical trials. Although a greater initial investment is required, the probability of at least one success should be higher with “multiple shots on goal,” they said.


DR. ANDREW W. LO: “If no new drugs are discovered that alter the course of this disease, we are looking at more than $1 trillion in paying for an estimated 13 million-plus AD cases by 2050. The war on Alzheimers has only just begun, and if we do not address this now, we could become bankrupt in the decades ahead just trying to care for AD patients. We simply need to bite the bullet.”

With 150 clinical trials the odds of at least two trials succeeding is 99.59 percent, they calculated, and through a series of bonds that could be issued by the fund, two successful trials would make the investment profitable and attractive to a broad range of investors, said Dr. Lo.

Because private drug development companies are accountable to their shareholders, who are primarily interested in getting profitable products to market as quickly as possible, it is unreasonable to them to provide the up-front funding required to reach this goal, he told Neurology Today.

“No CEO in his right mind is going to invest in research that may take decades to provide a marketable drug. That is why the government needs to take the lead.”

However, he added that if government funding is available for early-stage AD research and novel approaches are discovered, there is a good likelihood that the private sector will also get involved in promising research, something that occurred with cancer treatments after the 1971 boost in NIH funding.

“With cancer research, we have seen the impact that government involvement can have in catalyzing subsequent private-sector investment,” he said.


Michela Gallagher, PhD, the Krieger-Eisenhower professor of psychological and brain sciences and neuroscience at Johns Hopkins University, agreed that there are challenges with the current model for trials. “There is no question that the resources for clinical trials are a bottleneck and a limiting factor, especially given the costs and length of such trials,” she said. “The commentary identifies a broader landscape on target, but does not say much about trial design and stages of disease,” she told Neurology Today.

“The very big investment proposed in the article could be wasted by throwing more candidate therapies into repeating the kinds of trials that have failed in patients with a dementia diagnosis, and I am not sure how stage of disease for candidate therapies might be considered, if at all, under the proposal.”

Mary Sano, PhD, a professor and director of the Alzheimer's Disease Research Center at Mount Sinai School of Medicine in New York City, one of 29 National Institute on Aging (NIA) special Alzheimer's disease research centers, told Neurology Today in a telephone interview that she supports the megafund concept.

“This is a very interesting proposal, and highlights the benefits that could come from more up-front spending to identify and develop targets for AD treatments. I also think that the model of a superfund and the need for federal contribution for the early developmental stages of drug discovery to ‘de-risk’ the private sector investment is right on target. My impression is that some of the details of the cost estimates may have underestimated the potential savings realized by forwarding a portfolio of approaches rather than one at a time,” she said.

The research areas listed, however, “may all be based on the same mechanisms, and I am not sure this is the right way to model it,” she told Neurology Today in a telephone interview. “The disease and its progression may depend on problems in other [pathophysiological] cascades. Clearly amyloid beta and tau are involved, but perhaps we should be looking at the bigger picture.”

She noted that as yet genetic and clinical data cannot be matched up to proteins and their syntheses in a way that directs a therapeutic approach, something the model does not include.

“We cannot ignore basic science in this. A lot of people believe we need to measure amyloid-beta, but we also need to identify subsets of patients with different progression rates to understand why [the rates differ.]”

“A lot of the specific researcher areas included in the list have also been looked at already, but we could look at them more closely. It may be that some of these do not have any effect, but perhaps they do but it is not big enough for statistical significance. It might be a cheaper and more effective way to verify amyloid-beta or genetic factors.”

Regarding the estimated cost of the plan, Dr. Sano also said it may be inflated, but will still require joint government and private stakeholders to find those resources.

“I think they based the model on several assumptions; it might be possible to do it less expensively, especially if synergies develop between different researcher groups. Their cost estimate does not account for progress already being made in some of the proposed approaches such as hormones, growth factors and neuroinflammation,” she said.

“Even so, it is important to get this idea out there with a dollar figure. Maybe others will be able to develop similar models using different approaches.”


Below are the proposed projects for an AD megafund portfolio and the estimated “degree of validation” for each. Uppercase entries indicate hypotheses, boldface entries indicate categories, and remaining entries indicate projects. In cases in which hypotheses and categories are more speculative, they may constitute single projects. Entries containing numbers in parentheses indicate multiple projects.


Amyloid-beta passive immunotherapy

  • Abeta antibodies (6) - High
  • Pyro Abeta antibodies (3) - High
  • Antibodies against soluble oligomers (3) - High

Abeta synthesis

  • beta-secretase inhibitors (6) - Medium
  • gamma-secretase inhibitors and modulators (3) - Low
  • alpha-secretase agonism - Low

Abeta antiaggregation inhibitors/beta-sheet breakers - Low

Abeta clearance

  • Neprilsyn and plasmin - Low
  • Insulin-degrading enzyme - Low
  • Low-density lipoprotein receptor overexpression - Low


Phosphorylation inhibitors

  • CDK5 - Low
  • GSK3β - Low
  • MARK/par1 - Low
  • PKC - Low
  • MAPK - Low
  • PKA - Low
  • p70S6K - Low

Antiaggregants (TRx0237) - Low

Microtubule stabilizing agents (BMS 241027) - Low

Reduction of tau levels (Tau antibodies and antisense oligonucleotides) - Low


  • Activated receptor gamma and liver X receptors in coordination with RXR's - Low
  • SIRT1, sirtuin Low
  • GIVA-PLA2 Low


  • Complement receptor 1 - Low
  • TREM 2 - Low
  • PPAR agonists - Low
  • IL-1, IL-6, IL-12, IL-23 - Low
  • TNFR - Low
  • P2X7R - Low
  • Monoacylglycerol lipase - Low


  • Nilotinib - Low
  • Proteasome pathways - Low
  • Unfolded protein response - Low


  • Inactivation of gonadotropin-releasing hormone (GnRH) - Low
  • Allopregnanolone - Low
  • CERE-110: Adeno-associated virus delivery of nerve growth factor - Low


  • InsP3R - Low
  • CALHM1 - Low


  • Copper - Low
  • Zinc - Low





From Lo AW, et al. Sci Transl Med 2014: 6(241):241cm5; Reprinted with permission from AAAS


Lo AW, Ho C, Cummings J, Kosik KS. Parallel discovery of Alzheimer's therapeutics. Sci Transl Med 2014;241:241cm5.
Scott T, O'Connor A, Link A, Beaulieu T. Economic analysis of opportunities to accelerate Alzheimer's R&D. Ann NY Acad Sci 2014;1313:17–34.