The 10th International Conference on Alzheimer’s Disease and Related Disorders, ICAD for short, ended yesterday just outside the palatial capital of Spain. The conference attracted not only a record number of attendees—just above 5,000 from 50 countries—but also a visit by Queen Sofia, whose philanthropy supports AD care and research in her country. (The first ICAD conference, held 1988 in Las Vegas, hosted around 300 attendees.)

In several dozen informal interviews in hallways, ballrooms, on escalators and shuttle buses, attendees applauded that many scientists presented unpublished data in their talks and posters. Presentations included major new developments, such as the discovery that the progranulin gene causes a form of frontotemporal dementia (see ARF related news story) as well as the discovery of a physiological function for the enzyme BACE (see ARF related news story) Smaller nuggets of news solidified emerging trends or opened up new research directions. Some scientists grumbled about feeling crammed into a crowded poster area while the neighboring company exhibits enjoyed all the space and air that’s necessary for animated conversation. Others viewed the commercial presence, together with the large number of presentations on a variety of experimental therapies, as a positive sign of the field’s needed movement toward translational science as patient numbers grow inexorably.

Even a casual flick through the conference program makes clear that a large fraction of the presentations focused on a panoply of different early detection and diagnostic efforts. Research in this area has exploded compared even to as recently as 5 years ago. It included attempts to detect telltale fingerprints of preclinical AD in body fluids, such as innovative work on leukocyte gene expression profiles or more advanced attempts to validate known biomarkers in the cerebrospinal fluid. Efforts ranged from imaging methods and more refined neuropsychological tests to proxy markers derived from epidemiological research on risk factors in the cardiovascular and metabolic fields. On the imaging front, news included updates on the amyloid imaging agent PIB and its use in presymptomatic carriers of familial AD mutations, as well as talks on promising new approaches such as diffusion tensor imaging and perfusion MRI to measure the degradation of the brain’s white matter that is thought to precede overt AD.

This early detection work reflects an emerging consensus among scientists that Alzheimer disease develops for a decade, perhaps even longer, before clinical signs become apparent. In fact, researchers increasingly compare the phase of diagnosed AD as we know it to terminal, metastatic cancer—the end stage of a disease that ideally should be treated years before the patient shows up at the neurologist’s door. The need for early detection is pressing, and many scientists wonder whether some drugs fail partly because they are tested too late in the disease.

The lack of validated, consensus biomarkers notwithstanding, this year’s ICAD program indicates that therapeutic approaches appear to grow exponentially at the present stage of AD research. The majority of them dig into some aspect of the amyloid hypothesis, but not all. Outliers that buck this overwhelming trend include intranasal insulin, growth factor gene therapy, gonadotropal hormones, tau immunotherapy, and dietary supplements. Immunotherapy approaches appear to have mushroomed, but many scientists remain as wary of their potential side effects as they are hopeful about their ability to remove forms of Aβ or amyloid. Finally, if γ-secretase inhibitors could speak, they might borrow a quote from Mark Twain and declare that the reports of their death have been greatly exaggerated. β-secretase inhibitors, still largely guarded behind the doors of pharmaceutical companies, are beginning to show their face, as well.

What works? To date, some trials remain ongoing and blinded, other approaches look promising in pilot trials only to fail in larger ones, and yet others appear to be limping along with rather small effect sizes. Piecing together the shards of the shattered AN1792 trial, scientists appear to be finding hints that the patients might yet have benefited a whit from the prototype vaccine after all. That said, the croupier is still taking bets on which of the current approaches will survive the minefield of cost, trial design headaches, patient recruitment and dropout woes, side effects, bad press, and struggle with the FDA that together characterize today’s drug development environment.

Some issues were notable for their absence. For example, there were fewer discussions than at prior conferences about whether Aβ oligomers, fibrils, or plaques were the toxic species in AD. Researchers appeared to have adopted the stance that all of these are damaging when present in excess over a long period of time (though more are also coming around to think that, at the proper levels, Aβ may indeed have a physiological role to do with synaptic activity). Broadly speaking, oligomers are suspected of triggering acute cognitive deficits, whereas plaques are thought to damage the structure and transmission capability of the brain and to fuel chronic inflammatory states. Likewise, investigators no longer debated whether Aβ or tau are detrimental factors in AD. Most view both proteins as critical, and Aβ as upstream of tau. At the Alzforum symposium, Bart de Strooper referred to the “Amyloid Tau Hypothesis” as a framework for AD research. What’s more, some scientists suggested that tau pathology appears to occur downstream of many amyloids, not just amyloid-β but also prion amyloid and synuclein deposits, for example. Yet another shift appears to occur around the notion that, increasingly, basic scientists no longer focus as relentlessly on Aβ or tau as they tended to do before, but view them as but two players in a broader drama of oxidative, synaptic, and proteasomal stress, confounded by systemic changes such as high blood pressure, insulin resistance, and other components of what is collectively called metabolic syndrome. Consequently, future treatments will likely have to include combinations of drugs directed against Aβ, against tau, as well as neuroprotective, cardiovascular, and other agents.

Details from roughly 340 talks and 400+ posters in six days can make the most capacious brain overflow. More than 300 conventioneers took advantage of a break offered by the Alzforum and joined our 10th anniversary symposium. Called “Mapping the Next Decade of Alzheimer Research,” it took a crack at integrating major ideas and trends in AD research. Admission was possible only for those who passed a spatial learning paradigm called the Madrid Paper Maze. Probants had to navigate a trail of signs to find the hidden platform—that is, a location changed at the last minute to a different quadrant of the convention center. We will post coverage of this event, as well as a stream of news stories from the ICAD conference, over the next two weeks. As always, contributions from our readers are warmly invited.—Gabrielle Strobel.

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  1. What a pleasure to read Gabrielle Strobel’s elegant ICAD summary. Would that more of us possessed her stylistic talents when writing about complex scientific research.

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References

News Citations

  1. Birds of a Feather…Mutations in Tau Gene Neighbor Progranulin Cause FTD
  2. Madrid: BACE Found to Have Big Job in Wrapping Motoneurons

Other Citations

  1. Mapping the Next Decade of Alzheimer Research

Further Reading

News

  1. Chew ’em Up and Spit ’em Out: Aβ Leaves Cells via Exosomes
  2. Madrid: BACE News Roundup, Part 2
  3. Madrid: BACE News Roundup, Part 3