At the 7th Leonard Berg Symposium held 1-2 October 2009 at Washington University in St. Louis, Missouri, scientists and patient advocates came together to exchange the latest news on detecting disease presymptomatically and to compare what’s known in rare genetic and in common forms of the disease. There was a palpable sense of excitement in the auditorium that, overall, enough lines of evidence are coming together to make preclinical detection possible in practice. Paradoxically, perhaps, this optimism arose alongside a general acknowledgment that autosomal-dominant AD is surprisingly heterogeneous, and that its status as a faithful model for the much larger population of general late-onset AD is far from cut and dried. Here are some highlights.

Ira Shoulson is a leading neuro-geneticist and clinician for Huntington disease (HD) at the University of Rochester School of Medicine and Dentistry, New York. He led the conference with a keynote on what the HD experience can teach the AD field. In HD, predictive genetic testing has been possible since 1983; hence, scientists in this community have had more time than their colleagues in AD to study the acceptance and psychological effects of such testing, as well as the characteristics of the presymptomatic period of carriers. Even so, research into preclinical HD is arguably less advanced, partly because fewer large-scale studies exist to observe how the natural history of HD unfolds. In AD, early stage diagnosis is becoming routine, at least at some academic tertiary care centers. There, clinicians try to implement biomarker-enhanced diagnoses of “prodromal” AD (Dubois et al., 2007) or similarly early stages called by a different name (WashU clinicians would call it incipient or very early AD), and the amnestic subtype of the MCI clinical categorization system appears largely to capture the same group of people. Increasingly, specialized centers will diagnose people who do not meet criteria for dementia if they have a mild memory complaint and a pathological CSF or brain scan. The rallying call in AD now is to move the diagnosis back even further, before the first symptoms appear. In contrast, the diagnosis of Huntington’s in the past 20 years has moved back only a year or two as clinicians have become more astute at recognizing early clinical signs, Shoulson said, but it is still an entirely clinical diagnosis made much later than he would wish.

In HD, people on average live 40 years of their lives at risk and 20 more years with the illness, though age of onset varies. For each person with HD, five are living at risk for the disease, but no robust biomarker signatures are in place to identify “silent” disease in these people. Scientists do know that certain abnormalities, such as cortical thinning, predate symptomatic HD, as do certain cognitive impairments, but in practice this has not translated into presymptomatic diagnosis and prevention research. To gather more powerful data on the HD preclinical phase, researchers collaborated to launch PHAROS, an observational study that to date has followed nearly 1,000 at-risk, presymptomatic people for five years. One-third of them have the extended glutamine repeat and will develop HD. “We asked people if they’d come back every nine months for evaluation. We would not share with them what we found, and we wanted their blood and put it in a database. This was very daunting, particularly securing confidentiality and privacy. It was, in part, what led to the passage of Genetic Information Nondiscrimination Act (GINA),” Shoulson told the audience (see ARF related news story on GINA).

PHAROS appears to have been worth the effort. Its initial data show that all motor and cognitive domains monitored indeed reveal abnormalities in carriers compared to their fellow non-carriers. On most tests, the differences grew over time, whereas in some tests they were present from the first assessment and then stayed constant over time. Importantly, however, on each test the carrier vs. non-carrier curves were separate throughout the duration of the study, showing that carriers already do a little more poorly in those functions that will develop overt symptoms years later. “People carrying expanded repeats did worse at baseline and worsened more over time on both motor and cognitive scores,” Shoulson said. This is instructive for the Dominantly Inherited Alzheimer Network (DIAN), which will also compare carriers to non-carriers in the decade or so before disease onset. DIAN, however, uses a different panel of assessments more heavily weighted toward imaging and CSF biomarker data. The PHAROS study stored no CSF but did store serum and urine samples; no data are available from the fluids yet. In PHAROS, as in DIAN, the hope is to use the data to identify subsets of people who are within five years prior to their diagnosis and offer targeted drug trials to them.

John Morris then summarized the rationale for DIAN and added to it the latest data in the WashU group’s ongoing studies to define exactly a detectable biological identity of those five years. Scientists have known for a decade that a sizable fraction of aging people have pathological AD—amyloid plaques and neurofibrillary tangles—without the disease’s symptoms (Price and Morris, 1999), and in the past five years, amyloid imaging has vividly confirmed this finding. Many scientists have interpreted this to mean that there likely exists a long, clinically silent stage during which AD pathogenesis operates biochemically and neurobiologically in ways that should be identified for diagnosis and early intervention. “Our efforts since then have been to characterize that stage,” Morris said.

The finding that people live with AD pathology but no symptoms also renewed a debate about whether perhaps that pathology is benign. It is absolutely not, Morris said emphatically in St. Louis. In his view, people with this pathology will develop the symptoms of AD. Exactly when that happens in a given person depends on factors such as their brain and cognitive reserve, inflammatory state, vascular health, and perhaps exercise and other environmental factors. Other speakers appeared to agree with this view (see Part 6 of this series).

New data to advance this old debate is coming on several fronts, Morris said. For one, an upcoming paper by Martha Storandt and colleagues at WashU found that, even in people who do not meet criteria for dementia, the presence of amyloid in the brain as seen by PIB PET imaging comes with a sharp decline in global composite cognitive performance (Storandt et al., 2009). For another, a WashU study led by David Johnson (now at the University of Kansas) and James Galvin reported in the October Archives of Neurology a measurable drop in cognitive performance among 444 volunteers during the transition from healthy aging to symptomatic AD (Johnson et al., 2009). People’s performance curves suddenly veered downward three years to one year before they got clinically diagnosed, even though the clinicians at WashU strive to pick up AD early. Notably, visuospatial performance caved in first, suggesting that a sole focus on episodic memory in clinical testing may miss earlier telltale signs. Episodic and working memory declined measurably in the year before diagnosis.

This result echoes studies from a growing group of other investigators who find changes in visuospatial and other domains years before a person becomes impaired enough to receive a clinical diagnosis. For example, at last July’s International Conference on Alzheimer’s Disease (ICAD) in Vienna, Jean Francois Dartigues of the University of Bordeaux, France, presented extensive and similar data from Paquid, a community-based natural history study in the Bordeaux area that has assessed 3,777 elderly people every other year for 14 years. In Vienna, Dartigues reported that people who were eventually diagnosed with incident dementia by DSM-IV criteria (i.e., years down the road from when they would get diagnosed at WashU) started declining subtly in processing speed, semantic memory, and verbal fluency some 12 years prior to formal diagnosis. Other, broader domains of memory and executive function commonly declined a few years thereafter, all of which preceded depression and the person’s own sense that something was wrong (Amieva et al., 2008). At ICAD, Dartigues detailed declines in multiple cognitive tests preceding an AD diagnosis that clearly differed from the curves of normally aging people. Both studies imply that studies of normal aging may contain a sizable fraction of people who in fact have preclinical AD, and thus perhaps overestimate the effects of truly healthy aging.

Storandt’s, Galvin’s, and Dartigues’ data comes from prospective work in either self-selected or community-based elderly people. What about dominantly inherited AD? At the Leonard Berg Symposium, Martin Rossor of University College London, UK, noted that from the very beginning of research with carriers of APP and presenilin mutations, changes in verbal, visual, and spatial memory were found to precede a broader deterioration that signaled the onset of clinical AD (e.g., Newman et al., 1994). Francisco Lopera is a neurologist at Antioquia University School of Medicine, Medellín, Colombia, who works with the world’s largest known pedigree carrying a presenilin mutation and attended the Leonard Berg Symposium. His research has pointed to verbal and semantic memory as early indicators, as well. And John Ringman of the University of California, Los Angeles, found stark differences in both the trail making test (which taxes visuospatial and executive speed) and verbal memory tests when he compared 30 mutation carriers and 21 non-carriers from 10 Mexican families with presenilin mutations. These differences between non-carriers and carriers arose with age; they were not evident when carriers were still 20 years away from their family’s expected age of onset but were about five years prior (Ringman et al., 2005). Since then, a newer study of 42 Mexican American people at risk of a pathogenic presenilin mutation has begun, and many of these subjects are opting to participate in DIAN, Ringman said in St. Louis. While these tests broadly point to the same functional domains, getting scientists to agree which tests to use will be one of the bigger challenges of any joint prevention initiative, several speakers at the Berg Symposium acknowledged. To name but a few, cued semantic recall tests and attention tests measuring intrusion errors are also increasingly cropping up as sensitive indicators very early on, and cognitive psychologists are known for fiercely debating the pros and cons of their favorite tests.

Based on this and other data, it seems that what scientists have found out about the preclinical cognitive decline in autosomal-dominant familial AD largely jibes with findings from late-onset AD, Rossor and other speakers said. “Cognitive decline in early familial AD is similar to that seen in LOAD,” said Ringman. This, in turn, holds out hope that biomarker data from the DIAN network may likewise be generalizable to the common forms of AD. A predictive biomarker signature is indispensable because longitudinal studies aren’t an option for the diagnosing physician, who ideally needs to get the job done in a single visit.—Gabrielle Strobel.

This is Part 3 of a seven-part series on presymptomatic detection. See also Parts 1, 2, 4, 5, 6, and 7.


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News Citations

  1. GINA No Genie for Alzheimer Disease Patients and Relatives
  2. St. Louis: Imaging Preclinical AD—Can You See it Coming in the Brain?
  3. St. Louis: Scientists, Families Target Preclinical Detection, Trials
  4. St. Louis: The Family View—What Do Study Volunteers Want From DIAN?
  5. St. Louis: Biomarkers Pre-dementia—Like eFAD, Like LOAD?
  6. St. Louis: Is Rare Familial Alzheimer’s a Model for the Millions?
  7. St. Louis: An eFAD Prevention Trial—One Man’s View

Paper Citations

  1. . Research criteria for the diagnosis of Alzheimer's disease: revising the NINCDS-ADRDA criteria. Lancet Neurol. 2007 Aug;6(8):734-46. PubMed.
  2. . Tangles and plaques in nondemented aging and "preclinical" Alzheimer's disease. Ann Neurol. 1999 Mar;45(3):358-68. PubMed.
  3. . Cognitive decline and brain volume loss as signatures of cerebral amyloid-beta peptide deposition identified with Pittsburgh compound B: cognitive decline associated with Abeta deposition. Arch Neurol. 2009 Dec;66(12):1476-81. PubMed.
  4. . Longitudinal study of the transition from healthy aging to Alzheimer disease. Arch Neurol. 2009 Oct;66(10):1254-9. PubMed.
  5. . Prodromal Alzheimer's disease: successive emergence of the clinical symptoms. Ann Neurol. 2008 Nov;64(5):492-8. PubMed.
  6. . The earliest cognitive change in a person with familial Alzheimer's disease: presymptomatic neuropsychological features in a pedigree with familial Alzheimer's disease confirmed at necropsy. J Neurol Neurosurg Psychiatry. 1994 Aug;57(8):967-72. PubMed.
  7. . Neuropsychological function in nondemented carriers of presenilin-1 mutations. Neurology. 2005 Aug 23;65(4):552-8. PubMed.

External Citations

  1. Genetic Information Nondiscrimination Act (GINA)
  2. Dominantly Inherited Alzheimer Network (DIAN)

Further Reading


  1. . Longitudinal study of the transition from healthy aging to Alzheimer disease. Arch Neurol. 2009 Oct;66(10):1254-9. PubMed.