ICAD 2010: detection may hold the key to treatment

Abstract

The Alzheimer’s Association International Conference on Alzheimer’s Disease was held on July 10–15 in Honolulu (HI, USA). Over 3800 attendees participated, attending sessions that included more than 1700 posters and 200 oral presentations. The meeting, first organized in 1988 by Khalid Iqbal and Bengt Winblad, became an annual event in 2009, and under the current design includes not only well-established themes of interest, but investigator-initiated sessions also. The Alzheimer’s Association started managing the conference in 2000 in partnership with the founders, and abstracts for the meeting are published in the association’s journal, Alzheimer’s & Dementia. Key themes of this year’s conference included validation of biomarkers, drug development, the value of screening for cognitive loss and dementia and the proposal of a new criteria for Alzheimer’s disease.

Imaging amyloid & biomarkers of disease

One of the most exciting presentations of the meeting described the results of the study utilizing an amyloid PET imaging tracer, Florbetapir F, to image amyloid accumulation in the brain. Clark et al. (Avid Radiopharmaceuticals, PA, USA) reported data from 35 cases that came to autopsy with a range of neuropathological diagnoses, including indicated high correlation between postmortem global and regional PET scan images, (which were rated visually on a 4-point scale) and postmortem histopathological determination of amyloid plaque density in the brains of individuals with and without Alzheimer’s disease (AD) [1]. Among the autopsy cases, approximately a third were cognitively normal, approximately half were considered to have AD, and six cases were diagnosed with non-AD dementia. This study reported significant high correlations between imaging data and amyloid burden, as measured by the Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) neuropathologic rating scale. These results permit antemortem assessment of localized amyloid burden. While the presence of amyloid does not rule out the presence of other defining pathologies, such as Lewy bodies, Pick bodies or cerebrovascular changes, it is the strongest correlation demonstrated to date of an in vivo biomarker for hallmark amyloid, and it appears to have regional specificity. Perhaps the greatest potential of Florbetapir F is the ability to identify a population with a homogeneous pathology, which might be important in developing therapeutic approaches for a targeted pathology.

Clinical trial progress

The International Conference on Alzheimer Disease (ICAD) meeting has traditionally been a place to present cutting edge clinical trial results and the field awaits promising information. Several important Phase III studies were ongoing and not described at the meeting, including the results of the γ-secretase inhibitor semagacestat, which may decrease β-amyloid production, and the potentially β-amyloid-clearing treatments bapineuzumab, solanezumab and intravenous immunoglobulin (IGIV).

Results of the CONNECTION study of latrepirdine were presented, describing the first international study with this drug in AD [2]. The study enrolled 598 subjects with mild-to-moderate AD, who were not taking antidementia drugs, and assessed them taking one of two doses of latrepirdine (2 and 5 mg three-times a day) or placebo for 26 weeks. No treatment benefit occurred in the primary outcomes of cognition, measured by the Alzheimer Disease Assessment Scale (ADAS-Cog) or global clinical change, measured with the Clinicians Interview Based Impression of Change (CIBIC). An earlier multicentered study conducted in Russia observed a significant benefit with the 20 mg dose in both 6-month and 1-year analysis. Of particular interest in the CONNECTION study, was the absence of decline in either the placebo-treated or latrepirdine-treated group, which may be due to the relatively short 6-month treatment interval used in this trial. The ongoing CONCERT trial examines similar doses of latrepirdine in AD, with administration for 1 year in individuals currently on a cholinesterase inhibitor. The result will be particularly important to determine whether the drug continues to have potential as a treatment.

Several smaller studies reported intriguing findings. Craft et al. (University of Washington and VA Puget Sound Health Care System, WA, USA) described the results of a single site pilot study using intranasal insulin to improve memory and function in individuals with mild cognitive impairment (MCI) or AD [3]. The study enrolled 109 participants who were randomly assigned to one of two doses of intranasal insulin (20 or 40 IU/day) or placebo for 4 months. Results indicated benefit over placebo in a measure of memory and a measure of function, at some, but not all doses. With only a subset available to examine, Craft presented data suggesting that the outcomes might be associated with central markers of amyloid and tau. Another therapeutic approach that holds great interest is using local delivery of NGF to stimulate cholinergic cell regeneration, particularly in the basal forebrain. Investigators from the Karolinska Institute (Sweden) described encapsulated cell delivery of NGF, which was stereotaxically implanted in to the basal forebrain and the vertical limb of the diagonal band of the nucleus [4]. Successful implantation – sustained for 6 months – and removal was reported for the six individuals enrolled in this study. Removal of the implants offers a method to minimize exposure should penetration to more extensive areas become problematic as some earlier studies had suggested.

To screen or not to screen

Many presentations addressed the issue of screening for cognitive loss and dementia. Several described instruments for assessing cognition, including ones requiring various levels of automation. While the ability to identify frank dementia may seem straightforward, Sager et al. (University of Wisconsin, WI, USA) described the community based, Wisconsin Memory Screening Initiative, which assessed individuals over the age of 65 known to not have dementia with an animal naming test, which takes less than 5 minutes [5]. Among those who were assessed, 34% screened positive and 60% of those who were available for assessment received a dementia diagnosis. Thus, in the general population over 65 years of age thought to be cognitively intact, approximately 20% appear to have significant cognitive impairment. Similarly striking findings were reported by MacCarten et al. (VA Medical Center, MN, USA) from the Dementia Demonstration Project conducted by the Veterans Integrated Service Network, including the Minneapolis (MN, USA) region (VISN 23) [101]. The 3-min Mini-Cog was used to assess over 8000 individuals over the age of 70 years. More than a quarter were found to be impaired and were offered a more extensive evaluation. Of those who participated in the next evaluation, 76% had a diagnosis of dementia and another 20% had significant cognitive impairment. This suggests that 24% of the population over 70 have an undetected dementia diagnosis. Detection rates within this same system, but in clinics not conducting systematic screening, are less than 3%, which highlights the effectiveness of screening. In those identified with cognitive loss or dementia, Veterans Affairs outpatient costs for the year before and the year after screening were compared and costs after detection were reduced by 13%. While this study does not identify where costs or savings were realized, a report of the formal and informal costs of individuals with MCI reported by Zhu et al. (Mount Sinai School of Medicine and James J Peters Medical Center, NY, USA) may provide some hints [102]. In the report of the placebo arm of a 3-year trial of individuals with MCI, she found that medical care costs were a much larger proportion of healthcare expenses than in AD, in which informal care costs are the largest component of cost. Also, they reported that while both medical and non-medical costs escalate in MCI, the largest escalations were seen in those who did not have dementia. Perhaps savings can be achieved by early detection and follow-up, reducing the unnecessary use of medical resources.

New diagnostic criteria

One of the most controversial topics of the meeting was the proposed new criteria for the clinical diagnosis of AD. Research criteria, published over 25 years ago, do not take advantage of the growing knowledge of the disease and its progression. For example, the existing criteria have age cutoffs (between 40 and 90 years of age) that do not reflect what we know today concerning the disease incidence and course. Currently, the criteria do not include supporting information in the diagnosis, such as genetic information or biomarker results. The new criteria propose to integrate the biological and epidemiological information we have to date. The diagnosis of ‘all-cause dementia’ is similar to the Diagnostic and Statistical Manual of Mental Disorders diagnosis, in that it focuses on impairment in social or occupational function that is a clear decline from a previous level and due to cognitive loss in two or more areas. However, unlike Diagnostic and Statistical Manual of Mental Disorders, memory impairment may be apparent but is not required. The criteria for the clinical diagnosis of AD include insidious onset with amnestic and nonamnestic subtypes. Probable AD would be defined by evidence of clinical decline. However, if this type of information was not available, biomarker positivity or mutation carrier status could provide support for the diagnosis. This approach suggests that we have growing confidence in biomarkers as an indicator of specific disease. Diagnostic criteria were also proposed for MCI, consisting of four basic elements:

• • Concern regarding cognitive change

• • Impairment of cognition

• • Preservation of independent function

• • The absence of dementia

A second layer to diagnostic specificity is to identify the etiology of MCI. Genetic and biomarker data that confer the AD diagnosis described above would be key to establishing an etiology. Perhaps most controversial is the attempt to define a ‘preclinical’ AD. This asymptomatic condition would be defined by biomarkers associated with AD pathology in the absence of any clinical features [103]. These criteria come with an important caveat that more information is needed to confer diagnostic authority of current markers, shown to be present in approximately a third of the elderly asymptomatic individuals without evidence of well-established progression. The challenge to know the true predictive value of a biomarker was raised by the work of Schneider et al. (University of Southern California, CA, USA), who report only minimal improvement in predicting disease progression, as measured by typical clinical trial outcomes, with cerebrospinal fluid biomarkers of amyloid and tau [6].

Overall, this year’s meeting provided hope for a new direction in the diagnosis of Alzheimer disease, that may provide the specificity needed to advance therapeutics in the field. Abstracts for the meeting can be accessed free online in Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association.

Financial & competing interests disclosure

Mary Sano has been a consultant to the following companies: Medivation, Novartis, Pfizer, Bristol Myer Squbb. Esai Pharmaceitical, Elan, Genetech USA, UBC health care Analytics, INC, Takeda, Sanofi-Aventis, Bayer, and Medpace. No compensation was received from the above entities for attendance at the meeting. Mary Sano is a member of the program committee for the AAICAD meeting and received partial reimbursement for attendance at the meeting. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.