Recent advances in dementia research

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Recent reports from the 2008 International Conference on Alzheimer's Disease and numerous articles indicate substantial progress in the diagnosis and treatment of Alzheimer's disease. However, the progress was partially a result of two well-designed anti-amyloid studies with disappointing results. Paradoxically, the effect is a heightened awareness of alternative therapeutic avenues that
have emerged with substantial promise.

Kennedy GJ, Leon LA. Recent advances in dementia research. Primary Psychiatry 2008; 15(11):27-30.

INTRODUCTION

What follows is a selection of abstracted reports1 available online from the 2008 International Conference on Alzheimer’s Disease and two articles2 published within a month of the conference. This column is not meant to be a comprehensive or representative survey of data. Rather, it is an effort to highlight trends in current research. Though some outcomes were disappointing, the sheer volume of work on diagnosis and treatment promises substantial near-term progress.


DIAGNOSTIC MEASURES AND PROCEDURES

With the growing incidence of Alzheimer’s disease, the development of early detection methods identifying at-risk individuals is crucial. Recognizing affected individuals before their cognitive symptoms become evident allows for early intervention as well as further research and potential preservation of function with future disease-modifying therapies. Several studies reported advances in this area.


Protein in WBC

Brain cells in patients with Alzheimer’s disease have an abnormal tendency to enter the process of division and replication, making them more vulnerable to programmed cell death or apoptosis. This defect is also found in lymphocytes of patients with Alzheimer’s disease. In a study by Arendt and colleagues,3 the expression of a protein involved in white blood cell (WBC) production (CD-69) was measured on multiple cell lines of subjects with probable Alzheimer’s disease (n=32), healthy controls (n=30), and other dementias, namely Parkinson’s disease (n=26). CD-69 values showed variations in levels that allowed the researchers to differentiate between patients with Alzheimer’s disease (91% accuracy) and those with Parkinson’s disease (92% accuracy). The levels also distinguished people with Alzheimer’s disease from normal subjects 88% of the time when they had Alzheimer’s disease and 82% of the time when they had no cognitive deficits.


Brain Amyloid in Cerebrospinal Fluid

Accumulation of amyloid plaques in the brain is considered one of the primary causes of Alzheimer’s disease. Fagan and colleagues4 demonstrated an inverse relation between amounts of brain amyloid (according to positron emission tomography [PET] scans) and cerebrospinal fluid (CSF) levels of A42, which is the major constituent of amyloid plaques independently of patient’s cognitive status in a cohort of 132 patients 45–88 years of age. The group included individuals without cognitive deficits and those with very mild and mild dementia. Individuals with high amounts of brain amyloid according to PET scans had low levels of A42 in their CSF 97% of the time (n=37). People with low levels of brain amyloid had high CSF A42 in 84% of cases (n=95). This association of altered A42 dynamics between brain and CSF was found even in pre-clinical stages, which indicates that this is a very promising early detection marker.


Brain Enzyme in CSF

β-secretase (BACE1) is one of two enzymes involved in processing the amyloid precursor protein and producing toxic β-amyloid. Hampel and Shen5 conducted a study that found higher levels of BACE1 activity in CSF of people with mild cognitive impairment (MCI) when compared to healthy controls and subjects with Alzheimer’s disease. Initially, the researchers measured CSF BACE1 in 80 people with Alzheimer’s disease, 59 people with MCI, and 69 healthy controls in two international centers. MCI subjects had a significantly higher level of BACE1 activity when compared to the other two groups. BACE1 activity was correlated with levels of β-amyloid. In a second part of the study, 47 MCI subjects were evaluated over the course of 2 years to assess BACE1 levels in combination with CSF tau and phosphorylated tau to determine the predictive value of these markers for determining conversion to Alzheimer’s disease. Fifteen MCI subjects converted to Alzheimer’s disease, and it was shown that BACE1 protein levels and the ApoE genotype were the strongest predictors of conversion to Alzheimer’s disease after controlling for age and gender (accuracy 78%, sensitivity 80%, and specificity 77% for the combination). A blood-based test for BACE1 is in process.


Amyloid Imaging Agents

PET scans create images of brain amyloid using a radioactive tracer that is injected into the patient. One of the challenges in widespread use of PET scanning is that the first amyloid tracer is short lived and, therefore, must be produced on-site. Of the compounds being studied, 18F-AV-45 promising based on a study of 42 cognitively healthy individuals and 39 patients with Alzheimer’s disease. It was favored because of its rapid uptake and ability tot maintain brain levels for 50–90 minutes post-injection. It is now being used for research, but it could potentially be useful in a community setting.6


Anti-amyloid Agents

Because there are numerous recognized milestones along the path to amyloid deposition, an array of potential targets is available for intervention. Among several reports of amyloid-related studies, two stood out for their disappointing results despite rigorous methodologies. Bapineuzumab is a humanized monoclonal antibody engineered to reduce β-amyloid in the brain. As such it would harness the natural immune processes to reduce the cause or entity near the cause of Alzheimer’s disease. However, amyloid in humans is produced in the absence of disease; provoking an immune reaction to amyloid is not without risk. Administration of an externally derived antibody or passive immunization to amyloid might prevent the adverse events resulting from active immunization.7 To study the safety and tolerability of bapineuzumab, 234 patients with mild-to-moderate Alzheimer’s disease were randomized to either placebo intravenous infusions or to one of four doses of bapineuzumab ranging from .15–1 mg/kg. The placebo group included 110 participants; the bapinezumab groups included roughly 30 participants each. Infusions of either placebo of bapienuzumab were scheduled every 13 weeks for a total of six treatments over 18 months.

Primary outcome measures specified prior to participant enrollment included the Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-cog) and the Disability Assessment Scale for Dementia, neither of which exhibited statistically significant differences between bapineuzumab and placebo at 78 weeks. Post hoc analyses of participants who received all six infusions favored bapineuzumab group but were not significant. Post hoc analyses of participants free of the ApoE4 allele, which is associated with elevated risk of Alzheimer’s disease, showed significant benefits compared to placebo on the ADAS-cog as well as the Neuropsychological Test Battery and Clinical Dementia Rating scale and brain volume, as measured by magnetic resonance imaging (MRI). However, vasogenic edema of the brain was observed by routine MRI in 12 patients, all of whom received bapineuzumab. Eight cases occurred in the highest dose of bapineuzumab. Six cases presented with clinical symptoms, one requiring steroids. In six of the 12 cases, re-dosing with bapineuzumab did not result in recurrence of vasogenic edema.

The study is noteworthy for its use of brain imaging and genetics as well as its multiple measures of cognitive performance and disability. Although benefits were limited to people not genetically predisposed to the disease, the study was powered with sufficient participants to detect small effect sizes. In addition, infusion therapy was burdensome and treatment- related brain edema was dose related. Without a measure of the dynamics of amyloid metabolism, it remains unclear whether altering the deposition of amyloid plaques or removing plaques once established would be the mechanism of therapeutic action. The study6 sponsors authorized a phase III trial of 4,100 participants in December 2007.

More disappointing than the bapineuzumab phase II study were results from the phase III 18-month trial8 of tarenflurbil. Tarenflurbil modulates γ-secretase activity to selectively reduce β-amyloid without interfering with other critical activities of the enzyme. A phase II study suggested tarenfluribil’s disease-modifying potential for people with mild Alzheimer’s disease. Green7 reported that 1,649 people with mean Mini-Mental Status Examination (MMSE) scores of 23.3 were randomized to either tarenflurbil 800 mg or placebo for 18 months. Participants were not excluded if they used cholinesterase inhibitors or memantine. The primary endpoints were the ADAS-cog and Alzheimer’s Disease Cooperative Study Activities of Daily Living Inventory (ADCS-ADL) scales, with the clinical dementia rating being the secondary endpoint, none of which showed significant differences between drug and placebo. The placebo group declined at the expected rate, making the possibility that placebo responders or sampling irregularities masked benefits unlikely. Given the length of observation and sample size, failure to detect a small but genuine effect due to the confounding influence of cholinesterase inhibitors or memantine was ruled out as well. The design contrasts with that of the β-amyloid antagonist tramiprosate trial in which lack of demonstrated efficacy may have been the result of the confounding presence of cholinesterase inhibitors and memantine taken by the study participants.7 In addition, the study is the longest, largest placebo-controlled treatment trial of Alzheimer’s disease, regardless of the degree of severity.


A Cholinesterase-Inhibiting Antihistamine

Dimebon is a non-selective antihistamine with a weak capacity to inhibit butyryl- and acetylcholinesterase. It also weakly blocks the N-methyl-D-aspartate receptor-signaling pathway. In theory, these properties mimic both the Food and Drug Administration-approved cholinesterase inhibitors and memantine, which makes dimebon an appealing candidate for the treatment of Alzheimer’s disease. However, dimebon may exert its effects at the level of mitochondria to enhance neuronal function. It also inhibits neuronal death in models for Alzheimer’s disease. Doody and colleagues2 enrolled 183 patients, 155 of whom completed 26 weeks of either placebo or dimebon 20 mg three times daily. Participants had a mean age of 68 years, with an MMSE score of 18 and a mean of 5 years duration of dementia. Entry criteria included mild-to-moderate Alzheimer’s disease based on the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders9 and computed tomographies/MRIs of the brain consistent with Alzheimer’s disease from the National Institute of Neurological and Communicative Disorders and Stroke/Alzheimer’s Disease and Related Disorders Association. None of the participants had taken memantine or a cholinesterase inhibitor 6 months prior to entering the study.

The group-administered dimebon improved significantly from baseline to 26 weeks with a mean decrease in errors on the ADAS-cog of 1.9 (95% Confidence Interval [CI] -2.92 to -0.85; P=.0005). Compared to placebo, the dimebon group exhibited a mean decrease in ADAS-Cog errors of 4 (95% CI -5·73 to -2·28; P<.0001). Secondary outcomes also improved in association with dimebon. The MMSE score rose 1.8 points from 18.7 (.35) at baseline to 20.5 (.46; 95% CI 1.14 to 2.39; P<.0001). The ADCS-ADL score rose 1.3 points from 52.7 (1.32) to 54 (1.44; 95% CI -0.09 to 2.70; P=.024). The Neuropsychiatric Inventory (NPI) showed a decline in behavioral symptoms of 1 point from 11.8 (1.22) to 10.7 (1.33; 95% CI -2.62 to 0.56; P=.050). The Clinician’s Interview-based Impression of Change plus caregiver input (CIBIC-plus) also favored dimebon over placebo (0.6; 95% CI .92 to -0.31; P<.0001).

Dimebon showed statistically reliable improvements in the scientific measures of cognition required by the FDA (ADAS-cog), as well as dementia-related disability (ADCS-ADL), and behavioral disturbances (NPI). It also demonstrated benefits apparent to clinicians blind to the patient’s treatment or placebo status (CIBIC-plus) and on a cognitive screening exam in common clinical practice (MMSE). Dry mouth (14% vs. 1%) and depressed mood (14% vs. 5%) were more frequent among the dimebon than placebo group but were not associated with discontinuation of treatment. Although initially designed as a 26-week study the investigators extended the double-blind period of observation for a total of 52 weeks, ending with 61 individuals in the dimebon group and 59 in the placebo group. At 52 weeks the difference between drug and placebo on the ADAS-Cog scale expanded to -6.9 points (95% CI -9.43 to -4.28; P<.0001). The dimebon group’s cognitive performance remained above their starting point while the placebo group had continued to decline linearly. However the investigators do not suggest this is evidence of disease modification. Thus, dimebon shows modest efficacy with substantial safety. Additional studies will be necessary to confirm the results as well as test the safety and efficacy of dimebon in combination with other medications approved for the treatment of Alzheimer’s disease and other dementias.


Anti-Tau Agents

There have been two recent favorable reports on anti-tau agents. Schmechel and colleagues10 used AL-108, an experimental peptide derived from the activity-dependent neuroprotective protein. Incorporated into a nasal spray, AL-108 is designed to target neurofibrillary tangles, one of the early changes seen in MCI and Alzheimer’s disease. The double-blind, randomized, placebo-controlled study assessed safety, tolerability, and effects of 5 mg and 15 mg of AL-108 after 12 weeks of treatment. Subjects (n=144) included men and women 55–85 years of age with MMSE scores of ≥24 self-reported memory problems corroborated by a companion, and a Wecshler Memory Scale III age-adjusted Logical Memory score of ≤5. Cognitive testing was conducted at baseline as well as at 4, 8, 12, and 16 weeks. The results showed that the medication was well tolerated, as similar rates of adverse events (eg, headaches) were reported in placebo and AL-108 treated subjects. Twelve weeks of treatment showed significant dose-dependent and consistent improvement on various measures of memory. More specifically, at the higher dose of AL-108, there was statistically significant improvement in the delayed-match-to-sample test with a 34.2% change from baseline at 4 weeks (P=.067 compared to placebo) and a 62.4% change from baseline at week 16 (P=.038 compared to placebo). Digit span forward test was also significantly improved at week 8 with 11.2% change (P=.032) and maintained improvement at week 16 with 11.7% change from baseline (P=.052).

A second report11 is based on a study of methylthioninium chloride (MTC), a tau aggregation inhibitor that has been shown to dissolve tau tangle filaments and prevent aggregation in vitro. Wischik and colleagues11 conducted a 24-week, double-blind, randomized trial of MTC treatment in 321 people with Alzheimer’s disease at 17 centers in the United Kingdom and Singapore, followed by a 60-week, double-blind, treatment extension. Results showed that subjects with moderate impairment taking MTC had significant improvement on cognitive function after 24 weeks of treatment compared to placebo (-5.5 ADAS-cog units at the 60 mg dose with a P=.0208). MTC also showed to reduce the rate of cognitive decline (P=.0014) with no significant decline from baseline compared to non-MTC groups at the final 84-week analysis. Clinical findings were also correlated by imaging brain metabolism using single photon emission computed tomography and position emissoin tomograph, which showed that treatment with MTC at 60 mg eliminated the decline in cerebral blood flow seen in controls. These results are encouraging in terms of progress toward obtaining disease-modifying treatments.


CONCLUSION


Although the cerebral cascade of amyloidosis remains a prominent target for the modification of Alzheimer’s disease, its salience has been diminished first by the disappointing results with tramiprosate and more recently by the tarenflurbil and bapineuzumab trials. In contrast, the two reports with favorable outcomes of anti-tau medications are among the first to provide empirical evidence for those who suggest that amyloid may not be proximal to the cause of the disease. Subsequent studies support the preliminary findings, other tauopathies, such as fronto-temporal dementia, would come into therapeutic play. Enthusiasm for dimebon should be tempered by the lack of evidence of its safety when combined with the cholinesterase inhibitors and memantine. Long-term benefits and the possibility of disease modification await subsequent data.

The number of reports on promising diagnostic measures and procedures continues to grow. Yet, none of them approach the reliability and convenience of tests such as hemoglobin A1c for the diagnosis of diabetes.12 Nonetheless, the promise of early detection combined with disease modification promises a substantial reduction in the associated cost of both private and public dementia care. Recent reports further indicate a possible treatment that will prevent the crippling disability of the disease. They promise proof of Fries’s13 1980 hypothesis that morbidity can be compressed to the end of the life span, countering fears of an epidemic of disabled, dependent seniors. PP


REFERENCES

1. ICAD. Alzheimer’s Association International Conference on Alzheimer’s Disease 2008. Available at: www.alz.org/icad. Accessed October 10, 2008.

2. Doody RS, Gavrilova SI, Sano M, et al. Effect of dimebon on cognition, activities of daily living, behaviour, and global function in patients with mild-to-moderate Alzheimer’s disease: a randomised, double-blind, placebo-controlled study. Lancet. 2008;372(9634):207-215.

3. Arendt T. Diagnosis of Alzheimer’s Disease using peripheral blood lymphocyte expression of CD-69
following a mitogenic stimulus. Available at: www.alz.org/icad/_icad_release_072908_3pm_biomarkers.asp. Accessed October 3, 2008.

4. Fagan AM. Update on the relationship between in vivo amyloid imaging with 11c-PIB and CSF A42.
Available at: www.alz.org/icad/_icad_release_072908_3pm_biomarkers.asp. Accessed October 3, 2008.

5. Hampel H. Alteration of beta secretase (BACE1) functional candidate biomarkers in subjects with mild cognitive impairment and Alzheimer’s disease. Available at: www.alz.org/icad/_icad_release_072908_3pm_biomarkers.asp. Accessed October 3, 2008.

6. Pontecorvo MJ. Development of 18F-AV-45, a novel 18F-labeled A amyloid imaging agent. Available at: www.alz.org/icad/_icad_release_072908_3pm_biomarkers.asp. Accessed October 3, 2008.

7. Alzforum.com. Available at: http://alzforum/org/drc/detail.asp?id=1984. Accessed October 3, 2008.

8. Green RC. Safety and efficacy of tarenflurbil in subjects with mild Alzheimer’s disease: results from an 18-month multi-center phase 3 trial. Available at: www.alz.org/icad/_release_icad_072908_130pm_trials.asp. Accessed October 3, 2008.

9. Diagnostic and Statistical Manul of Mental Disorders. 4th ed. Washington, DC: American Psychiatric Association; 1994.

10. Schmechel DE. A phase 2, double-blind, placebo-controlled study to evaluate the safety, tolerability, and effect on cognitive function of AL-108 after 12 weeks of intranasal administration in subjects with mild cognitive impairment. Available at: www.abstractsonline.com/viewer/view-Abstract.asp?CKey={5FB5340C-F07B-4DD5-BEC7-AEAE4DECBA86}&MKey={CFC5F7C6-CB6A-40C4-BC87-B30C9E64B1CC}&AKey={50E1744A-0C52-45B2-BF85-2A798BF24E02}&SKey={507
5100B-928F-42CD-B0CD-19E3F395979F}. Accessed October 10, 2008.

11. Wischik CM. Tau aggregation inhibitor (TAI) therapy with remberTM arrests disease progression in mild and moderate Alzheimer’s disease over 50 weeks. Available at: www.abstractsonline.
com/viewer/viewAbstract.asp?CKey={E7C717CF-8D73-41E0-8DB0-FA92205978CD}&MKey={CFC
5F7C6-CB6A-40C4-BC87-B30C9E64B1CC}&AKey={50E1744A-0C52-45B2-BF85-2A798BF24E02
}&SKey={68E04DB5-AB1C-4F7B-9511-DA3173F4F755}. Accessed October 3, 2008.

12. Consensus Committee. Consensus statement on the worldwide standardization of the hemoglobin A1C measurement: the American Diabetes Association, European Association for the Study of Diabetes, International Federation of Clinical Chemistry and Laboratory Medicine, and the International Diabetes Federation. Diabetes Care. 2007;30(9):2399-2400.

13. Fries JF. Aging, natural death, and the compression of morbidity. N Engl J Med. 1980;303(3):130-135.


Dr. Kennedy is professor in the Department of Psychiatry and Behavioral Sciences at Albert Einstein College of Medicine, and director of the Division of Geriatric Psychiatry at Montefiore Medical Center in the Bronx, New York. Dr. Leon is a fellow in the Division of Geriatric Psychiatry at Montefiore Medical Center.

Disclosure: Dr. Kennedy is consultant to Myriad; on the speaker’s bureau of Pfizer; and has received grant support from Forest, Janssen, Myriad, Novartis, Pfizer, and Takeda. Dr. Leon reports no affiliation with or financial interest in any organization that may pose a conflict of interest.

Please direct all correspondence to: Gary J. Kennedy, MD, Director, Department of Geriatric Psychiatry, MMC, 111 East 210th St, Klau One, Bronx, NY 10467; Tel: 718-920-4236; Fax: 718-920-6538;
E-mail: gjkennedy@msn.com.