NPR-like radio blurb

The objective was to identify separate cognitive domains in the standard assessment tools (MMSE, ADAS-Cog) and analyze the process of decline within domains during three years in Alzheimer's disease (AD) patients with donepezil treatment.

To identify and counter risks we considered the relevance to AD drug development of the following factors: (1) effective dosing of the drug product, (2) reliable evaluations of research subjects, (3) effective implementation of quality controls over data at research sites, (4) resources for practitioners to effectively use CT results in patient care, (5) effective disease modeling, (6) effective research designs.

encountered in AD drug development can be avoided by changing practices. Current problems with human errors in clinical trials make it difficult to differentiate drugs that fail to evidence efficacy from apparent failures due to Type II errors.

Therapeutic strategies aimed at preventing Aβ formation, blocking its aggregation into plaques, lowering its soluble levels in the brain, and disassembling existing amyloid plaques are among the main strategies employed to slow the progression of AD. Recently, a few therapeutic programs have aimed at reducing tau phosphorylation and/or aggregation. Beyond plaque- and tangle-related targets, other aspects of AD pathophysiology, including mitochondrial dysfunction, failure of molecular transport mechanisms, oxidative damage, inflammation, and cell-cycle dysregulation, may also provide therapeutic opportunities.

Tramiprosate is a glycosa

minoglycan mimetic that binds to monomeric Aβ, thereby reducing aggregation and neurotoxicity while promoting clearance from brain

The effectiveness of the 5 U.S. Food and Drug Administration–approved pharmacologic therapies for dementias in achieving clinically relevant improvements is unclear.

Purpose: To review the evidence for the effectiveness of cholinesterase inhibitors (donepezil, galantamine, rivastigmine, and tacrine) and the neuropeptide-modifying agent memantine in achieving clinically relevant improvements, primarily in cognition, global function, behavior, and quality of life, for patients with dementia.

Data Synthesis: 96 publications representing 59 unique studies were eligible for this review. Both cholinesterase inhibitors and memantine had consistent effects in the domains of cognition and global assessment, but summary estimates showed small effect sizes.

Fortunately, basic research is identifying many of the pathways that contribute to this devastating disease (Fig. 1), providing unprecedented opportunities for the development of new treatments aimed at the root causes of AD. Here, we review several of these efforts and consider both shorter- and longer-term prospects for effectively treating AD.

Molecular and cellular processes presumed to participate in AD pathogenesis. Aß peptides produced by neurons and other brain cells aggregate into a variety of assemblies, some of which impair synapses and neuronal dendrites, either directly or through the engagement of glial loops. Build-up of pathogenic Aß assemblies could result from increased production or aggregation or from deficient clearance mechanisms. ApoE4 and tau promote Aß-induced neuronal injury and also have independent adverse effects. Microglia could be beneficial or harmful, depending on which of their signaling cascades and functions are engaged. This multifactorial scenario leads to progressive disintegration of neural circuits, isolation and loss of neurons, network failure, and neurological decline.

Five drugs are approved in the United States for the treatment of AD (2, 3), although tacrine is now rarely used because of hepatotoxicity (Table 1). Cholinesterase inhibitors are designed to combat impairment of cholinergic neurons by slowing degradation of acetylcholine after its release at synapses. Memantine prevents overstimulation of the N-methyl-D-aspartate (NMDA) subtype of glutamate receptors, which may contribute to the pathogenesis of AD and other neurodegenerative conditions by causing excitotoxicity (4). In clinical trials, both cholinesterase inhibitors and memantine have shown beneficial but modest effects on cognitive test scores, behavioral measures, and functional outcomes (5–9). However, because the benefits of cholinesterase inhibitors are small and may be seen in only a subset of patients, their cost effectiveness has been questioned (10). Because memantine is beneficial in patients already taking cholinesterase inhibitors and may even reduce their side effects, the two are often used together (9). Many AD patients also receive antipsychotics or anti-depressants to manage neuropsychiatric and behavioral symptoms or take over-the-counter preparations whose therapeutic value is uncertain, including ginkgo biloba and vitamins C and E

Predicting trouble. A high percentage of ADNI-MCI subjects who progressed to Alzheimer's disease had abnormal CSF levels of various versions of tau (top left) and β-amyloid (bottom left), two biomolecules thought to play a role in Alzheimer's pathology. CREDIT: IMAGES COURTESY OF JOHN TROJANOWSKI [Larger version of this image] Even so, companies are already incorporating ADNI-vetted biomarkers. "Every company that's working in AD [Alzheimer's disease] drug development is designing trials based on ADNI data right now, not as the only tool but as a significant tool," says neurologist Paul Aisen of UC San Diego, who co-chair's ADNI's clinical core and oversees government-sponsored clinical trials as director of the Alzheimer's Disease Cooperative Study.

At least one company is already using CSF biomarkers to screen subjects for a clinical trial, and others are considering it, says Aisen. Including only those people who show both β-amyloid aberrations and memory problems may help weed out misdiagnosed Alzheimer's cases and provide a better test of the proposed therapy. Some companies anticipate biomarkers will help establish that their treatments strike at the roots of the disease. Eli Lilly, which has two compounds in phase III trials for Alzheimer's, is using several biomarkers—including MRI, FDG-PET, and β-amyloid CSF and PET—in hope of demonstrating that these treatments provide biological as well as clinical benefits. "Our studies are set up so that they look quite a bit like ADNI," says Eric Siemers, the medical director of Lilly's Alzheimer's team.

Such evidence won't directly influence the decision to approve the drug. But demonstrating a positive change in a biomarker—in addition to establishing a clinical benefit—might earn a company the right to claim its drug slows the decline of Alzheimer's disease, something no drug currently on the market can claim. Says Katz: "You can imagine the marketing advantage to the first company that gets a drug whose label says it's approved to slow the progression of Alzheimer's disease."