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."

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