(Laurie Barclay, MD, August 2003)

Alzheimer's disease (AD) is the most common form of dementia, or loss of normal brain function including thought, memory, and language. This degenerative condition is named after Dr. Alois Alzheimer, who discovered the hallmark neuropathological feature of amyloid plaques and neurofibrillary tangles in 1906.

Cognitive dysfunction in AD is linked to neurotransmitter abnormalities, especially those involving acetylcholine. The widely held amyloid cascade hypothesis assumes that beta-amyloid protein deposits found in plaques are toxic to the brain. However, neurofibrillary tangles, inflammation, free radicals, and impaired cerebral metabolism may all play some role in the pathogenesis of AD, either alone or in combination.

Up to 4 million Americans currently have AD. Onset is usually after age 60, and risk doubles every 5 years beyond age 65. Prevalence is 3% at ages 65 to 74, and nearly 50% at age 85 and older. Average survival is 8 to 10 years after diagnosis but may be as long as 20 years.

In addition to age, family history is another major risk factor. However, familial AD, which usually occurs between the ages of 30 and 60, is relatively uncommon. The apolipoprotein E (apoE) gene has three forms, one of which is protective against AD, and another of which increases the risk of sporadic AD. Other genetic mutations may increase risk, while environmental risk factors may include head injury, low educational level, and toxic exposure.

Although there is currently no cure for AD, available drugs such as tacrine (Cognex), donepezil (Aricept), rivastigmine (Exelon), or galantamine (Reminyl) may help prevent some symptoms from becoming worse for a limited time during the early and middle stages of AD. Drugs such as tacrine and donepezil are anticholinesterase (AChE) inhibitors, which increase the duration of action of acetylcholine at cholinergic synapses.

Behavioral symptoms of AD, such as sleeplessness, agitation, wandering, anxiety, and depression, may respond to sedatives, antidepressants, and antipsychotic agents, although these drugs may worsen cognitive function and should be used cautiously.

On the theory that inflammation in the brain may contribute to neuronal damage in AD, trials are ongoing of nonsteroidal anti-inflammatory drugs such as rofecoxib (Vioxx) and naproxen (Aleve). Nutritional trials are underway with vitamin E, which may slow degeneration in AD by about 7 months, and ginkgo biloba, which may help treat AD symptoms.

Despite high hopes that estrogen therapy would reduce the risk of AD or even reverse symptoms in postmenopausal women, formal trials have been disappointing. One study showed that estrogen does not slow the progression of already diagnosed AD, and another trial of estrogen and progestin showed that women over age 65 had twice the rate of dementia, including AD, compared with the control group. Trials are also underway for substances used to reduce cardiovascular risk, including statin drugs, folic acid, B6 and B12 vitamins.

CenterWatch has identified a pipeline of 30 drugs in various stages of development for AD, many of which target neurotransmitter abnormalities.

Forest Laboratories has submitted a new drug application (NDA) for memantine, which attenuates disturbances in glutamatergic neurotransmission by modulating rapid, voltage-dependent interactions with N-methyl-D-aspartate (NMDA) receptors.

In Germany, memantine has been marketed for dementia syndrome for more than 10 years. Two European placebo-controlled studies in 418 patients suggested rapid, enduring improvement in the cognitive, psychological, social and motor impairments of dementia, which improved quality of life. Post-marketing surveillance of 531 German patients with advanced dementia revealed improvement in the overall clinical picture in 77% of patients receiving memantine and stabilization in 17%.

In a US study of 252 patients, 10 mg memantine twice daily for six months significantly improved cognition, activities of daily living, and overall clinical status while reducing demands on caregivers. Adverse events were comparable to those in the placebo group, but response rates were two to three times higher.

Aricept (donepezil hydrochloride, E2020), is already approved for mild to moderate AD and is now in phase III testing by Eisai for severe AD. In a placebo-controlled, randomized trial of 145 community-dwelling patients with severe AD not requiring total nursing care, those receiving 5-10 mg Aricept had statistically significant improvement or stabilization on a measure of global function and in activities of daily living, while placebo-treated patients had functional decline. Overall improvement in behavioral disturbances was also significantly greater than in the placebo group.

Completion rates for the study were 90% in the Aricept group and 86% in the placebo group. The most common reason for discontinuation was adverse events, which occurred in 7% of the Aricept group and in 5% of the placebo group. Common treatment-emergent adverse events, which were mostly mild or moderate, were hostility, headache, diarrhea, confusion, fecal incontinence, somnolence, vomiting, back pain, flatulence, rash, and urinary tract infection.

Another AChE inhibitor, in Phase III testing by Takeda Pharmaceuticals, is zanapezil (TAK-147). In animal models, TAK-147 ameliorates impairments of learning and memory without producing peripheral side effects, and it also activates the monoaminergic systems and energy metabolism. Because of its nerve growth factor (NGF)-like neurotrophic activity on central cholinergic neurons, it may prevent or slow disease progression as well as improving clinical symptoms via AChE inhibition.

Ganstigmine (CHF2819) is a novel AChE inhibitor derived from genserine, for which animal models suggest significant neuroprotection independent from its cholinergic activity. Chiesi Farmaceutici is currently in phase II testing of ganstigmine in once-daily dosing. In a randomized, double-blind, placebo-controlled trial in 29 patients with probable AD, this drug was well tolerated within a dosing range of 5 to 10 mg.

Phenserine, in phase IIb testing by Axonyx, is a highly selective, reversible AChE inhibitor. Preclinical data released in May suggests that phenserine also reduces production of amyloid precursor protein (APP), the precursor of the neurotoxic amyloid beta-peptide (A-beta). Because of this dual mechanism of action, phenserine has the potential to improve memory as well as to slow AD progression.

Another drug targeting A-beta production is a gamma-secretase inhibitor, in Phase II development by Bristol-Myers Squibb. This drug blocks the protease that cleaves APP to produce A-beta.

Telluride Pharmaceutical is in phase II/III development of Memex (nicotinamide adenine dinucleotide; NADH), which may stimulate cellular ATP production as well as endogenous L-dopa biosynthesis. In theory, helping AD patients regain their normal cellular energy production capacity may alleviate symptoms or even slow progression.

Based on a novel approach, the COGNIShunt System, in phase III testing by Eunoe, is a cerebrospinal fluid (CSF) shunt designed to increase CSF flow and clear neurotoxic cytokines and other neurotoxins that may contribute to AD progression. Phase I and II trials showed that the procedure and COGNIShunt System were safe and well tolerated in AD, without symptoms of overdrainage and with stabilization of mental function in shunted patients. CSF levels of potentially neurotoxic proteins associated with AD lesions, such as MAP-Tau and (beta)-Amyloid (1-42), decreased in shunted patients and remained low for twelve months.

Rather than targeting the cause of AD, Neurodex (AVP-923) decreases symptoms of pseudobulbar affect or emotional lability. This combination of dextromethorphan and an enzyme inhibitor that sustains elevated levels of dextromethorphan is in phase II/III testing by Avanir. Episodes of uncontrolled laughter or tearfulness unrelated to social context are not physically harmful, but they are distressing to both patients and their caregivers.

Although there is still no cure for AD, many drugs in the pipeline aim to improve memory loss or other symptoms through interventions in cholinergic or other neurotransmitter systems. Most promising in theory appear to be those agents with a dual cholinergic and neuroprotective effect, as these agents offer the potential to halt degeneration while improving cognitive function. Additional approaches target energy metabolism, inflammation, or A-beta. However, trials of vaccine directed against A-beta were halted due to adverse effects.