Emerging Drug Therapies for Dementia

Emerging drug therapies for dementia are increasingly chosen to tackle molecular targets important in Alzheimer’s disease (AD) pathobiology. Amyloid oligomers, amyloid deposits, and neurofibrillary tangles (NFTs) are characteristic findings in AD. Hence, drugs that interfere with these proteinaceous aggregates are receiving the most attention: a) alpha, beta, and gamma secretase modulators, b) inhibitors of amyloid beta (Ab) aggregation, and c) anti-Ab immunologic strategies. Oxidative stress and inflammatory reactions appear part of a loop of neurotoxicity with the proteinacous aggregates. Antioxidants and anti-inflammatory compounds have thus received much attention. Finally, other compounds may work by a variety of other mechanisms.
Key words: Alzheimer’s disease, amyloid, secretase inhibitors, antioxidants, anti-inflammatory agents.

Introduction
Alzheimer’s disease (AD) is the most common cause of dementia in the older adult. Hence, it has received the greatest attention in drug development. Fortunately, some of the advances in AD therapy may translate into benefits for other dementias as well. Therapies for AD currently approved by the Food and Drug Administration in the United States are symptomatic--that is, they help allay some of the symptoms of AD such as memory loss, other cognitive and behavioural changes, and impairment in activities of daily living. They have not been shown to alter the course of the illness. Numerous compounds with potential disease modifying effects are being investigated. Many of these compounds interfere with disease pathogenesis or progression. Some may have a neuroprotective effect that may delay onset of symptoms.

Current studies involve extension of uses of currently approved compounds, natural compounds, compounds approved for other medical conditions that may produce a benefit in AD, and novel compounds (Figure 1). To best understand emerging therapies for AD, it is easiest to subdivide them according to principal presumed target in AD: 1) amyloid beta (Ab), 2) oxidative stress, 3) inflammation, and 4) other. Many have multiple modes of action.

Amyloid beta
Aberrant production and/or decreased clearance of Ab peptides and hyperphosphorylated tau aggregates are widely accepted as implicated in AD pathogenesis. The severity of dementia inversely correlates with measures of synaptic density. Soluble oligomers of Ab are the earliest effectors of synaptic compromise in Alzheimer’s disease.¹ There are three prominent amyloid-based therapeutic strategies: a) secretase modulation, b) inhibition of Ab aggregation, and c) immunization against Ab.

Secretase Modulation.
Three secretases (a, b, and g) are involved in the sequential proteolytic processing of the amyloid precursor protein (APP). Alpha-secretase processing of APP occurs C-terminally of Lys16 in the Ab sequence and thus precludes Ab peptide generation. Soluble, nontoxic APP fragments are formed instead. Cleavage of APP by b- followed by g-secretase results in toxic Ab40 and Ab42 fragments--the latter being more fibrillogenic and insoluble. Inhibition of the b- and g-secretase targets is believed to have therapeutic potential.

Beta-secretase
Beta-secretase (or BACE, beta-site cleaving enzyme) is an aspartyl protease. Absence in knock-out mice shows minimal adverse effects,² but the properties of the active site of this enzyme make it difficult to find small-molecule inhibitors that cross the blood-brain barrier and bind with high affinity. In silico candidates (created by computer modeling)