19 Jul 1998

This roundtable session, supported by a grant from SmithKline Beecham and cochaired by G. Wilcock (Bristol, UK) and R. Kumar (Essex, UK), sought to provide a glimpse of future directions for the development of new therapeutic agents for AD. The speakers provided a rather broad range of perspectives on this topic. The first two presentations, by Grundman (Abstract 312) and H. Feldman (Abstract 313) dealt primarily with the design of clinical trials. Grundman reviewed the theoretical basis for different study designs, emphasizing the need to use designs that will reveal differences between agents that only treat symptoms (as is thought to be the case with existing cholinesterase inhibitors) as opposed to modifying the course of the disease (the ideal goal for new therapeutics). Candidates in the latter category are likely to include anti-inflammatory drugs, estrogen, neurotrophic agents and inhibitors of amyloid deposition or tangle formation (yet to be developed). Grundman reviewed two types of designs: randomized withdrawal and randomized start. Each model has its own advantages and disadvantages, depending on the extent to which the drug affects symptoms versus modifying progression. Results may be especially difficult to interpret if a drug has both types of effects. It is also possible that rates of progression may vary depending on the stage of disease. He also emphasized the ability to reduce the required sample size by extending the duration of a trial.

These theoretical issues were given practical consideration by Feldman, who provided examples of actual clinical trial data. The results of a clinical study with donepezil (Aricept), for example, showed clear alleviation of symptom progression but a subsequent regression to the status of patients receiving placebo following drug withdrawal (Rogers et al., 1998). A study of Exelon effectiveness (Rogers & Friedhoff, 1998), however, did not show a similar "catch-up" following drug withdrawal, suggesting that the underlying disease course might have been slowed. But Feldman cautioned that this interpretation assumes a linear rate of clinical progression. Evidence for an effect on disease progression has been obtained with studies of propentofylline, which exhibited effectiveness beyond the treatment period. Similar effects were not found with a delayed start trial, probably, Feldman suggested, due to limited sample size. Trials with deprenyl and vitamin E showed positive effects on some measures but not others. Feldman urged caution when relying on outcome measures that are not directly anchored to the disease process.

The session became even more focused on specific approaches to developing new treatments for AD beyond inhibiting cholinesterase activity. Kumar (Abstract 314) reviewed the rationale for developing drugs that would effectively replace lost cholinergic function without relying on residual cholinergic neurons (as is the case with AChE inhibitors). A variety of muscarinic agents have been examined. Compounds that show little discrimination between different muscarinic receptor subtypes (e.g., arecoline, bethanecol, oxotremorine) show some beneficial effects on cognitive measures but also give rise to undesired effects such as sweating and nausea. More selective compounds, partial muscarinic agonists such as Memric, have been developed that show fewer side effects. Unfortunately, they also show limited, nonsignificant, benefit on cognitive measures. Xanomeline, on the other hand, appears to be effective on cognitive measures but is poorly tolerated. Some of these agents also show effectiveness on behavioral measures other than cognitive performance. Kumar suggested that there may yet be hope for agents of this type to treat other symptoms of AD.

J. Ghiso (Abstract 315) brought amyloid to center stage with a discussion of proteins that are likely to be "molecular chaperones" of the Aβ peptide. The best candidates for chaperones in serum are apolipoproteins such as ApoJ (also known as clusterin), which shows high affinity binding to the Aβ peptide. The ApoJ/Aβ complex is quite stable and ApoJ prevents aggregation of the peptide as well as amyloid fibril formation. Prior interaction with ApoJ does not appear to modify the peptide, however, since it is still capable of aggregating after being isolated from the ApoJ/Aβ complex. This interaction also has functional consequences in that ApoJ protects cultured rat hippocampal neurons from Aβ toxicity. Since ApoE shows a relatively high affinity for aggregated Aβ, Ghiso suggested that ApoE and ApoJ may serve antagonistic functions as amyloid chaperones, the former promoting amyloid deposition and the latter preventing it. He noted that agents that promote ApoJ/Aβ complex formation or stability would potentially be useful in preventing amyloid deposition.

K. Iqbal (Abstract 316), tauist defender, reviewed evidence for the primacy of neurofibrillary degeneration in AD. The most likely mechanism leading to tangle formation involves hyperphosphorylated tau (p-tau), which is much more abundant (approximately 25-fold) in AD brain tissue than in control brain tissue. Iqbal believes that p-tau plays a pivotal role in destabilizing microtubules (which then leads to neuronal degeneration) and in forming tangles (not a cause of neuronal death itself). This hypothesis is supported by biochemical studies in which p-tau from AD brain was found to inhibit microtubule formation, an effect that could be reversed by dephosphorylation of tau. P-tau does not form paired helicial filaments, which is thought to be due to interactions between p-tau and normal tau. A role for tau is supported by the fact that tau is elevated in AD CSF and by recent studies demonstrating that mutations in the tau gene give rise to some forms of neurodegeneration. Iqbal proposes that AD drugs could be developed that would prevent hyperphosphorylation of tau.

The final speaker, D. Price (Abstract 317), provided an overview of the use of transgenic mouse lines as models of AD pathology. He noted that a recent panel had recommended the use of C57BL/6J mice as founders due to their good performance on a variety of behavioral tasks and that other strains are less optimal in this regard. Transgenic APPswe mice show Aβ deposits, an increased ratio of Aβ42/Aβ40, dystrophic neurites, gliosis and behavioral deficits. By 12 months, these animals show impaired performance on the water maze and the eight-arm radial arm maze. They also show extensive Aβ deposition in the outer portion of the dentate molecular layer and, at 26 months of age, numerous plaques in the cortex. Crossing this line with mutant presenilin transgenic mice gives animals that show accelerated plaque development, suggesting that PS1 mutations may enhance Aβ deposition. Price suggested that putting mutant tau into this mix may well provide the key to the ultimate AD mouse line.

The session concluded with several questions from the audience. Perhaps the most interesting question was put as a general one to all speakers asking for their opinion on what the future holds for new drugs. The answers were interesting, if not surprising, in light of the presentations. Ghiso-inhibitors of amyloid deposition; Price - inhibitors of the c-secretase that cleaves APP; Iqbal-agents that inhibit degeneration or promote microtubule stability; Grundman-cocktail approach; Feldman-ditto; Kumar-ditto. Taken as a whole, one might conclude that none of the current alternatives to AChE inhibitors for treating AD should be abandoned yet.—Keith A. Crutcher

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