The precise chain of events leading to the characteristic pathology is not known, but it is likely to involve a cascade of events, including oxidative stress, excitotoxic damage, altered cell-cycle regulation, pathological inflammation, oxidative and excitotoxic damage, failure of trophic responses, demyelination, apoptosis, and the failure of neurotransmitter function, among others. In this context, it makes sense to consider the therapeutic potential of combining agents with different mechanisms of action in the hope that impinging on multiple aspects of the illness process may afford a greater benefit than that seen with a single agent.

What follows is a somewhat selective overview of the available clinical evidence as we see it. The reality is that relatively few studies combine what we now might consider to be the most promising strategies: most data come from earlier studies addressing putative neurotransmitter dysfunction. It is important to note that some studies were true ‘combination’ studies, in which multiple agents were co-administered simultaneously, and others were ‘add-on’ designs, in which case a second agent was administered some time after a prior therapy was initiated. This distinction is methodologically important.

Cholinergics
The earliest and most obvious efforts addressed what might happen if different cholinergic therapies were combined. There is compelling evidence for structural and functional cholinergic impairment in AD, and emerging evidence that cholinergic therapeutics might confer clinically discernible benefit.

Tacrine and Lecithin
What may have been the first combination study in AD addressed the effects of tetrahydroaminoacridine (THA) combined with lecithin.² Ten patients diagnosed with ‘primary progressive dementia’ were studied in four trials of random order: placebo, lecithin alone, THA alone, or a combination of lecithin and THA. Medications were administered in divided doses of THA 90mg and/or lecithin 180mg at three intervals over a 14-hour period. Cognitive testing was performed two hours after the final dose. Each of the four studies was separated by a minimum of 56 hours. While highly topical for its time, the study was essentially negative.

In a double-blind, cross-over study with two sequential randomized periods of treatment lasting for eight weeks each, Gauthier et al. evaluated the combination of the maximal tolerated dose of THA (up to 100mg/day) plus lecithin 4.7g/day in 52 AD patients.³ This study showed no clinical benefit to combination use of THA and lecithin as measured by global ratings, a functional scale, and a behavioral scale. A doubleblind cross-over study with four-month follow-up by Chatellier and Lacomblez randomized 67 AD patients to tacrine (dose ranging from 50 to 125mg/day) and tacrine (1,200mg/day) versus placebo.⁴ There was no significant improvement on the Mini Mental State Examination (MMSE) or the Stockton geriatric rating scale. A fourth, small, double-blind study in 10 patients showed no therapeutic effect. ⁵

Acetylcholinesterase Inhibitors and Acetyl-L-Carnitine
Acetyl-L-carnitine (ALC), an intracellular carrier of acetyl groups that are necessary for acetylcholine synthesis (which was thought to have the potential to enhance the effect of acetylcholinesterase inhibitors [AChEIs]), was tested in combination with an AChEI (either donepezil or rivastigmine).⁶ After a three-month period on an AChEI only, 38% of patients were classified as ‘responders’ and 48% as ‘non-responders’ as determined by changes in the MMSE and Alzheimer’s Disease Assessment Scale-Cognitive (ADAS-Cog). The 21 patients who were nonresponders entered a three-month open-label study of ALC 2g/day in addition to the AChEI. The proportion of responders increased from 38% after treatment with AChIE alone to 50% on combination therapy. This study reports a positive response rate after the addition of ALC, but further studies have not yet been performed.