Alzheimer's disease is one of the most prolific and costliest afflictions in the U.S. According to the Alzheimer's Association, more than 5 million Americans alone suffer from the ailment, which is expected to cost the U.S. more than $1 trillion by 2050. Despite the size of the problem, top drugmakers have struggled to develop treatments for Alzheimer's as of late.

Big Pharma's Eli Lilly raised eyebrows across the health care sector last year when it cut its development of phase 2 BACE inhibitor LY2886721. Swiss rival Roche also cut developmental of a similar drug, BACE inhibitor RG7129, which was in early-stage trials, and many more Alzheimer's disease therapies have been cut during clinical development over the past decade and a half.

That's not stopping Merck (NYSE:MRK) and AstraZeneca (NASDAQ:AZN), however, as these two leading big pharma giants are making headway on Alzheimer's treatments via mid- to late-stage studies. But can these two companies succeed where so many others have failed in what could be a huge market for investors?

Merck and AstraZeneca battle against history
Merck has taken center stage in the race to develop the promising BACE inhibitors, a type of drug that combats one of Alzheimer's top causes by blocking a certain enzyme that contributes to generating a specific kind of brain plaque-causing protein. Merck got the jump on its competition last December, when it announced it would proceed with a pair of phase 3 trials for its Alzheimer's-fighting candidate MK-8931.

Considering the trouble Alzheimer's drug research has had in the past, it's wise for investors to keep watch with a cautious eye. However, should Merck beat the odds, this drug could be among the company's biggest pipeline successes. Analysts have pegged MK-8931 as a potential $5 billion-a-year drug if it can hurdle years of Alzheimer's failures across the industry. That's a critically needed piece of potential for Merck's R&D department, which has been hampered by criticism over spending and a lack of successful discoveries in the recent past.

But Merck now has company in its late-stage push. Late last week, AstraZeneca announced alongside its earnings report that it will launch its own BACE inhibitor, AZD3293, into combined phase 2/3 trials of its own. Data will be a long time off -- Merck is ahead of AstraZeneca so far, and AstraZeneca doesn't expect data until 2017 at the earliest -- but for AstraZeneca, the possibility of hitting on blockbuster potential is too good to pass up. Analysts project that AZD3293, if successful, could reach or exceed $1 billion in annual sales.

It's one glimmer of hope in what has been a disappointing run for AstraZeneca so far. The firm's full-year revenue in 2013 fell 6% at a constant currency, and the company said that it expects 2014 sales to fall by single-digit percentages as well. Even by 2017, AstraZeneca only expects revenue roughly in line with 2013's figures. That makes projects such as AZD3293 all the more critical to overcome the likes of the patent cliff's challenges, even with the high failure rate of Alzheimer's candidates lately.

Merck's MK-8931 has claimed leadership in the race so far by overcoming the safety fears that downed Eli Lilly's BACE inhibitor last summer. Lilly's drug failed over fears of liver toxicity, and while the company noted that the class of drugs wasn't to blame for the failure, all eyes will be fixed on safety data from Merck and AstraZeneca's trials down the road, despite their early successes.

Setting sights on the long term
There's still a long way to go before MK-8931 or AZD3293 will see the light of day from regulators, but long-term investors in both Merck and AstraZeneca need to keep a close eye on the progress of these high-potential drugs. Both firms have borne R&D failures and costly patent losses as of late, and the promise of billions of dollars of sales a year from fighting Alzheimer's is too important to ignore -- even if recent history has resulted in disappointment after disappointment from some of Big Pharma's biggest names. If Merck or AstraZeneca come through in the battle against Alzheimer's, patient investors today will be poised to win big down the road.

This article represents the opinion of the writer, who may disagree with the “official” recommendation position of a Motley Fool premium advisory service. We’re motley! Questioning an investing thesis -- even one of our own -- helps us all think critically about investing and make decisions that help us become smarter, happier, and richer.