Alexander, who recently took time off from his job with the League Two side due to illness, was in charge for the defeat against Notts County on Tuesday night.
A statement on the club's official website read: "It is our sad duty to report that Keith Alexander passed away today after arriving home from Macclesfield Town's game at Notts County last night.
"Keith was a splendid man. He will be sorely missed at the Moss Rose and by everyone involved in football. Our thoughts and sympathies are with his family at this very difficult time."
Alexander had a brain scan last year having suffered cerebral aneurysms in 2003.
Last year, he told the Daily Mirror: "I'm lucky to be here. Cerebral aneurysms are burst blood vessels in the head and, when doctors went through the back of my skull to operate on me, they found two.
"Everything was fine, except I didn't return from hospital until 5pm and we had lost 2-0. But to put it in perspective, only today I received a letter from a woman whose sister is very poorly after a similar aneurysm illness, and she didn't think the outlook was good.
"I rang her up and told her I felt like that for a couple of months afterwards, but I'm still here, out and about.
"People know I came through it and, if I can help others to do the same, that is the least I can do.
"There is no evidence that, in my case, it was brought on by the stress of being a manager in the lower divisions, which is just as well. I reckon the pressure at this end of the spectrum must be greater than the top end."
Alexander was given a clean bill of health after the scans last year and suggested the scare had been down to a virus at the club.
"Perhaps I shouldn't have come into work that day, but my generation just goes to work, no matter what," he told the Macclesfield Express. "You get on with it and don't make excuses.
"My wife wasn't very happy with me but the good news is that I am perfectly well, really perfectly well and have been given a complete all-clear."
Alexander played as a striker for clubs including Grimsby and Lincoln and made three international appearances for St Lucia. He entered management in 1993 with Lincoln and went on to manage Ilkeston Town, Northwich Victoria and Peterborough before becoming Macclesfield boss in 2008.
Peterborough director of sport Barry Fry, who worked with Alexander as a player at Barnet and again at London Road when he was manager, revealed he had been concerned recently about his friend's health.
"I really can`t believe it," he said. "I'd been worried lately about his health but he assured me he was fine. He recently had a bout of hiccups that he couldn't get rid of and he went into hospital for that, but he wasn't feeling ill when I spoke to him last. He was bubbly.
"He'd had a few days off but he couldn`t wait to get back on the training pitch. You won`t find a more dedicated man at any club, he always gave 150%. I feel so sad for his family."
Macclesfield chairman Mike Rance said: "He was a splendid man, a real gentleman and an absolute privilege to work with. He was strong, sensible, commanded respect throughout the game and was unique in many ways."
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