You need to go through a TCP handshake for every connection you open. You can reuse the connection but that means queuing requests and hitting the latency as a multiplier. Browsers also have a cap on parallel connections so when you get enough requests it queues either way. HTTP/2 reduces the problem with multiplexing but it still doesn't go away.
If your app has to make 40 requests pulling in js files, CSS files fonts, API calls etc. to show something useful that will be visibly slow the moment a user is out of region. If it's a single server rendered piece of html it's a single request.
Then for real fun be in an enterprise environment with Kerberos Auth adding a load more round trips to the server. For even more fun add in a mobile browsing solution that only has ingress in a far region when the site is hosted locally!