travel between Italian lake district and Germany

Looks like a combo of train, bus, and flight thru Bergamo might serve you best if you choose Varenna.

What I like to do when considering transport between places I am not very familiar with is look at www.rome2rio.com. While I would not book thru that site, it is helpful in looking at possibilities. For example I played around with Varenna-Esino (the name of the station) and Nuremberg. You could also look at Lake Maggiore or Lake Garda as options. Play around with it a little.

I would go to Varenna and then take the train northbto Tirano on the Swiss border. Take a Swiss train over the very scenic Bernina Pass to Pontresina or a nearby village for overnight. Then continue on to Austria. I can look up the exact route for you, or you can find it yourself on bahn.de.

Put in Pontresina as your starting point and Nuremberg for the end.

OK! I looked it up. It is a long journey, 8-9 hours, with lots of changes, most of them involving a bus leg.

The one I would choose actually starts in Samedan, one village past Pontresina. We spent two nights there in a very nice little place with a great breakfast. Basically they have four rooms above a wonderful bakery..

https://www.laagers.ch

From Samedan, the all-train journey goes through Austria, with 5 changes on the way, travel time under 8 hours.. Depart Samedan at 10:16 am and change at hour, Sargans, Feldkirch, Linda, and Augsburg. These are all small stations with easy changes. And there are pleasant villages along the way for an overnight if you want to break up the journey.

The train ride over the Bernina Pass is stunning on a nice day. There are a few panorama trains (Bernina Express), but hourly service with regular trains. The continuation to Chur, also part of the Bernina Express, is on the Albula line is also very special, with loops and spiral tunnels down to Chur, passing over the famous Landwasser Viaduct, featured on a thousand Swiss travel posters. The Bernina Express (and Glacier Express, also on the Albula line) have mandatory seat reservation fees, but regular trains operate the route on an hourly basis with no extra expense.
https://en.wikipedia.org/wiki/Landwasser_Viaduct

Thank you very much to all who have replied to my request for help! A few more questions:

After arriving in Milan by plane, we plan to go to Varenna on the same day.
From Varenna (where we will stay 2 nights) on Lake Como, what is the best means of transportation to Tirano? Should we try to connect with the BE bus in Sorico? Or can we get a train to Tirano? Is it reasonable to travel from Varenna to Pontresina or Samdedan in one day?
We will take the Bernina Express train from Tirano. From Pontresina or Samedan (haven't decided which we will stop for a night or two), should we go all the way to Chur and then to Austria to Nuremberg or should we skip the leg to Chur and head directly north into Austria-Germany?
If we go to Chur, should we plan for an overnight in Chur before heading to Nuremberg (I think that leg from Chur takes about 6 hours) for our river cruise.
We are in our early 70s and I would like a leisurely pace! This may be our last trip to Europe. We have done solo trips like this one -- the last one was to central Switzerland two years ago. This one seems more complicated.

From Varenna (where we will stay 2 nights) on Lake Como, what is the best means of transportation to Tirano? Should we try to connect with the BE bus in Sorico? Or can we get a train to Tirano?

If you took the train from Milano Centrale to Varenna (after changing from the Malpensa Express) it would be the same train station in the same direction you were traveling on arrival all the way to the end of the line. Between the TreNord station you arrive at in Tirano and the Bernina line station is just a few dozen yards.

Is it reasonable to travel from Varenna to Pontresina or Samedan in one day?

I would, happily. I'd gone all the way to Chur and return (only to Tirano, not the little bit more to Varenna at that time, and made stops along the way, but I don't take the fancy trains, just the normal hourly ones). Just one "d" in Samedan, btw.

To see the schedule and prices, go to www.trenitalia.com. Start at Malpensa Aeroporto, to Varenna-Esino, then to Tirano.

For Swiss trains, www.sbb.ch/en.

Varenna to Samedan is easy in a day, a journey of 3.5 to 4.5 hours, depending on the connections. We did it in the opposite direction on our way to Venice a few years ago.

If you look at the schedules, you will see some connections with a bus leg. Stick with the trains to be sure you go over the Bernina Pass.

Looking at a day in late October, I see an 8:24 am departure from Varenna, with a change at Tirano to the named Bernina Express train (reservations mandatory). It goes to St. Moritz and you change there for the short ride (a few minutes) to Samedan.

An hour later, at 9:24 a train departs Varenna for Tirano, connecting there to a regional train over the Bernina Pass. This one has a change in Pontresina to reach Samedan.

You could also stay in either St. Moritz or Pontresina, but we found the hotel in Samedan was much less expensive, and convenient to the train.

When you look at the schedules, make sure you use Varenna-Esino for the station. And it is best to buy your tickets for the Varenna to Tirano leg online in advance, as the Varenna station has neither a ticket machine nor an agent. You can get a ticket from the travel agent around the corner, but we found it much simpler to buy it on Trenitalia in advance.

Thanks to everyone for the wonderful suggestions! We may go from Pontresina to Innsbruck to Nuremberg to break up the trip. We have always traveled by train 2nd class but since we are getting older, may buy the Eurail Pass for 3 countries this time. Any thoughts on this?

Not a fan of Eurail passes. The train from Milan to Tirano, stopping at Varenna Esino is a Regionale with only 2nd class seats. Milan to Varenna is 6.70 EUR fixed price, and Varenna to Tirano is 7.30 EUR. The pass is not valid on the train from Malpensa airport to Milan. So adding Italy to the pass would be a complete waste.

$830 for a 3-country 1st class 5-day twin pass for $830 USD for Switzerland, Austria, Germany seems like a lot of money. 5-day is the minimum number of days for a 3-country select pass.

The USD equivalent for the 3 trips you describe, Tirano to Pontresina, to Innsbruck, to Nuremberg is $738 for 1st class walk up tickets. If you can lock your self in on the last two legs by buying advance nonrefundable tickets, you would save about $200.