Preview won't save all my highlights and annotations

First log into a basic admin user account, Set up users, guests, and groups on Mac,  and see if the problem persists. This tells us if the problem is limited to your user account or is system wide.

If the problem doesn't exist in the other account go back to your user account and boot into Safe Mode according to Start up your Mac in safe mode - Apple Support and test to see if the problem persists. Reboot normally and test again.

NOTE: Safe Mode boot can take up to 10 minutes as it's doing the following; 

• Verifies your startup disk and attempts to repair directory issues, if needed

• Loads only required kernel extensions (prevents 3rd party kernel/extensions from loading)

• Prevents Startup Items and Login Items from opening automatically

• Disables user-installed fonts 

• Deletes font caches, kernel cache, and other system cache files

Download and run Etrecheck. Etrecheck is a diagnostic tool that was developed by one of the most respected users here in the ASC and recommended by Apple Support  to provide a snapshot of the system and help identify the more obvious culprits that can adversely affect a Mac's performance.

IMPORTANT:

Before running Etrecheck assign Full Disk Access to Etrecheck in the Etrecheck's Privacy preference pane so that it can get additional information from the Console and log files for the report:

Also click and read the About info to further permit full disk access.

Copy the report

and use the Additional Text button to include the report in your reply.

Then we can examine the report and see if we can determine what might be causing the problem.

All I can suggest now is to boot into the Recovery volume (boot with the Command + R keys held down) and reinstall the system. It doesn't wipe the drive, only reinstalls the system and the apps that come with it. However, it's always good practice to make sure you can a current and full backup before engaging any such operations.

Although late for the questionnaire try annotating a PDF and then do a Print to PDF. See if that will keep the annotations.

I am using Big Sur 11.3.1 and have no issues with annotations (that includes highlights too) with remaining in the PDF when it is reopened. Nothing is lost. Preview autosaves changes to the current PDF as they are made — unless the PDF has change restrictions on it which would require a Save as operation to another PDF document, or the PDF resides on an unsupported filesystem where annotations cannot be saved in the PDF via autosave. My PDFs all reside on my Mac.

I don't see any of the usual suspects but did not a couple of concerns:

Adobe Flash Player installed - Adobe Flash Player is installed on this computer. This is a security risk and no longer supported.

There are no websites that are still using Flash. Adobe killed it at the end off last year. You should completely uninstall it and its preference pane.

You're using BitTorrent. It's also a security risk as many sites that use it for downloading have included malware/adware in the installer. I would not download any app with it but instead go to the developer's site and download from there.

A PDF with 40 questions, all night answering them inside Preview, highlighting them, lots of annotations... And suddenly more than half gone!

This is unacceptable!

Right now my hair is falling.