One thing that occurred to me as I was reading this was "Exactly how much of this story is true?" Others were: Was the information about Poe in this book historical, or was it fiction? Did people really live like this?
The mysterious man, Auguste Dupin, provides a lot of material for questions. Why did he help Edmund, when he appears so delusional and disoriented? Is he kind and sympathetic, or does he have a different motive? Who is Auguste Dupin, and why doesn't he use his own name?
This books shows the darker side of human nature in some of its most confounding, frustrating, and difficult-to-understand lights. Mr. Arnold, Edmund and Sis's stepfather (who they knew under the name Ratchett) is an example of the kind of person whose cruelty seems to know no bounds and have no reason behind it. Arnold would marry a woman only for her money, abandon her children to die of starvation, and murder to cover up his misdeeds. This kind of conscienceless evil is exceedingly difficult to understand, and raises many questions about whether or not humanity can be essentially good if such people exist.
Poe's shadowy character, which may or may not reflect the reality of his life (see the link below) also makes one wonder about the motives of human beings. Edmund is simple to understand -- he wants his family back, and he wants to survive. But Poe (Dupin) has no such clear motives. Does he want to be a good person? Does he live only for his drugs and alcohol? Could such a man be really devoted to Mrs. Whitman, as he claims to be? Is such a character necessary to create the kind of dark poetry and literature Poe produced?
Finally, ask yourself if this is a believable story -- either as history (that this sort of world existed once, with these sorts of people in it), or as emotionally true. Do the characters do what you expect them to do? When they surprise you, does their uncharacteristic action make sense to you later as you read on in the book? Have you ever known people to be like these characters, and, if not, why? All of these can help you understand the book better, and help you make sense of some of the tragedy and cruelty in this novel.