How would you manage cognitive changes in a patient with memory impairment and significant brain atrophy with no diagnostic testing consistent with Alzheimer's disease?

It would depend on the clinical history, pattern of atrophy, and diagnostic biomarkers. If I had a patient with a typical clinical history of AD with progressive episodic memory loss substantiated by neuropsychological testing, IADL impairment, and hippocampal atrophy on imaging, I probably would not be pursuing additional biomarker testing. An exception would be if the patient was being evaluated for anti-amyloid therapy. If I had a less clear-cut cause, I would usually obtain an FDG-PET scan. If things are still murky at that point, I would obtain CSF and send for AD biomarkers (abeta1-42, p-tau).

If I take from your question that there is a patient with a clinical history and atrophy pattern suggestive of AD and with negative PET and CSF biomarkers, I would very much reconsider the diagnosis of AD. A clinically similar entity is limbic predominant age-related TDP-42 encephalopathy (LATE) which may manifest with hippocampal atrophy and episodic memory loss but with negative biomarkers. As far as I am aware, there is no in-life way to confirm this diagnosis. I would favor managing them the same way we provide symptomatic therapy for AD; cholinesterase inhibitors and memantine. These drugs were approved to treat a population of clinical AD patients without biomarker assessments, which makes it reasonable to use these drugs in this biomarker-negative population. Of course, they would not be eligible for anti-amyloid therapy without an established diagnosis of brain amyloidosis.