The Second Question in Dementia Diagnosis

I've been thinking a lot about an article I wrote last week. It was titled The Alzheimer's Blood Test Was Negative. Now What? I wrote it to explain what further diagnostic testing looks like when someone is experiencing cognitive decline, but their Alzheimer's testing comes back negative.

And I still stand behind that answer. We go back to the clinical picture. We look again at medications, sleep, mood, and other medical conditions that could be contributing. We evaluate the brain MRI. Depending on the symptoms, we might consider specialized testing for Lewy body disease, frontotemporal degeneration, vascular cognitive impairment, or another neurological condition.

That is where we are in clinical practice today. But after I finished writing that piece, something about it kept pulling at me.

Look at how precisely we can answer the Alzheimer's question today. We can measure biomarkers in blood, use PET imaging to look for amyloid in the brain, or analyze Alzheimer's-associated proteins in cerebrospinal fluid (CSF).¹ And then look at what happens when those tests are negative. The pathway suddenly becomes much less clear.

That doesn't mean the evaluation I outlined last week is wrong. It is the appropriate next step with the tools we currently have. But it made me realize just how far behind we still are in our ability to give that same biological clarity to patients whose cognitive decline isn't caused by Alzheimer's disease. And my heart aches for the people who fall into that gap.

After months or years of knowing something isn't right, sitting in waiting rooms, going through testing, and holding their breath for an answer, they end up with a strange kind of certainty: We know what you don't have. But we still don't know what you do. And what a terrible place that must be to stand.

Knowing Matters, Even When We Can't Fix It

In medicine, we tend to view diagnosis through the lens of action. We identify the disease so we can choose the treatment. But that is not the only reason a diagnosis matters.

I've joked before that when I get to heaven and someone offers to answer all my questions, I want a complete explanation of this body. I want to know every strange glitch that happened, what caused it, what I did to it, what I didn't do to it, and what was simply built differently from the start.

None of those answers would change anything. I certainly wouldn't be able to fix them. I'd still want to know. There is something deeply human about that desire for an answer.

When your memory starts slipping, or your personality feels altered, or you can't get the words out, knowing why matters enormously. A diagnosis may not come with a cure. But it can give someone an explanation.

• That's why I can't find the words.
• That's why Dad has started seeing things that aren't there.
• That's why Mom doesn't seem like herself anymore.

It gives families something to research, learn about, and plan around. It helps them prepare for what lies ahead. It aids in navigating choices about work, driving, finances, and caregiving. And sometimes, there is immense value simply in being able to say: This is what is happening to me.

An Uneven Landscape

This is where dementia diagnosis has become strangely uneven. For Alzheimer's disease, we are increasingly able to pinpoint the underlying pathology itself.² Newer blood biomarkers are now bringing that biological information into clinical diagnostic pathways, particularly in specialized care.³

But if Alzheimer's testing is negative, there isn't another routine blood panel we can order that neatly sorts a patient into Lewy body disease, frontotemporal degeneration, or vascular cognitive impairment. At least, not yet.

We have tools, of course. Brain MRIs can identify vascular changes or patterns of atrophy. FDG-PET can provide additional clues when the clinical picture suggests conditions such as frontotemporal degeneration or primary progressive aphasia, while DaTscans can support a suspected diagnosis of dementia with Lewy bodies.^4,5 We are also seeing real progress in detecting alpha-synuclein pathology: seed amplification assays (SAA) can identify misfolded alpha-synuclein in CSF, while skin biopsies can detect phosphorylated α-synuclein in cutaneous nerve fibers via immunofluorescence microscopy.^6,7 Genetic testing can also offer critical answers in select cases, particularly with suspected frontotemporal degeneration.⁸

Yet much of the diagnosis still depends on the story the symptoms tell. What changed first? Is someone primarily struggling with memory, or are the earliest changes showing up in language, behavior, judgment, movement, or even sleep? Those details, combined with the neurological exam and imaging, can help point us toward what may be causing the changes.

That isn't bad medicine. It is expert clinical care with the tools available to us. But the contrast is stark when compared to how rapidly Alzheimer's diagnosis is becoming biomarker-driven.

Living in the Unknown

Alzheimer's disease accounts for the majority of dementia cases, so focusing significant research and resources on Alzheimer's makes sense. But most isn't everyone. There remains a substantial group of people experiencing progressive cognitive decline who will have negative Alzheimer's biomarker testing. For them, the diagnostic journey becomes a longer, more uncertain path.

They may eventually receive a diagnosis of Lewy body dementia or frontotemporal dementia. Imaging may reveal vascular changes that explain the picture. A newer biomarker may offer a key piece of evidence. Or the answer may remain “probable” or “possible” for a very long time.

Diagnostic uncertainty isn't just a clinical puzzle. Someone has to live inside it. And in neurodegenerative disease, time matters. The person waiting for an answer is living with a condition that may gradually take away their ability to process the very explanation they were seeking.

Answering the Second Question

The advances in Alzheimer's biomarkers deserve to be celebrated. They are transforming the field. But our success in answering “Is this Alzheimer's?” makes the follow-up question impossible to ignore: “If it isn't, what is happening to me?”

We need better biomarkers for Lewy body disease. Better ways to untangle the pathologies behind frontotemporal degeneration. Better tools for identifying mixed pathologies. We need a diagnostic landscape where obtaining biological clarity isn't significantly easier for one disease than it is for the rest. Until our technology catches up, a negative Alzheimer's test cannot be where the conversation stops.

Sometimes medicine can tell someone exactly what is happening and offer a treatment. Sometimes we can name what is happening even though we cannot stop it. And sometimes, all we can honestly say is that we know something is wrong, we know some of the things it isn't, and we are going to keep looking alongside you. That last answer may be the best our science can currently offer. But we should never forget how hard it is to be the person receiving it.

References

1. Jack CR Jr, Andrews JS, Beach TG, et al. Revised criteria for diagnosis and staging of Alzheimer's disease: Alzheimer's Association Workgroup. Alzheimers Dement. 2024;20(8):5143-5169. doi:10.1002/alz.13859
2. Hansson O, Blennow K, Zetterberg H, Dage J. Blood biomarkers for Alzheimer's disease in clinical practice and trials. Nat Aging. 2023;3(5):506-519. doi:10.1038/s43587-023-00403-3
3. Palmqvist S, Whitson HE, Allen LA, et al. Alzheimer's Association clinical practice guideline on the use of blood-based biomarkers in the diagnostic workup of suspected Alzheimer's disease within specialized care settings. Alzheimers Dement. 2025;21(7):e70535. doi:10.1002/alz.70535
4. McKeith IG, Boeve BF, Dickson DW, et al. Diagnosis and management of dementia with Lewy bodies: Fourth consensus report of the DLB Consortium. Neurology. 2017;89(1):88-100. doi:10.1212/WNL.0000000000004058
5. Gorno-Tempini ML, Hillis AE, Weintraub S, et al. Classification of primary progressive aphasia and its variants. Neurology. 2011;76(11):1006-1014. doi:10.1212/WNL.0b013e31821103e6
6. Siderowf A, Concha-Marambio L, Lafontant DE, et al. Assessment of heterogeneity among participants in the Parkinson's Progression Markers Initiative cohort using α-synuclein seed amplification: a cross-sectional study. Lancet Neurol. 2023;22(5):407-417. doi:10.1016/S1474-4422(23)00109-6
7. Gibbons CH, Levine T, Adler C, et al. Skin biopsy detection of phosphorylated α-synuclein in patients with synucleinopathies. JAMA. 2024;331(15):1298-1306. doi:10.1001/jama.2024.0792
8. Moore KM, Nicholas J, Grossman M, et al. Age at symptom onset and death and disease duration in genetic frontotemporal dementia: an international retrospective cohort study. Lancet Neurol. 2020;19(2):145-156. doi:10.1016/S1474-4422(19)30394-1