The Alzheimer's Blood Test Was Negative. Now What?

There has been a lot of excitement around blood tests for Alzheimer's disease—and rightfully so.

Alzheimer's disease is thought to contribute to 60–70% of dementia cases, and some of the newer blood biomarkers are now accurate enough to identify Alzheimer's pathology without immediately turning to a PET scan or lumbar puncture.^1,2

But that leaves a major question that patients and families are starting to ask in clinic:

What about everyone else?

What happens when Alzheimer's testing is negative, but the cognitive changes are very real?

Not Every Dementia Has an Alzheimer's-Style Blood Test

Biomarker technology for Alzheimer's disease has moved extraordinarily quickly over the past few years. The same isn't yet true for every disease that causes cognitive decline.

Lewy body disease, frontotemporal degeneration (FTD), vascular cognitive impairment, and other neurological conditions each have different diagnostic pathways. Some now have promising—and in certain cases commercially available—biomarker tests. Others still rely heavily on the pattern of symptoms, physical examination, neuropsychological testing, MRI scans, and ruling out reversible causes.

When Alzheimer's testing comes back negative, the next step isn't simply ordering “the blood test for the other dementias.”

That test doesn't exist. At least not yet.

If Lewy Body Disease Is Suspected

When clinicians suspect Lewy body disease—whether Dementia with Lewy Bodies (DLB) or Parkinson's disease dementia—we look for a specific constellation of clinical clues. These can include visual hallucinations, fluctuations in attention or alertness, REM sleep behavior disorder (acting out dreams), parkinsonism (tremors, stiffness, slowness), and autonomic symptoms like sudden drops in blood pressure.

Lewy body disease is characterized by the abnormal accumulation of a protein called alpha-synuclein in the brain. That gives us something specific to look for when testing is needed.^3,4

This is also where non-Alzheimer's biomarker testing gets most interesting:

• CSF Alpha-Synuclein Testing: A type of test called a seed amplification assay (SAA) is designed to detect very small amounts of abnormal alpha-synuclein in spinal fluid. The test essentially amplifies the signal, making these tiny amounts easier to detect, and has shown strong diagnostic performance in research studies.³
• Skin Biopsy: Abnormal phosphorylated alpha-synuclein can also be identified through small skin biopsies taken in an outpatient clinic. I have done this testing myself as part of clinical research trial procedures, and it is easy, quick, and relatively painless.⁴

Can you ask for these tests today? In some cases, yes. Skin biopsy testing for phosphorylated alpha-synuclein and CSF SAA testing are now commercially available.⁵ However, their use in routine clinical care is still evolving, and formal guidelines for exactly how these tests should be used have not yet been established.⁵

If Frontotemporal Degeneration (FTD) Is Suspected

Frontotemporal degeneration (FTD) can look very different from Alzheimer's disease. Instead of memory being the obvious first problem, early changes may show up in personality, behavior, judgment, or language. FTD also tends to affect people at a younger age than Alzheimer's.

FTD is a little more complicated biologically than Lewy body disease. Different forms of FTD can be associated with the abnormal accumulation of different proteins, most commonly tau or TDP-43.⁶ That makes developing one biomarker that identifies FTD much more challenging.

There isn't currently a routine blood test that can tell us someone has FTD. Diagnosis depends heavily on the pattern of symptoms, along with brain imaging such as MRI and, in some cases, FDG-PET.^6,7

• Neurofilament Light Chain (NfL): Blood levels of NfL rise when nerve cells are damaged. Elevated NfL can support evidence of active neurodegeneration and help distinguish an FTD presentation from a primary psychiatric condition, but it is not specific to FTD.⁶ It tells us neurons are under stress, not why.
• Genetic Testing: Genetics play a much larger role in FTD than in typical late-onset Alzheimer's disease. Several genes are associated with inherited forms of FTD, including GRN, MAPT, and C9orf72, so genetic counseling and testing may be an important part of the evaluation.⁶

That's an important distinction: a test can show us evidence of neurodegeneration without telling us exactly what disease is behind it.

If Vascular Cognitive Impairment Is Suspected

For vascular cognitive impairment, brain imaging plays a particularly important role.⁸

An MRI allows us to look for evidence of vascular injury in the brain. Clinicians look for prior strokes, extensive white matter changes (subcortical ischemic vascular disease), microbleeds, or strategic infarcts in areas critical for memory and executive function.⁸

The question isn't just whether vascular disease exists on the scan—many older adults have some degree of white matter change—but whether the location and severity of that vascular injury reasonably explain the person's specific cognitive pattern.⁸

And Sometimes, the Answer Is Mixed

Human brains don't always respect our neat diagnostic categories.

Someone can have Alzheimer's pathology alongside Lewy body pathology, or Alzheimer's disease with significant vascular disease. In older adults, mixed pathology is extremely common.⁹

This is why a positive Alzheimer's test doesn't automatically mean Alzheimer's explains 100% of the clinical picture—and why a negative test simply opens the door to evaluating the other candidates.

So What Actually Happens After a Negative Alzheimer's Test?

If an Alzheimer's biomarker test comes back negative, the answer isn't a shotgun panel of every biomarker available.

The test should follow the clinical question—not the other way around.

A thorough next step looks like this:

1. Go back to the bigger picture. A negative Alzheimer's test is a reason to look again at everything that might be contributing to the cognitive changes. Medications, sleep problems, depression or anxiety, vitamin deficiencies, thyroid problems, and other medical conditions can all affect how someone is thinking and functioning.
2. Take another look at the MRI. Brain imaging can provide important clues about what might be going on, including patterns of brain volume loss, vascular changes, previous strokes, or other structural problems.
3. Consider seeing a specialist. If the cause still isn't clear—or the symptoms don't look typical for Alzheimer's—a memory specialist or behavioral neurologist may be able to narrow down the possibilities.
4. Choose additional testing based on what you're looking for. That might include an FDG-PET scan, DaTscan, spinal fluid testing, a skin biopsy for alpha-synuclein, or genetic testing. Not everyone needs all of these tests. Which ones make sense depends on what the rest of the evaluation is pointing toward.

The Bottom Line

Blood-based biomarkers are a massive leap forward for Alzheimer's diagnosis. But Alzheimer's disease is only one part of the dementia landscape.

If an Alzheimer's test comes back negative and a loved one is clearly experiencing progressive cognitive changes, the evaluation shouldn't stop. Lewy body disease, frontotemporal degeneration, vascular injury, and non-neurodegenerative contributors all have their own clinical patterns and diagnostic pathways.

Blood tests have given us an incredible new way to look for Alzheimer's disease. But when the result is negative and the cognitive changes are still there, that shouldn't be the end of the evaluation.

It just means Alzheimer's may not be the answer—and it's time to keep looking for what is.

References

1. World Health Organization. Dementia. Updated July 3, 2026. Accessed August 21, 2026. https://www.who.int/news-room/fact-sheets/detail/dementia
2. 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
3. Siderowf A, Concha-Marambio L, Lafontant DE, et al. Assessment of heterogeneity among participants in the Parkinson's Progression Markers Initiative cohort using alpha-synuclein seed amplification assays: a cross-sectional study. Lancet Neurol. 2023;22(5):407-417. doi:10.1016/S1474-4422(23)00109-6
4. 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
5. Coughlin DG, Adler CH, Barbosa W, et al. CSF α-synuclein seed amplification assays and skin immunofluorescence: clinical applications, research opportunities, and knowledge gaps. Neurology. 2026;106(3):e214648. doi:10.1212/WNL.0000000000214648
6. Liampas I, Kyriakoulopoulou P, Karakoida V, et al. Blood-based biomarkers in frontotemporal dementia: a narrative review. Int J Mol Sci. 2024;25(21):11838. doi:10.3390/ijms252111838
7. Ward J, Ly M, Raji CA. Brain PET imaging: frontotemporal dementia. PET Clin. 2023;18(1):123-133. doi:10.1016/j.cpet.2022.09.010
8. Biesbroek JM, Biessels GJ. Diagnosing vascular cognitive impairment: current challenges and future perspectives. Int J Stroke. 2023;18(1):36-43. doi:10.1177/17474930211073387
9. Forrest SL, Kovacs GG. Current concepts of mixed pathologies in neurodegenerative diseases. Can J Neurol Sci. 2023;50(3):329-345. doi:10.1017/cjn.2022.34