Nasal Brush Biopsy Flags Preclinical Alzheimer’s Disease

 Because of your extra risk of dementia post stroke, you'll want this test so your doctor CAN IMPLEMENT THOSE EXACT ALZHEIMER'S PREVENTION PROTOCOLS THAT WERE WRITTEN AGES AGO! Oh NO, your doctor failed at that! Well, you're screwed, but your doctor is still getting paid for incompetence!

Nasal Brush Biopsy Flags Preclinical Alzheimer’s Disease

A quick, outpatient nasal swab can detect early biological changes linked to Alzheimer’s disease (AD) years before cognitive or memory symptoms present.

Sampling cells in the upper nasal cavity via a minimally invasive brush biopsy may be able to detect AD years before symptoms appear.

Investigators analyzed brush biopsy samples from the olfactory cleft — the narrow upper region of the nasal cavity that houses the olfactory epithelium — and identified immune and neuronal changes that mirror those seen in the brains of people with AD. These signatures distinguished individuals with preclinical and clinical AD from healthy control individuals.

“The nasal biopsy approach is still a research tool rather than something ready for routine care,” study investigator Vincent D’Anniballe, an MD-PhD student with the medical scientist training program at Duke University in Durham, North Carolina, told Medscape Medical News.

“Potentially,” said D’Anniballe, “because the sampling can be repeated and gives us a window into living nerve and immune cells, it could one day help track whether a treatment is changing Alzheimer’s-related biology over time.”

The study was published online on March 18 in Nature Communications.

A Window Into Central Neuropathology

Loss of smell is one of the earliest signs of AD. The olfactory epithelium — located in the upper nasal cavity — harbors olfactory sensory neurons that can accumulate hallmark AD pathology, including amyloid-beta plaques and neurofibrillary tangles, suggesting the olfactory epithelium may “faithfully mirror central AD neuropathology,” the researchers wrote.

To investigate, they profiled olfactory epithelium brush biopsies obtained from healthy control individuals, individuals with cerebrospinal fluid (CSF) biomarker-confirmed AD, and cognitively typical individuals whose positive CSF biomarkers signal a preclinical AD stage.

The biopsy results revealed a “continuum of disease-linked shifts detectable in biomarker-positive, cognitively unimpaired patients and mirrored in the clinical AD.”

Activated CD8 memory T cells and inflammatory myeloid programs were present in adults with preclinical AD and were also present — often at greater magnitude — in adults with clinical AD.

In addition, olfactory sensory neurons in adults with preclinical and clinical AD showed stress-related transcriptional signatures that mirrored those previously reported in postmortem AD brains, suggesting that the olfactory epithelium reflects disease activity occurring deeper in the brain.

A combined gene-expression score derived from the olfactory biopsies was able to distinguish individuals with preclinical and clinical AD from healthy control individuals with about 81% accuracy.

“At this point, our study cannot separate cause from effect. The fact that we see immune cell changes so early suggests they may be a part of the disease process, but we still need follow-up studies to know whether they are driving the disease or reacting to it,” D’Anniballe noted.

Looking ahead, the researchers plan to expand their work to larger patient groups and explore whether olfactory brush biopsy could be used to monitor disease progression or response to therapy over time.

“The biggest hurdles are proving in larger studies that it is reliable and scalable before it can work as a practical clinical test,” said D’Anniballe.

A ‘Compelling’ Early Signal

Reached for comment, Sheena Aurora, MD, vice president of medical affairs at the Alzheimer’s Association, said the results are “intriguing,” given that loss of smell is one of the first symptoms of AD in some people and “targeting the olfactory epithelium is a novel approach.”

However, she noted that the study is very small and preliminary. As a result, the findings need to be replicated and confirmed in larger, more representative study populations before the technique could be considered clinically viable.

Another study limitation is the fact that olfactory cleft biopsies have highly variable rates of success, said Aurora, who wasn’t involved in the research.

If it is eventually validated, this approach could help support diagnosis alongside existing amyloid and tau measures, guide the selection and monitoring of patients for disease-modifying therapies, and provide a way to study early AD-related changes in the brain and adjacent tissues, she noted.

Also weighing in on the findings, Shaheen Lakhan, MD, PhD, a neurologist and researcher based in Miami, said this study “turns the nose into a window into the brain. For the first time, we’re seeing Alzheimer’s biology unfold in living neural tissue before symptoms even begin.”

“What’s striking is that the inflammatory signature of Alzheimer’s is already present in people who are cognitively normal. That fundamentally shifts how we think about when this disease begins,” said Lakhan, who was not involved in the research.

“The olfactory epithelium is one of the only places where you can safely sample living human neurons. That’s been the missing piece in Alzheimer’s research. This is not a nasal swab. It’s a targeted biopsy of olfactory neural tissue, which is why it captures real brain biology, not just surface signals,” he added.

Lakhan said the findings point to a potential pharmacodynamic biomarker, offering a way to directly observe how interventions — whether drugs or digital therapeutics — affect neural and immune pathways in living human tissue.

If validated, he added, the approach could transform early detection and clinical trials by providing an earlier, biologically grounded signal of disease activity and treatment response.

He emphasized, however, that the work remains an early proof-of-concept, albeit with a strong and biologically coherent signal.

Funding for the study was provided by the National Institutes of Health. D’Anniballe reported having no disclosures. Duke University and four authors are named inventors on a US patent application related to methods for obtaining olfactory cleft brush biopsy samples and measuring gene-expression biomarker panels to detect/diagnose and guide treatment of preclinical AD. Aurora and Lakhan reported having no relevant disclosures.