The Nose Knows: Loss of Smell Could Be The First Alarm Bell for Alzheimer’s Disease

By Ram Rao, Ph.D., Principal Research Scientist for Apollo Health

Alzheimer’s disease (AD) is notorious for its insidious onset; memory lapses and cognitive decline often appear only after significant brain damage. Past research studies have shown that AD may initially present as a loss of smell, appearing long before any memory-related symptoms. Building on these observations, a recent study by researchers at DZNE and LMU Munich provides mechanistic insights into olfactory dysfunction and highlights smell testing as a potential early indicator of presymptomatic AD.

The study findings reveal that neuronal fibers connecting the olfactory bulb to the locus coeruleus are marked for removal by microglia (our brain’s immune cells) due to changes in cell membranes. These changes, particularly the external exposure of phosphatidylserine (PS), signal deterioration well before losses in memory systems. Phosphatidylserine (PS) typically resides on the inside of a neuron’s membrane. But when neurons become hyperactive (a characteristic feature in very early AD), PS shifts outward and acts as a distress signal. Microglia (our body’s defense molecules) respond by trimming back the nerve fibers, thereby impairing the olfactory pathway. Evidence from mice, human tissue studies, and PET scans collectively confirms that nerve fiber pruning occurs in the earliest stages of the disease, long before memory loss becomes apparent.

This discovery positions the sense of smell and olfactory function as more than a casual check — it could become a cornerstone of early AD screening. Subtle changes in the sense of smell could alert clinicians to the possibility of preclinical AD, which can then be confirmed with additional tests such as BrainScan. For patients, early detection opens the door to timely use of emerging treatments — including Apollo Health’s B7 and the ReCODE Program — that may help slow or even stave off AD progression.

The study’s cross-species/multi-modal approach — from animal models to PET imaging bolsters its significance. It suggests that future diagnostic protocols could include smell evaluation paired with other AD biomarkers and/or brain imaging techniques.

What this means for patients and clinicians:

• For Patients/Caregivers: Be attentive to persistent loss or distortion of smell, even in the absence of memory issues. It is worth discussing this with your healthcare coach or practitioner.
• For Practitioners: Consider integrating smell tests into routine assessments for older adults or those at risk, and follow it up with blood tests (e.g., p-Tau 217, GFAP, and Nfl) to confirm the cognitive decline.

Loss of smell could be the brain’s first alarm bell for AD as an early, tangible warning in a disease too often noticed only after it’s too late. This insight empowers both patients and clinicians with a new opportunity: detect earlier, intervene sooner, and ultimately, treat smarter. Ultimately, catching AD in its earliest phase could shift the disease’s trajectory by not simply delaying the decline but preserving quality of life as well. 

An important Note to add: An important question that arises is whether the sense of smell recovers in parallel with memory improvement. While smell loss appears to be an early marker of cognitive decline and olfactory training has been shown to restore smell in certain contexts, there is currently no direct evidence linking these two outcomes (reversal of cognitive decline in tandem with restoration of smell sensation) in patients who have successfully reversed memory loss through dietary, cognitive, pharmacological, or lifestyle interventions. This gap highlights the need for future research to determine whether sensory recovery accompanies cognitive restoration, a finding that could have significant implications for early diagnosis and comprehensive treatment strategies.