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Abstract

This review examines the application of olfactory testing in the early stages of mild cognitive impairment (MCI) associated with Alzheimer’s disease (AD), highlighting its potential and challenges in early screening and intervention. Olfactory function is typically divided into three domains: odor identification, odor discrimination, and odor threshold. Among these, odor identification and discrimination are closely linked to higher cognitive processes and exhibit significant impairment in patients with AD and MCI. Moreover, the anatomical and functional characteristics of the olfactory system make it a promising target for the early detection of neurodegenerative disorders. This review also outlines various olfactory assessment tools and evaluates their clinical utility. Future research should aim to enhance the accuracy and cultural adaptability of olfactory tests and integrate them with multimodal diagnostic approaches to advance early detection and intervention strategies for AD.

Graphical Abstract

Keywords

alzheimer’s disease early screening mild cognitive impairment olfactory dysfunction olfactory testing

Introduction

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder typically marked by memory loss, language deficits, executive dysfunction, and personality changes. Pathologically, AD is associated with neuronal loss, brain atrophy, and widespread neuroinflammation, and it accounts for 60%-80% of all dementia cases.^1-3

According to the recent biological framework established by the National Institute on Aging and Alzheimer’s Association (NIA-AA), Alzheimer’s disease is formally defined as a biological process characterized by the presence of AD neuropathologic changes (ADNPC), including amyloid-β plaques and tau neurofibrillary tangles, which can be identified through validated biomarkers even prior to the onset of clinical symptoms. This biological definition emphasizes AD as a continuum that begins asymptomatically and progresses through clinical stages ranging from mild cognitive impairment (MCI) to dementia.⁴

With a rapidly aging global population, the number of individuals affected by AD is expected to reach 78 million by 2030 and 139 million by 2050, posing a profound burden on healthcare systems and families.^2,5

Importantly, AD-related neuropathological changes begin more than two decades before clinical symptoms appear.⁶ However, once symptoms are evident, current treatments offer limited efficacy.¹ Current therapies, including cholinesterase inhibitors and memantine, merely alleviate symptoms without modifying disease progression. Recently, two anti-amyloid monoclonal antibodies—lecanemab and donanemab—have been approved following successful phase 3 trials (Clarity AD and TRAILBLAZER-ALZ 2). These antibodies selectively bind β-amyloid to facilitate its clearance via microglia, resulting in approximately 25%-35% slowing of cognitive decline in early-stage AD. However, their application faces significant limitations, including risks of amyloid-related imaging abnormalities (ARIA-E/H), high cost, and limited patient access. Thus, early intervention during the mild cognitive impairment stage remains critical.^7,8

Intervening during the stage of mild cognitive impairment (MCI)—a prodromal phase of AD—has been shown to delay progression by up to five years and reduce disease prevalence and healthcare costs substantially.⁹ Notably, up to 25% of individuals with MCI may revert to normal cognition following timely intervention, underscoring the potential of early detection strategies.^10,11

Recent meta-analyses have revealed that olfactory deficits may emerge even during the stage of subjective cognitive decline (SCD), a preclinical phase preceding MCI. Jobin et al found that individuals with SCD already demonstrate significantly reduced odor identification compared to cognitively normal peers, with associations to early AD-related pathology such as tau accumulation and medial temporal lobe atrophy. These findings suggest that olfactory testing could serve as a low-cost, non-invasive addition to the SCD framework for identifying individuals at elevated risk of progression.^12,13While these results underscore the potential of olfactory dysfunction as a preclinical marker, the MCI stage remains the most feasible and clinically actionable window for intervention, especially given current therapeutic thresholds and diagnostic capabilities. Characterizing olfactory changes across both stages may therefore enhance early screening precision and guide optimal timing of treatment.

Among emerging biomarkers, olfactory dysfunction has gained increasing attention as a non-invasive, cost-effective tool for identifying individuals at risk. Olfactory deficits are prevalent not only in early AD but also during the MCI stage and may even precede memory decline.^14-17 Studies suggest that olfactory impairment is a stronger predictor of cognitive decline than episodic memory loss in cognitively normal adults.¹⁸ Despite its subtlety in daily life, olfactory dysfunction is frequently unrecognized by patients and can be objectively detected through standardized testing.^19,20

Neuroanatomically, the olfactory system—including the olfactory bulb, tract, and primary olfactory cortex (eg, piriform cortex)—is tightly interconnected with hippocampal subfields, entorhinal cortex, and the amygdala, all of which are early targets in Alzheimer’s disease.^17,21 Longitudinal MRI over five years revealed that progressive atrophy in the hippocampal tail, CA4, dentate gyrus, and subiculum predicted declines in odor-identification performance in older adults, suggesting these subregions are sensitive preclinical markers.²² Complementarily, region-of-interest volumetric analyses demonstrated that individuals with mild cognitive impairment exhibit significantly reduced grey-matter volume in the piriform cortex, amygdala, entorhinal cortex, and the olfactory subregion of the left hippocampus compared to cognitively normal controls.²³ Notably, volume of the left hippocampal olfactory subregion was positively correlated with episodic memory performance, underscoring a shared neurodegenerative trajectory between olfactory and memory networks in the MCI stage. These findings reinforce the anatomical basis for olfactory testing as an early biomarker for AD.²⁴ Moreover, olfactory performance has been correlated with scores on cognitive screening tools like the Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA).²⁵

Compared to neuroimaging or cerebrospinal biomarkers, olfactory testing is more accessible and feasible for routine clinical use, even in primary care settings. Its predictive accuracy, coupled with its practicality, makes it a promising adjunct in early screening and monitoring.^26,27 This review synthesizes current evidence on olfactory dysfunction as a prodromal marker of AD, particularly during the MCI phase, and evaluates its potential applications, limitations, and clinical implications. By exploring this relatively underutilized modality, we aim to contribute to the development of effective early detection strategies for Alzheimer’s disease.

Classification and Mechanisms of Olfactory Function

The olfactory system, comprising peripheral (olfactory epithelium and nerve bundles) and central components (olfactory bulb and related pathways), shows promise in early MCI and AD detection.^21,26 Olfactory function is generally divided into odor identification, discrimination, and threshold. With odor memory emerging recently as an important domain that bridges sensory processing and higher cognitive decline.²¹

Olfactory Threshold

Odor threshold—the lowest detectable concentration of a scent—is primarily considered a measure of peripheral sensory integrity, as pathologies confined to the olfactory epithelium, septum, or nasal cavity can selectively reduce sensitivity without affecting higher-order tasks such as odor identification.^28-31 Nevertheless, threshold performance is not entirely independent of central processes. Meta-analytic evidence now shows small-to-moderate correlations between olfactory detection threshold and both episodic (r = 0.25) and semantic memory (r = 0.17) in cognitively normal older adults, with the strength of this association increasing with age.³² These findings align with neuroimaging and lesion studies implicating hippocampal and prefrontal regions—structures vulnerable to aging and early Alzheimer pathology—in odor detection as well as memory function.^33,34

Thus, while odor threshold testing may help detect early changes, its ability to distinguish MCI from normal aging remains uncertain.

Odor Discrimination

Odor discrimination—differentiating among multiple scents—requires intact sensory function and cognitive resources such as attention, memory, and semantic processing.^35,36 Tasks may also involve delayed recognition, increasing their diagnostic sensitivity.³⁷

Some genetic studies link the ApoE ε4 allele to poorer discrimination performance, though results across populations remain inconsistent.^38-42 Discrimination deficits emerge early and worsen with disease progression, even predicting the transition from normal cognition to MCI and AD.^15,43-47

Therefore, odor discrimination is a sensitive indicator for early detection and progression monitoring, even if genetic influences remain debated.

Odor Identification

Odor identification entails perceiving, recognizing, and naming an odor.²¹ This cognitively demanding task depends on intact olfactory sensation and semantic memory.⁴⁸ Early declines in identification, often observed in AD and dementia, reflect semantic deficits evident even in prodromal stages.⁴⁹

Impairments are prominent in amnestic MCI (aMCI), aligning with its progression to AD.^21,50-52 Compared to discrimination, memory, or threshold tests, identification tasks often reveal greater deficits,^53,54 underscoring the increased difficulty AD patients face with complex olfactory processing.^37,55

Odor identification tests are cost-effective, time-efficient, and suitable for early screening and follow-up in clinical settings.⁵⁶ Despite their cognitive demands,^37,57 cultural background and odor familiarity can influence performance, necessitating culturally adapted tests.^47,58

In conclusion, odor identification is a valuable tool for early screening. Accounting for sociocultural variability will enhance its diagnostic accuracy across populations.

Recent meta-analytic evidence further confirms the systematic associations between olfactory function and declarative memory in cognitively normal older adults. In a comprehensive analysis of 17 studies, both olfactory identification and detection threshold were significantly correlated with episodic and semantic memory (r = 0.19-0.25). Notably, age moderated the strength of these associations, particularly for detection threshold, suggesting a shared vulnerability in medial temporal and prefrontal brain regions. These findings support the role of olfactory measures—both peripheral and central—as sensitive markers of memory function in aging and as potential early indicators of Alzheimer’s disease pathology.³² Given the tight link between olfaction and declarative memory, particularly episodic memory, odor memory emerges as a critical domain warranting focused discussion.

Odor Memory

Odor memory—the ability to encode, store, and retrieve olfactory information—has recently attracted attention as an important domain linking basic olfactory processing to higher cognitive functions.²¹ Unlike identification or threshold tests, odor memory tasks engage episodic processes supported by medial temporal lobe (MTL) structures, such as the hippocampus and entorhinal cortex, which are among the first to be affected in Alzheimer’s disease pathology.²¹

Functional imaging studies confirm activation of MTL regions during olfactory tasks, highlighting their anatomical and functional convergence with memory systems.⁵⁹

Research indicates that odor memory is significantly impaired in individuals with Alzheimer’s disease and in those at increased genetic risk, such as APOE ε4 carriers, even prior to observable cognitive symptoms.^60,61 These findings suggest that odor memory assessment may complement traditional olfactory measures, offering additional sensitivity for the early detection of neurodegenerative changes.

Interaction of the Olfactory System with the Nervous System

Structure and Function of the Olfactory System: Signaling Pathways from Olfactory Receptors to the Brain

The olfactory system plays a vital physiological and psychological role as the central mechanism for detecting and processing external odors. Its intricate structure and highly coordinated signaling pathways enable the conversion of chemical stimuli into neural signals, which are then transmitted to the brain for further processing.⁶²

The olfactory center in the human brain is primarily divided into two cortical regions: the primary olfactory cortex (POC) and the secondary olfactory cortex (SOC).⁶³ The POC includes the anterior olfactory nucleus, olfactory tubercle, frontal and temporal piriform cortices, subregions of the amygdala, and the internal olfactory cortex,^64-66 while the SOC comprises the orbitofrontal cortex, insula, thalamus, hippocampus, and other related regions.⁶³ The POC primarily receives input from the olfactory bulb and is closely associated with olfactory processing. Notably, it is among the earliest regions affected by neuropathological changes in mild cognitive impairment (MCI) and Alzheimer’s disease (AD).⁶⁷ (see Figure 1).

Figure 1.

Map of the Olfactory Center

Olfactory modulation involves direct connections between the olfactory tract and several brain regions, including the piriform cortex, entorhinal cortex, hippocampus, and amygdala. These connections influence higher-order functions such as memory, emotion, fear, and vigilance.⁶⁸ Thus, the olfactory system plays a critical role not only in odor perception but also in the regulation of emotion and memory. This structural and functional complexity highlights its potential as a diagnostic target in neurodegenerative diseases.

The main components of the olfactory system include olfactory receptor cells, olfactory nerves, olfactory bulbs, olfactory tracts, and the olfactory cortex.²¹ Olfactory receptor cells are located in the olfactory mucosa within the upper nasal cavity.⁶⁹ This mucosa—composed of the olfactory epithelium (OE) and lamina propria (LP)—efficiently captures odor molecules.⁷⁰ The OE contains olfactory receptor neurons (ORNs), which are bipolar neurons with cilia, along with various supporting cells. The axons of ORNs form synapses with dendrites of secondary olfactory projection neurons (mitral and tufted cells) within the olfactory glomeruli.^62,71,72 These neural connections convert chemical signals into electrical impulses, which travel through the olfactory bulb to higher brain regions (see Figure 2).

Figure 2.

Olfactory System Diagram

The olfactory epithelium also contains supporting cells, Bowman’s gland duct cells, horizontal and spherical basal stem cells, and microvillous cells. Supporting cells surround the dendrites of ORNs and regulate metabolic, secretory, and phagocytic functions. Odor molecules reach the OE through the olfactory lumen and bind to specific odorant receptors, which are part of the G protein-coupled receptor (GPCR) family.⁶⁶ These receptors are located on the cilia of ORNs and are directly exposed to the external environment within the nasal cavity.⁷³

When an odor molecule binds to a receptor, it activates the ORN, generating an action potential that is transmitted via the olfactory nerve to the olfactory bulb and subsequently to various brain regions—especially those involved in memory, emotion, and behavioral regulation.⁷⁴

Importantly, the olfactory system, alongside the visual system, is one of the few neural pathways that directly interfaces with the external environment without passing through the blood-brain barrier. This unique feature makes olfaction a promising, non-invasive source of central nervous system (CNS)-derived biomarkers.^68,74-76 Furthermore, olfactory testing has gained attention in chemosensory research due to its simplicity, low cost, and ease of administration.

The olfactory system begins developing during mid-gestation and exhibits minimal variability across vertebrates. From early infancy to adulthood, it not only shapes sensory perception but also modulates behaviors such as food preferences and social bonding. For instance, human newborns show a preference for their mother’s breast odor, suggesting that odor-related memory formation begins in utero.^77,78

In summary, the olfactory system converts chemical stimuli into neural signals through a complex and highly specialized pathway and interacts with multiple brain regions to support functions such as memory and emotion. These features underscore its promise as a non-invasive tool for the early detection of MCI and AD.

Advances in the Study of Olfactory Impairment to Distinguish AD from Other Neurodegenerative Diseases

In recent years, growing attention has been directed toward olfactory dysfunction in patients with dementia, particularly Alzheimer’s disease (AD), a neurodegenerative condition characterized by memory loss and cognitive decline. Olfactory impairment is now recognized as one of the earliest clinical manifestations of AD.⁵⁰ Studies have consistently shown that patients with AD exhibit significantly reduced olfactory identification and discrimination abilities compared to healthy controls, and that these impairments often precede the onset of cognitive symptoms.²¹

The pathological hallmarks of AD include β-amyloid (Aβ) plaques and neurofibrillary tangles (NFTs), composed respectively of Aβ protein (derived from amyloid precursor protein, APP) and hyperphosphorylated tau protein.⁷⁹ These features serve as diagnostic criteria for AD.⁸⁰ The olfactory bulb is among the earliest regions to accumulate Aβ deposits, and the spatial-temporal pattern of this deposition is closely linked to olfactory dysfunction.⁸¹ In the aged Tg2576 mouse model, Aβ-induced apoptosis, neurotransmitter imbalances, and neuroinflammation have also been observed.⁸²

Biopsy studies of the olfactory epithelium in AD patients have revealed a strong association between elevated Aβ levels and olfactory dysfunction.⁸³ Longitudinal studies tracking the progression from mild cognitive impairment (MCI) to AD have demonstrated strong correlations between olfactory decline and changes in adjacent brain regions, such as the hippocampus and the olfactory cortex.^80,84,85 Numerous clinical, case-control, and cross-sectional studies have consistently found that olfactory loss is significantly associated with cognitive decline and progression to MCI or AD dementia.⁵⁰ These findings support the potential of olfactory impairment as an early biomarker of AD-related amnestic MCI.

Olfactory function tests typically evaluate three domains: odor identification, odor threshold, and odor discrimination. Of these, odor identification has shown the strongest correlation with cognitive decline and progression to AD dementia.⁴⁹ Importantly, olfactory testing can help differentiate between AD and other neurodegenerative disorders, such as Parkinson’s disease (PD) and dementia with Lewy bodies (DLB). For instance, patients with AD show greater impairment in odor discrimination tasks, whereas PD patients perform worse on odor threshold tests.^16,53 This suggests that PD affects lower-level perceptual processes, while AD impairs higher-order olfactory functions requiring cognitive integration.⁸⁰ Recent studies have also compared resting-state olfactory network connectivity in PD and AD. Findings indicate reduced connectivity between the olfactory bulb and striatal-thalamic-frontal regions in PD relative to AD, as well as reduced orbitofrontal connectivity in striatal-frontal circuits.⁸⁶ Moreover, olfactory tests have proven effective in distinguishing AD from other conditions such as Lewy body disease (LBD), depression, and vascular dementia (VaD), although they are less effective in differentiating frontotemporal dementia (FTD) (see Figure 3).⁸⁷

Figure 3.

Pathomechanisms of Olfactory Impairment in Neurodegenerative Diseases (Abbreviation: OFC, Orbitofrontal Cortex; ST, Corpus Striatum; Thal, Thalamus; Hipp, Hippocampus; Ento, Entorhinal Cortex)

Collectively, these findings not only offer strong theoretical support for clinical practice but also open new avenues for research. In summary, the role of olfaction in neurodegenerative disease extends beyond traditional sensory perception; it provides valuable insights for early screening and serves as a promising direction for future investigations.

Olfactory Detection Tools and Their Application in Mild Cognitive Impairment (MCI)

Olfactory function tests are generally categorized into two types: objective examinations and psychophysical assessments. Objective methods, such as electrophysiological measurements and brain imaging techniques, offer high accuracy but are unsuitable for routine clinical screening due to their cost and complexity.⁸⁸ In contrast, psychophysical tests are widely used in clinical research because they are easy to administer and cost-effective. These tests typically assess three domains: odor identification, odor discrimination, and odor detection threshold, each of which has varying degrees of correlation with cognitive function.^88,89

University of Pennsylvania Smell Identification Test (UPSIT)

The University of Pennsylvania Smell Identification Test (UPSIT), developed in the 1980s, is a standardized tool used to assess suprathreshold odor identification ability.^88,90 UPSIT contains 40 odorant capsules distributed across four test booklets, each with 10 items. Participants scratch the capsule to release the odor and choose the correct option from four multiple-choice responses.^91,92 The test provides a quantitative assessment of olfactory function and can also be used as a self-assessment tool.⁹³ Results are categorized into five levels: normal, mild, moderate, and severe impairment, and anosmia (complete loss of smell).⁹⁴

Studies have shown that patients with MCI generally score lower on UPSIT compared to healthy individuals. For instance, Nogi et al. (2021) found that older adults with MCI exhibited significant deficits in odor identification.⁹⁵ Additionally, longitudinal studies have demonstrated that lower UPSIT scores in MCI patients are predictive of progression to Alzheimer’s disease or other dementias.¹⁸ In a large multi-center sample, UPSIT scores ≤34 predicted conversion from CN to AD dementia within 5 years with 90 % sensitivity and 50 % specificity.⁹⁶ Meta-analytic data confirm an overall sensitivity of 0.79 and specificity of 0.78 for CN vs AD when UPSIT is used.⁹⁷ Longitudinal tau-PET work further shows that poorer baseline UPSIT scores predict greater tau accumulation in entorhinal and olfactory regions over ∼2.5 years in CN elders,⁹⁸ supporting UPSIT as an early indicator of AD-related change.

Despite its high sensitivity and specificity, the UPSIT is time-consuming and complex to administer, making it more suitable for research rather than routine clinical screening.⁹⁹ To address this limitation, a simplified version—the Cross-Cultural Smell Identification Test (CC-SIT)—was developed. This version features a shorter test time and easier administration, and is now widely used in preliminary screenings for olfactory disorders.¹⁰⁰

T&T Olfactometer Test

The T&T Olfactometer Test is designed to measure odor detection thresholds by determining the lowest concentration of specific odorants that a subject can perceive. The test uses five odorants—phenylethanol, methylcyclopentane, isovaleric acid, undecanolactone, and methylindole—chosen for their diverse chemical properties and odor profiles, The average recognition score across all five substances is used to assess olfactory function.¹⁰¹

The procedure involves placing an odorless filter paper dipped in the odorant approximately 1 cm below the subject’s nostrils. Participants sniff each sample repeatedly to identify the lowest detectable concentration. Based on their performance, results are categorized into five levels: normal, mild hyposmia, moderate hyposmia, severe hyposmia, and anosmia.¹⁰²

The T&T Olfactometer Test has shown promise in identifying early olfactory changes associated with Alzheimer’s disease (AD), as it sensitively measures threshold impairments often present in the prodromal phase.^103-105 These olfactory deficits are closely associated with AD-related neuropathologies, such as hippocampal and cortical atrophy.¹⁰⁵ Therefore, the test may serve as a supplementary screening tool for individuals at risk before cognitive symptoms appear, although its diagnostic accuracy for early-stage AD remains to be prospectively validated.^103-105

Sniffin’ Sticks Test

The Sniffin’ Sticks Test (SS-16), developed by Hummel and Kobal, is a widely used tool for assessing olfactory function,¹⁰⁶ The test involves presenting an odorized pen approximately 2 cm in front of the participant’s nose for 3 seconds.¹⁰⁷ Participants then choose the correct odor from four options, with a 30-second interval between trials.^108,109 One point is awarded for each correct answer, with a maximum score of 16; higher scores indicate better olfactory function.⁵²

The application of the Sniffin’ Sticks Test in the screening of Alzheimer’s disease (AD) has produced significant results, particularly in identifying olfactory recognition deficits commonly observed in patients with AD. As a result, the Sniffin’ Sticks Test has become a reliable early screening tool for detecting changes in olfactory function.¹³ Studies have shown that individuals with AD, especially in the early stages of the disease, typically perform poorly on this test, with significantly lower olfactory scores compared to healthy controls.^45,110

Beyond its use in AD, the Sniffin’ Sticks Test has demonstrated substantial clinical value in screening for mild cognitive impairment (MCI). Patients with MCI often exhibit varying degrees of olfactory dysfunction, and their test scores are consistently lower than those of cognitively healthy individuals.⁴⁵ Several studies have confirmed that these deficits are particularly noticeable during the early stages of MCI-related cognitive decline.⁵⁶ Across 11 studies using the 16-item identification subtest (SS-16), pooled sensitivity for separating CN from MCI was 0.67, specificity 0.79 and AUC 0.81. When SS-16 was combined with Cognitive Scale, the AUC rose to 0.96.⁹⁷ indicating that SS-16 can serve as an effective, low-cost tool for early detection of both AD and MCI. Therefore, the Sniffin’ Sticks Test serves not only as an effective tool for early AD screening but also as a valuable adjunct in identifying early cognitive impairment in individuals at risk of MCI.

However, cultural differences can influence the validity of the Sniffin’ Sticks Test. Certain odor descriptors may not evoke the same recognition or perception across different cultural contexts.⁸⁹ To improve both accuracy and cultural relevance, researchers have adapted the test content to reflect local cultural settings. For example, in a Chinese adaptation, some odors such as “ pine ” and “ grapefruit ” were replaced with more culturally familiar scents like “ wood ” and “ grapefruit ”,¹¹¹ enhancing the test’ s applicability and validity.

In conclusion, the Sniffin’ Sticks Test is a simple, effective, and clinically valuable tool for assessing olfactory function. It plays a crucial role in the early screening of Alzheimer’s disease and serves as a useful screening method for mild cognitive impairment. As cultural adaptations and standardization efforts continue to advance, the global applicability of the Sniffin’ Sticks Test is expected to expand.

Odor Recognition Testing for Chinese Populations: Characteristics and Applicability

Given cultural variability in odor perception, researchers in China have developed olfactory identification tools specifically tailored to the local population.¹¹² The China Specific Odor Identification Test (CSIT), introduced by the Institute of Psychology at the Chinese Academy of Sciences in 2019, was designed to align with the cultural context of Chinese individuals.¹¹² The CSIT consists of either 16 or 40 odor sticks, each containing 1 mL of liquid odorant derived from everyday items commonly encountered in Chinese life.¹¹²

During testing, the tip of the odor stick is held approximately 2 cm in front of the subject’s nostrils for 2-3 seconds. Participants may sniff multiple times until the odor is clearly perceived, then select one of four similar options.¹¹³ The entire test typically takes 5-10 minutes, after which a CSIT score is calculated based on recognition performance.¹¹³ Final scores are categorized into five levels of olfactory function—normal, mild impairment, moderate impairment, severe impairment, and anosmia—using a regression algorithm adjusted for age and gender via specialized software.¹¹³ Normal function corresponds to a CSIT score of 14-16, mild impairment to 11-13, moderate impairment to 9-11, severe impairment to 7-9, and anosmia to ≤6.¹¹³ The reliability of the CSIT has been validated in several studies, particularly its high test–retest reliability (up to 0.92). It has also been cross-validated with the University of Pennsylvania Smell Identification Test (UPSIT) and the Sniffin’ Sticks Test (SS-16).¹¹² In terms of recognition accuracy, Chinese participants scored approximately 15% higher on the CSIT than on the UPSIT or SS-16, further supporting its cultural appropriateness and clinical utility.¹¹² Thus, the CSIT provides a valid and reliable tool for assessing olfactory function in Chinese populations.

Because the CSIT was developed with close attention to cultural and individual differences, it not only offers an effective tool for olfactory assessment in China but also highlights the importance of cultural considerations in the development of diagnostic instruments. This localized approach ensures greater linguistic and contextual relevance, thereby improving the generalizability and accuracy of olfactory testing in culturally distinct populations.

AROMHA Brain Health Test

This localized approach ensures greater linguistic and contextual relevance, thereby improving the generalizability and accuracy of olfactory testing in culturally distinct populations.

In addition to these conventional and culturally adapted tools, recent years have seen the emergence of innovative digital approaches aimed at enhancing accessibility, scalability, and cross-cultural applicability. One notable example is the AROMHA Brain Health Test (ABHT), a recently developed digital olfactory assessment tool specifically designed for cognitive screening, with particular emphasis on remote and large-scale applications.¹¹⁴

The test consists of a series of bilingual (English and Spanish) odor cards mailed to participants and a web-based interface that guides them through three psychophysical subtests: odor percept identification (OPID), percepts of odor episodic memory (POEM), and odor discrimination (OD). Participants also rate odor intensity and self-evaluate their confidence in identification, allowing metacognitive assessment.¹¹⁴

In a recent validation study, ABHT successfully distinguished individuals with mild cognitive impairment (MCI) from those with subjective cognitive complaints (SCC) and cognitively normal (CN) participants, even in unobserved home-based settings. The test demonstrated high feasibility among older adults—including participants over 90 years old—and was shown to be linguistically and culturally adaptable. Performance outcomes were consistent across languages and administration modes.¹¹⁴

Compared to traditional tools, the ABHT offers several advantages: it requires no professional supervision, supports remote administration, and integrates both behavioral and metacognitive measures. Its practicality and scalability position it as a promising direction for the future of global olfactory screening, especially in aging populations and resource-limited settings (see Figure 4).

Figure 4.

Application of Olfactory Tools.^114,115 ((A), University of Pennsylvania Smell Identification Test (UPSIT); (B), T&T Olfactometer Test; (C), Sniffin’ Sticks Test; (D), Odor Recognition Testing for Chinese Populations;(E), AROMHA Brain Health Test)

Summary and Future Prospects

Olfactory testing demonstrates considerable potential as a tool for the early screening of Alzheimer’s disease (AD). Its non-invasive nature, convenience, and independence from educational level offer distinct advantages for early screening. Furthermore, its low cost makes it particularly valuable in resource-limited settings. However, existing studies have highlighted challenges in cross-cultural applicability, underscoring the need for appropriate adaptation and optimization of olfactory tests in diverse cultural contexts. Future research should therefore prioritize improving both the accuracy and cultural adaptability of these assessments and aim to develop culturally specific olfactory testing tools to enhance global applicability.

Additionally, future studies could explore multimodal diagnostic strategies that integrate olfactory testing with other non-invasive methods—such as cognitive assessments and eye-tracking technologies—to provide a more comprehensive diagnostic perspective. Advances in neuroimaging, molecular biology, and artificial intelligence are also expected to enhance the sensitivity and precision of olfactory testing, further expanding its value in clinical settings.

Notably, olfactory impairment may serve as a significant early biomarker of AD. Regular monitoring of olfactory function could help identify high-risk individuals and enable timely preventive interventions. For patients with mild cognitive impairment (MCI), olfactory testing may assist clinicians in tracking disease progression and optimizing treatment strategies. Future research should also investigate interventions targeting olfactory dysfunction, including olfactory training and lifestyle modifications, which may delay or prevent cognitive decline and offer novel avenues for early intervention in AD.

In light of recent advancements, remote olfactory testing platforms have shown strong potential for large-scale, at-home cognitive screening. The AROMHA Brain Health Test (ABHT), introduced earlier in this review, exemplifies how bilingual, self-administered odor assessments can be feasibly conducted and validated across languages. Its demonstrated cultural adaptability and ability to distinguish between cognitive states highlight the promise of digital tools for early detection, particularly in underserved or remote populations.¹¹⁴

In conclusion, olfactory testing represents a promising approach for early AD screening, with broad applications in technological innovation, standardization of testing procedures, and interdisciplinary collaboration. Continued basic and clinical research will be essential for developing more effective diagnostic tools and ultimately improving patient outcomes and quality of life. (see Figure 5).

Figure 5.

Bidirectional Relationship Between Olfactory Dysfunction and Alzheimer’s Disease and Mechanistic Hypotheses

Footnotes

Acknowledgments

The authors thank Zi-Xi Tian for the assistance with figure preparation.

ORCID iDs

Feiyan Zhou

Zhiqian Tong

Ethical Considerations

This study was approved by the Ethics Committee of Wenzhou Medical University (2022-071).

Author Contributions

1. PDCogniCare Research project: A. Conception,B. Organization,C. Execution;2. Systematic review: A. Search / screen,B. Data extraction,C. Quality assessment;3. Manuscript Preparation: A. Writing of the first draft,B. Review and Critique. FYZ: 1B,1C,2A,2B,2C,3A;JAX: 2A,3A;JK: 3B;ZQT: 1A,1B,3B. Feiyan Zhou: Data curation,Formal analysis,Investigation,Methodology,Visualization,Writing – original draft,Writing – review & editing. Jinan Xu: Writing – review & editing. Ke Jiang: Formal analysis,Writing – review & editing. Zhiqian Tong: Conceptualization,Project administration,Supervision,Writing – review & editing.

Funding

The authors disclosed receipt of the following financial support for the research,authorship,and/or publication of this article: This work was supported by the Major Program of the National Natural Science Foundation of China (62394314),and the National Natural Science Foundation of China (82071214).

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research,authorship,and/or publication of this article.

Data Availability Statement

The data used to support the findings of this study are included within the article. * *

Declaration of Generative AI in Scientific Writing

No use of generative AI in scientific writing upon submission of the paper.

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