Rapid Loss of Smell Linked to Dementia and Alzheimer Disease in Older Adults

Older adults with normal cognition who experience rapid olfactory decline are more likely to be subsequently diagnosed with MCI or dementia compared with older adults with slower or no decline in olfaction.

Loss sense of smell, as measured by the rate of change, is linked to neurodegenerative changes in brain regions that are most affected by Alzheimer disease (AD), and is predictive of increased risk for the development of mild cognitive impairment (MCI) or dementia, according to a longitudinal study published in Alzheimer’s & Dementia.

Among patients with AD, olfactory dysfunction is common. Yet, it’s unclear whether early olfactory decline is associated with the later development of cognitive impairment and AD. For this study, researchers sought to examine whether the rate of olfactory decline can be used as an early biomarker of disease progression in dementia via frequent serial olfactory testing in a well-characterized group of patients with AD.

Researchers used magnetic resonance imaging (MRI), cognitive testing, and clinical classification of MCI and AD to evaluate participants. They hypothesized that older adults who demonstrated rapid olfactory decline during a period of normal cognition would exhibit smaller gray matter volumes, worse impaired cognition, and a more common incident diagnosis of MCI or AD compared with older adults with slower or no decline in olfaction.

A cohort of 515 adults (mean age 76.6 years; 78% women; 94% White) with repeated olfactory and cognitive testing, neurologic examinations, and available medical histories was selected from the Rush Memory and Aging Project — a longitudinal, epidemiologic cohort study. In a subsample of 121 individuals, structural MRIs were obtained as well.

These findings support previous literature that olfactory impairment may be an accessible biomarker for AD neuropathogenesis and risk.

During the olfactory test phase of the study, participants underwent serial olfactory testing (ie, 3 or more valid Brief Smell Identification Test [BSIT] scores over 1.30-18.0 years). With the use of all available BSIT scores and age at the time of each test, each participant’s individual rate of olfactory decline was calculated. The 515 participants all maintained normal cognition while completing 3 or more odor identification tests, with the intention being to obtain olfactory testing during normal cognition — that is, prior to any preclinical or diagnosed AD.

A total of 100 participants were diagnosed with incident MCI or dementia, based on annual cognitive function testing between the end of repeated olfactory testing and the final clinical diagnosis. A subsample of 104 participants with normal cognition and 17 with MCI underwent the structural MRI phase of the study at the onset of the olfactory testing phase. At the completion of the olfactory testing phase, 95 participants maintained normal cognition, 25 demonstrated MCI, and 1 had converted to early AD.

The results of the study showed that more rapid olfactory decline during periods of normal cognition were predictive of a significantly higher incidence of subsequent MCI or dementia (odds ratio [OR], 1.89; 95% CI, 1.26-2.90; P <.01). The association was stronger in younger adults (OR for interaction between rate of olfactory decline and age at baseline; 0.94; 95% CI, 0.89-0.99; P <.05). Faster olfactory decline was also associated with smaller gray matter volume in the primary olfactory region (β=–0.11; 95% CI, –0.21 to –0.00) despite controlling for apolipoprotein E (APOE) ε4 allele status.

Further, participants with poor baseline BSIT scores (OR, 1.25; 95% CI, 1.05-1.48; P <.05) and global cognition z-scores (OR, 1.68; 95% CI, 1.21-2.33; P <.01) had an increased likelihood of incident MCI and dementia. Additionally, participants who were homozygous or heterozygous for the APOE ε4 allele had the highest likelihood (OR, 2.59; 95% CI, 1.30-5.09; P <.01) of incident MCI and dementia compared with those without the APOE ε4 allele.

Limitations of the study warrant mention. Since the calculation used for rate of olfactory decline was based on slope of measured timepoints assuming linearity, this may actually oversimplify the complexity of olfactory changes in normal aging and during the preclinical period. Further, the study population comprised 94% White individuals, which may limit the ability to generalize the study findings to the diverse US population.

“These findings support previous literature that olfactory impairment may be an accessible biomarker for AD neuropathogenesis and risk,” the researchers stated.

They recommend that “additional studies be conducted to further characterize the relationship between longitudinal olfactory change and AD pathogenesis, as well as to increase generalizability in larger, more heterogeneous populations.”

Disclosure: Some of the study authors have declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures. 

This article originally appeared on Neurology Advisor


Pacyna RR, Han SD, Wroblewski KE, McClintock MK, Pinto JM. Rapid olfactory decline during aging predicts dementia and GMV loss in AD brain regions. Alzheimers Dement. Published online July 28, 2022. doi:10.1002/alz.12717