Alzheimer’s Disease and Smell Loss

Anosmia (smell loss) or hyposmia (reduced smell) could be an early and important sign of Alzheimer’s disease before other symptoms begin. The degree of smell loss may correlate with an increased risk of developing Alzheimer’s. Anosmia may worsen as the disease progresses from early-stage mild cognitive impairment to Alzheimer’s disease.

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Alzheimer’s disease is the most common form of dementia worldwide. Central to the pathology is the atrophy (shrinkage) of the brain, especially the hippocampus and cortex caused by neuronal & synaptic loss. Neuronal loss occurs due to a build-up of amyloid-beta plaques and neurofibrillary tangles of hyperphosphorylated-tau – two key pathological hallmarks in Alzheimer’s disease.

Whilst Alzheimer’s disease symptoms are obvious as the disease progresses, early detection may be important in slowing down the disease – especially with the continued development of novel therapies or better disease management from early on. The problem, however, is that early detection (biomarkers) is limited or difficult to assess in the clinic and a firm diagnosis can only be made after extensive clinical, neuroimaging, pathological and post-mortem analysis.

Smell loss in Alzheimer’s disease

One American study found that older individuals (around 3000 people aged between 57-85) with impaired smell (hyposmia) had over 2 times the odds of developing dementia within 5 years, independent of other risk factors. Those with the poorest smell discrimination (complete anosmia) were the most likely to develop dementia within 5 years. The degree of olfactory deficit correlated with the severity of dementia that occurred i.e., small deficit related to mild cognitive impairment vs healthy controls, and high degree of deficit related to Alzheimer’s.

Of all those assessed, 4.1% were subsequently diagnosed with dementia within 5 years of which 47% had olfactory dysfunction at the initial evaluation. This was in contrast to 80% of all those assessed who had normal olfactory function who did not develop dementia within 5 years. Furthermore, a meta-analysis of 39 studies showed a large effect size (Cohens d=1.73) was reported between smell loss and Alzheimer’s disease, though there is a high degree of heterogeneity – especially between MCI and Alzheimer’s with respect to smell loss.

Although smell loss is not often considered to be a key symptom of Alzheimer’s disease, it is, however, one of the earliest symptoms to present in patients (if it occurs). It is also important to note that smell loss alone is not a sufficient indication of Alzheimer’s disease, and is indeed also found in many other neurological conditions including early on in Parkinson’s disease in particular, as well as in multiple sclerosis, amyotrophic lateral sclerosis and Huntington’s disease.

The development of disease-specific odor tests is vital in differentiating between diseases – if at all possible (more research is needed at this stage). Nonetheless, smell loss is an important symptom that occurs in a variety of neurological conditions (as discussed). Thus, if odor tests show impairments, it would be important to administer standard tests such as MMSE alongside neuroimaging as a robust method in evaluating the earliest stages of Alzheimer’s.

Furthermore, hyposmia (impaired smell) can also be attributed to normal aging, however, the extent of hyposmia or anosmia, especially earlier than what would be expected as part of normal aging is a strong indicator of the increased likelihood of developing dementia within a few years from the start of such symptoms – before any noticeable cognitive impairments begin to occur.

What causes smell loss to occur in Alzheimer’s disease?

Just as amyloid plaques and neurofibrillary tangles contribute to neuronal and synaptic loss in the brain itself, they are also thought to be causative in olfactory dysfunction. It is thought that neuropathology occurs in regions such as the olfactory system begins prior to impairments within the hippocampus and cortex. Furthermore, the olfactory system has limited self-repair mechanisms thus making it more vulnerable to Alzheimer-related damage.

Based on these findings, a simple discriminatory odor test may be able to evaluate the risk of Alzheimer’s disease (or other neurological conditions) before disease symptoms begin to appear. These could then be validated by other diagnostic tools such as clinical tests, biomarkers and neuroimaging, etc. Early identification can lead to early intervention with a higher chance of improved prognosis and a long-term plan put in place.

In summary, smell loss could be an early and important biomarker of Alzheimer’s disease that occurs before any noticeable cognitive impairments begin. Those with smell loss in mid-age have an increased likelihood of developing Alzheimer’s within a decade, and those with the most impairments to smell (complete loss) are at the highest risk. Therefore, smell discrimination tests could be an easy and effective measure in evaluating the potential for Alzheimer’s disease to develop and allow for early interventions and management plans.

References

Kotecha et al, 2018. Olfactory Dysfunction as a Global Biomarker for Sniffing out Alzheimer's Disease: A Meta-Analysis. Biosensors (Basel). 8(2):41. https://pubmed.ncbi.nlm.nih.gov/29652815/
Adams et al, 2018. Olfactory Dysfunction Predicts Subsequent Dementia in Older U.S. Adults. J Am Geriatr Soc. 66(1):140-144. https://pubmed.ncbi.nlm.nih.gov/28944467/

Alzheimer’s Disease and Smell Loss

Smell loss in Alzheimer’s disease

What causes smell loss to occur in Alzheimer’s disease?

References

Further Reading

Dr. Osman Shabir