Alzheimer's: Why losing sense of smell may be early sign of disease

  • Alzheimer’s disease is the commonest form of dementia, affecting more than 6 million people in the United States.
  • Early diagnosis is key to managing the disease, but initial symptoms, such as memory issues, are often dismissed as normal signs of aging.
  • A new study has found that carriers of the APOE ε4 gene, who are at higher risk of developing Alzheimer’s disease, may lose their ability to identify odors earlier than those who do not carry the gene variant.
  • As this impaired sense of smell may be an early sign of future cognitive problems, testing people’s sense of smell could help identify those at greater risk of Alzheimer’s.

According to the Alzheimer’s Association, around 1 in 9 people over the age of 65 has Alzheimer’s disease (AD) in the United States, a total of 6.7 million people. With an aging population, experts expect this number to exceed 12 million by 2050.

Alzheimer’s is an incurable, progressive disease, but it is not inevitable in aging. If a person starts to experience memory problems and cognitive deficits, these should not be dismissed as normal signs of aging, as early diagnosis allows treatment that can alleviate symptoms.

Around 13.7% of people worldwide carry a gene variant, APOE ε4, that increases the risk of Alzheimer’s disease. This gene is found in 40% of people who are diagnosed with the condition.

A new study published in Neurology found that people who carry this gene variant may experience an impaired sense of smell before any symptoms of Alzheimer’s disease, such as mild cognitive impairment, appear.

The researchers suggest that testing a person’s ability to detect odors may be useful for identifying those at risk.

“This is an interesting study assessing the relationship between declines in odor sensitivity and odor identification in APOE ε4 carriers and the risk of future cognitive decline.”

– Dr. Emily D. Clark, D.O., Assistant Professor of Psychiatry and Associate Director of the Alzheimer’s Disease Care, Research, and Education Program (AD-CARE) at the University of Rochester.

Examing odor sensitivity among those with APOE ε4 gene

The study participants came from the National Social Life, Health and Aging Project (NSHAP) — a study of older adults’ social lives and health run by the University of Chicago.

For this study, over 865 people took an at-home survey that included testing their sense of smell. The tests were repeated at 5-yearly intervals, with odor identification being assessed in 2005, 2010, and 2015 and odor sensitivity being tested in 2010 and 2015. In 2010 and 2015, participants also completed thinking and memory tests. In 2010, the mean age of the participants was 72.3 (range 62-95)

The study aimed to determine whether APOE ε4 is linked to a decline in the sense of smell and cognition and, if so, how. The researchers took DNA samples to determine which of the respondents carried the gene variant.

Study author Dr. Matthew S. GoodSmith, of the University of Chicago, told Medical News Today: “In our cross-sectional analysis, about 25% of the participants carried the APOE ε4 gene (of this, 1% were homozygous, 24% were heterozygous).”

Smell tests included odor sensitivity — the ability to detect odors at different concentrations — and odor identification, which assessed people’s ability to determine what the odor was.

Could losing sense of smell be an early sign of Alzheimer’s?

Throughout the study, those with the gene were 37% less likely to have good odor detection than people without the gene.

At age 65, people with the APOE ε4 variant could detect fewer odors than those without the gene, suggesting that their ability to detect odors had already declined by this age. However, non-carriers, who started with a better ability to detect odors, showed a more rapid decline after age 65.

In contrast, when identifying odors, there was no difference between carriers and non-carriers at 65, but carriers’ ability declined more rapidly, particularly from age 75. Cognition showed a similar pattern, with faster declines in cognition in those with the APOE ε4 variant.

Although they found no link between odor detection and cognition, the researchers’ findings suggest odor identification and cognition are linked.

Dr. Clark, who was not involved in the study, told MNT: “The authors found impairments in odor sensitivity in APOE ε4 carriers presented earlier in life (65-69 years old) than impairments in odor identification (75-79 years old). Furthermore, deficits in odor sensitivity preceded cognitive decline in APOE ε4 carriers.”

“This suggests that impaired odor sensitivity may be an early marker of future cognitive impairment in APOE ε4 carriers,” she added.

How APOE ε4 leads to damage to olfactory system

The study found that odor sensitivity is impaired before problems develop with odor identification and that the initial olfactory impairment is independent of cognition issues.

“It has been shown that many structures involved in olfaction (including the olfactory epithelium and the olfactory bulb) express high levels of APOE.

– Dr. GoodSmith.

The researchers suggest that the olfactory epithelium (nerve cells and supporting cells in the nose) is affected first in APOE ε4 carriers, and damage to the olfactory cortex in the brain occurs later. However, they emphasize that further study is needed to confirm their findings.

Dr. Clark commented: “It is possible that the APOE ε4 allele is responsible for disruptions in otherwise normal functioning activity in these structures, leading to impaired odor sensitivity and identification.”

Could the findings lead to an early test for Alzheimer’s?

“It is important to note that, in our study, we had no way of keeping track of which patients would ultimately go on to develop Alzheimer’s,” Dr. GoodSmith told us. “And, since our data was derived from survey data collected from adults living at home who were able to tolerate a long interview process, respondents with severe dementia were unable to participate.”

“That being said,” he added, “our findings shed light on the interplay between smell loss and cognitive decline in patients at high genetic risk for developing Alzheimer’s. We hope that, with additional research, testing the sense of smell may develop into a useful screening or diagnostic tool in the future.

So, although these are early findings, Dr. Clark agreed that they may point toward new methods of detecting early Alzheimer’s disease:

“These findings, if further validated, provide a novel opportunity for the use of olfactory testing as an early screening marker in clinical research studies. As the clinical research field is focusing more on intervention in early symptomatic and prodromal Alzheimer’s disease, the ability to use something like olfactory performance as an early biomarker would make identifying appropriate populations easier and possibly more cost-effective.”

However, she added a note of caution: “Further validation of these findings and a better understanding of the underlying mechanisms behind these changes are needed before this can be accepted as a screening test in clinical practice.”

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