The APOE ε4 Allele: An Early Indicator of Alzheimer’s Disease through Olfactory Decline


Alzheimer’s Disease (AD) is a devastating neurodegenerative condition that affects millions of people worldwide. Identifying early indicators of AD is crucial for timely intervention and disease management.

Recent research has suggested a link between the APOE ε4 allele and susceptibility to faster decline in odor identification, which subsequently leads to AD.

Odor identification involves recognizing and naming odors and detecting them (odor sensitivity). However, whether APOE ε4 is associated with the decline of odor sensitivity and whether this decline acts as a harbinger of cognitive decline and AD remains uncertain.

The present study aims to explore the impact of the APOE ε4 allele on the decline of odor sensitivity, odor identification, and cognition using data from the National Social Life Health and Aging Project (NSHAP), a nationally representative survey study of home-dwelling US older adults. By investigating the relationship between APOE ε4 and olfactory function longitudinally, this study seeks to shed light on the role of olfaction in neurodegeneration during aging and its potential as a predictive tool for cognitive decline.


The researchers utilized data from NSHAP, which included measures of olfaction and cognition over time. Olfaction was assessed by measuring odor identification in 2005, 2010, and 2015 and odor sensitivity in 2010 and 2015, using validated tests. Cognition was evaluated using a modified version of the Montreal Cognitive Assessment in 2010 and 2015.

Genotyping was performed using DNA samples collected in 2010 to identify APOE ε4 carriers and non-carriers. The study population was stratified by age, and the relationships between APOE ε4, odor sensitivity, odor identification, and cognition were analyzed cross-sectionally using ordinal logistic regression and longitudinally using mixed effects models adjusted for confounders.


The study included 865 respondents with data on odor sensitivity, 1156 respondents with data on odor identification, and 864 respondents with data on cognition, all of whom had genetic data available. The results revealed that odor sensitivity deficits in APOE ε4 carriers were evident in the age group of 65-69, while odor identification deficits did not appear until the age group of 75-79.

Surprisingly, odor sensitivity did not decline more rapidly with aging in APOE ε4 carriers compared to non-carriers, indicating that this aspect of olfactory function may not be as strongly impacted by the APOE ε4 allele (carrier status and aging interaction: OR=1.44, 95% CI (0.94-2.19), p=0.092).

However, odor identification declined more rapidly in carriers (aging 10 years interaction: OR=0.26, 95% CI (0.13-0.52), p<0.001). Similarly, cognition declined more rapidly in APOE ε4 carriers, aligning with the pattern observed for odor identification (interaction: OR=0.55, 95% CI (0.34-0.89), p=0.015).


The findings from this study indicate that the APOE ε4 allele influences the decline of odor sensitivity earlier than it affects odor identification or cognition. While odor sensitivity deficits were evident in APOE ε4 carriers in the age range of 65-69, deficits in odor identification and cognitive decline became apparent later, at ages 75-79. These results suggest that testing for odor sensitivity may serve as an effective means to predict future impaired cognitive function, potentially providing an early indicator of AD.

Understanding the underlying mechanism linking the APOE ε4 allele to olfactory decline and subsequent cognitive impairment will be crucial in elucidating the role of olfaction in neurodegeneration during aging. Further research is warranted to explore the exact pathways through which APOE ε4 affects olfactory function and how this ultimately contributes to AD pathogenesis. The findings from this study hold promise for the development of innovative diagnostic tools and therapeutic strategies that may help delay or prevent the onset of AD, improving the quality of life for millions of individuals affected by this devastating disease.

In Summary…

The APOE ε4 allele is a genetic variant that is associated with an increased risk of developing Alzheimer’s disease (AD). APOE ε4 is also associated with a decline in odor sensitivity, which is the ability to detect and recognize odors.

The reason for the association between APOE ε4 and odor sensitivity is not fully understood, but there are several possible explanations. One possibility is that APOE ε4 affects the function of the olfactory bulb, which is the part of the brain that processes odors. The olfactory bulb is a densely packed structure that contains millions of olfactory receptor neurons. These neurons are responsible for detecting odors and sending signals to the brain. APOE ε4 may damage or impair the function of these neurons, leading to a decline in odor sensitivity.

Another possibility is that APOE ε4 affects the production of amyloid beta plaques, which are a hallmark of AD. Amyloid beta plaques are sticky deposits that build up in the brain and damage nerve cells. APOE ε4 may increase the production of amyloid beta plaques, which could lead to damage to the olfactory bulb and a decline in odor sensitivity.

The decline in odor sensitivity in APOE ε4 carriers may be a harbinger of cognitive decline and AD. Studies have shown that people with APOE ε4 who have a decline in odor sensitivity are more likely to develop AD later in life. This suggests that odor sensitivity may be a useful early marker for AD.

However, it is important to note that not everyone with APOE ε4 will develop AD. And, not everyone who has a decline in odor sensitivity will develop AD. The decline in odor sensitivity is just one risk factor for AD. Other risk factors include age, family history, and lifestyle factors such as smoking and obesity.

If you are concerned about your risk of AD, talk to your doctor. There are things you can do to reduce your risk, such as eating a healthy diet, exercising regularly, and not smoking.

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