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Allergy, Sensitivity and all-cause Dementia

Older man blowing dandelions

Busy clinicians need an accurate, cost-effective screen for early dementia and strategies to decrease dementia risk in their patient populations. An estimated 5.8 million people in the United States currently suffer from dementia, and that number is expected to rise to about 14 million people by 2060. Women and minority populations are expected to have the greatest increase in incidence. Women of all races have a risk about twice that of men, which is due mostly to the longer female lifespan.

A new study indicates that such screening may be possible. Because the imaging and comprehensive cognitive testing typically used in Alzheimer’s diagnosis is expensive and time-consuming, the researchers developed a model that used “non-cognitive” factors to screen patients and sort them into clinical stages of cognitive function or dysfunction.

Since dementia and Alzheimer’s disease are associated with the presence of other chronic inflammatory conditions, the researchers developed a “non-cognitive” screening model that included a variety of factors available from a thorough medical history and in-office examination:
    

  • Dementia risk factors
    o    Age
    o    Gender 
    o    Blood pressure
    o    Education level
    o    Mini-mental state exam (MMSE)
    o    APOEε4 allele genetics
  • Risk of Chronic inflammatory disorders
    o    Cardiovascular, hypertension, depression)
    o    Medication use (lipid-lowering, antidepressants, etc.)
  • Neurology
    o    Dexterity
    o    Gait
    o    Self-reported sleep quality and duration
    o    Parkinson’s signs 
    • Tremor, bradykinesia, rigor, postural instability
  • Quality of life
    o    Self-reported physical activity
    o    Social network size

Compared to a comprehensive model that included advanced cognitive assessments, the “non-cognitive” model demonstrated good predictive ability for 3-5 years from the baseline assessment. As expected, additional cognitive assessments further refined the model and predictive power. The researchers felt that the most powerful overall dementia predictors were the MMSE, hand strength, and APOEε2 genetic status while advancing age and APOEε4 genetics were the most powerful “non-cognitive” Alzheimer’s predictors.

The research, while fascinating, failed to assess another known risk factor – allergy. Atopic disease (allergy) and perhaps, environmental sensitivity (IgG, IgA), may also be contributing inflammatory factors for dementia. Both allergy and APOEε4 genetics need to be considered to fully evaluate the patient. Multiple epidemiology studies indicate that chronic inflammation and Alzheimer’s/dementia risk are linked in individuals with allergy/asthma, dysbiosis, gum disease, or toxic exposures such as air pollution. However, human studies that specifically look at immunoglobulins (Ig) and risk also show associations with immune dysregulation:

  • Subjects with a triad of atopic disorders (allergic rhinitis, atopic dermatitis, asthma) had a significantly increased risk of all-cause dementia compared to non-allergic controls. The dementia risk appears to associate with the severity of the atopic reactions. 
  • Alzheimer's Allergic patients differed significantly in MMSE scores and CSF biomarkers from those without allergies. While there was no association with mild or subjective cognitive impairment, allergy was associated with a higher trend in p-tau and t-tau proteins found in Alzheimer’s brain pathology.
  • The study suggests that Alzheimer’s pathology and cognitive decline are associated with increased plasma IgA levels in an APOEε allele-dependent manner, where the association is lost in APOEε4 carriers typically at higher risk for Alzheimer’s. In other words, subjects with normal APOEε4 genetics were at risk from higher serum IgA levels.
  • Individuals with primary immunodeficiency disease self-report higher levels of memory impairment (“brain fog”) and have higher rates of anxiety and depression than normal controls. Depression is a known risk factor for dementia.

A total immunoglobulin level, whether IgE, IgG, or IgA, is always a combination of auto-antibodies and antibodies against environmental antigens.

Auto-antibodies + environmental antibodies = Igtotal

It is also important to note that total IgE levels are also affected by gender, obesity, and alcohol use; this is likely true for all types of immunoglobulins because they are metabolized in the liver. Male gender, a higher body mass index, and heavy alcohol use were shown to increase total IgE levels in a large epidemiology study in Spain.

Fortunately for patients, it is possible to assess the effects of environmental exposures on IgE, IgG, and IgA, and once identified, the offending antigen exposures can be eliminated, decreasing overall inflammation.

 Slide for IgE and IgG4 interpretation
 More IgG and IgG4 interpretation

Conclusion

In the USA, the number of dementia patients is expected to rise to approximately 14 million people by 2060. Risk reduction and early identification via accurate, efficient, screening methods can help reduce the number of new dementia patients and may help prevent the progression of existing dementia. The evaluation of less well-known risk factors, such as total IgE and serum IgA, in those at risk of dementia, is clearly indicated by the available human studies and easily implemented. Astute clinicians can start reducing their patients’ risk immediately using US BioTek’s Ig (immunoglobulin) testing. 


References:
Bereczki D. The description of all four cardinal signs of Parkinson's disease in a Hungarian medical text published in 1690. Parkinsonism Relat Disord. 2010 May;16(4):290-3.

Centers for Disease Control and Prevention (2019) Minorities and Women Are at Greater Risk for Alzheimer's Disease. https://www.cdc.gov/aging/publications/features/Alz-Greater-Risk.html Accessed 25 October 2022.

Joh HK, Kwon H, Son KY, Yun JM, Cho SH, Han K, Park JH, Cho B. Allergic Diseases and Risk of Incident Dementia and Alzheimer's Disease. Ann Neurol. 2022 Sep 12. doi: 10.1002/ana.26506.

Pocevičiūtė D, Nuñez-Diaz C, Roth B, Janelidze S; Netherlands Brain Bank, Giannisis A, Hansson O, Wennström M. Increased plasma and brain immunoglobulin A in Alzheimer's disease is lost in apolipoprotein E ε4 carriers. Alzheimers Res Ther. 2022 Aug 26;14(1):117.

Sarlus H, Eyjolfsdottir H, Eriksdotter M, Oprica M, Schultzberg M. Influence of Allergy on Immunoglobulins and Amyloid-β in the Cerebrospinal Fluid of Patients with Alzheimer's Disease. J Alzheimers Dis. 2015;48(2):495-505.

Sowers KL, Gayda-Chelder CA, Galantino ML. Self-reported cognitive impairment in individuals with Primary Immunodeficiency Disease. Brain Behav Immunity. 2020;9:10070. https://doi.org/10.1016/j.bbih.2020.100170.

Yang J, Oveisgharan S, Liu X, Wilson RS, Bennett DA, Buchman AS. Risk Models Based on Non-Cognitive Measures May Identify Presymptomatic Alzheimer's Disease. J Alzheimers Dis. 2022;89(4):1249-1262.
Older man blowing dandelions

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