Ramey GD, Tang A, Phongpreecha T, Yang MM, Woldemariam SR, Oskotsky TT, Montine TJ, Allen I, Miller ZA, Aghaeepour N, Capra JA, Sirota M. Exposure to autoimmune disorders is associated with increased Alzheimer's disease risk in a multi-site electronic health record analysis. Cell Rep Med. 2025 Feb 18;:101980. Epub 2025 Feb 18 PubMed.
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University of Massachusetts Chan Medical School
I believe this is among the first, if not the first, large-scale, systematic study of electronic medical records (EHR) testing associations between Alzheimer’s and 26 autoimmune diseases. I found the paper super interesting because several studies have reported that women are at increased risk of AD, compared to men. Similarly, women are at increased risk for several autoimmune diseases. Moreover, chronic neuroinflammation leading to AD diagnosis or progression has been implicated as one of the key mechanisms, which is paralleled in autoimmune diseases.
I took several interesting notes from the paper:
The authors observed AD risk conferred by autoimmunity in both males and females, with the differences more pronounced in females. This lines up nicely with the role of autoimmunity contributing to sex differences in AD.
Moreover, some of the autoimmune diseases that were found in both the UCSF and Stanford EHR to be associated with AD risk include inflammatory bowel disease, autoimmune thyroiditis, type 1 diabetes (T1D) and rheumatoid arthritis. Research by several groups, including ours, has found that innate immunity contributes to transcriptomic perturbations associated with AD and autoimmune diseases such as T1D. So it is likely that the autoimmunity similarly plays an important role across AD and autoimmune diseases.
Next, the authors performed a set of analyses to test for reverse causality, i.e., will the associations hold up if they removed AD cases that were within a year or three years after an autoimmune disease diagnosis. The results of these super interesting analyses suggest that reverse causality is unlikely.
This work raises exciting questions for the field, including our group. From a molecular biology and human genetics perspective, this work opens doors to molecular and genetics questions, such as:
1. Are there shared genetic risk factors that can account for why women are more susceptible to AD and autoimmune diseases?
2. Are there cytokines or other molecular factors shared between the brain and the rest of the body (e.g., blood, pancreas), or secreted by the brain into the cerebrospinal fluid that contribute to both autoimmunity and AD?
View all comments by Elaine LimUniversity of Toronto
This paper contributes significantly to our understanding of the role of dysregulated adaptive immunity in the pathogenesis of Alzheimer’s disease. It represents a significant body of knowledge regarding how autoimmunity may contribute to AD risk.
The authors achieve this by providing robust and comprehensive epidemiologically based statistical analyses, identifying a clinical risk association between autoimmune conditions and AD, thereby highlighting immune dysregulation as a potential contributor to AD. Using the large, real-world UCSF and Stanford electronic health record databases and case-control and cohort study designs, they show that autoimmune disorders are associated with an increased risk of being diagnosed with AD.
Ramey et al.’s results corroborate and extend (1) a Danish cohort study that reported associations between autoimmune disorders and AD with small effect sizes; (2) a Swedish National Patient Register analysis that highlighted higher incidence rates of several autoimmune disorders including thyroiditis, type 1 diabetes, Addison’s disease, Sjӧgren’s syndrome, and pernicious anemia in patients with dementia; and (3) a longitudinal U.K. Biobank cohort study that revealed increased AD hazard linked to four major autoimmune disorders (rheumatoid arthritis, multiple sclerosis, psoriasis, and inflammatory bowel disease).
Ramey et al. enhance these previous studies in five ways: (1) by employing a large (>300,000) and more diverse cohort of patients, suggesting generalizability of the increased risk association between autoimmune disorders and AD; (2) by investigating 26 autoimmune disorders; (3) by analyzing disease subtypes to identify physiological systems that may be involved in AD pathogenesis; (4) by carefully incorporating sex as a biological variable; and (5) by conducting extensive age-of-onset analyses to characterize AD risk.
The authors are scrupulous not to over-interpret their observations, confuse correlation with causation, or ignore the potential presence of confounders.
A strength of this study arises from the authors’ efforts to divide the various types of autoimmune diseases into physiological system categories. By doing so, they are able to show that the autoimmune disorders associated with increased AD risk are primarily endocrine, gastrointestinal, dermatologic, and musculoskeletal. Interestingly, vascular and neurological autoimmune disorders were not associated with an increased AD risk. I think this result is extremely interesting, and perhaps unanticipated, since AD is a neurological problem often with a major vascular component.
The microbiome and its role in AD is gaining popularity as a possible focus of research. The present results connect gastrointestinal autoimmune disease with AD and may support the role of the microbiome in AD.
This study finds that autoimmune disorders are associated with increased AD risk in both sexes. I think this is an interesting observation. Among the many recognized risk factors for AD, head trauma, obesity, undertreated hypertension, undertreated hypercholesterolemia, and smoking are all more commonly associated with male behaviour. Yet AD is more prevalent in women. This study shows that immune dysfunction (which is more common in women) is a risk factor for AD. Clearly not all risk factors are equal, and immune dysfunction may outweigh others in terms of significance.
Now that the AD research community is looking at other pathogenic mechanisms, not exclusively at on protein misfolding, the role of the immune system is gaining importance. Since the immune system is divided into two components (innate and adaptive), there is ongoing debate regarding the relative contributions of innate and adaptive immunity to AD. Does AD arise more from innate immunity dysfunction or adaptive immunity dysfunction? Many studies point to innate immunity. However, autoimmune diseases (which involve autoantibodies) are clearly disorders of adaptive immunity. I think this study makes a valuable contribution to appreciating the balance between innate and adaptive immunity as co-contributors to AD pathogenesis. For a review, see Weaver, 2023).
Autoimmune diseases often occur together. The co-occurrence of more than two autoimmune diseases within the same person is relatively common. The combination of two autoimmune diseases is called polyautoimmunity, with common examples being a systemic lupus erythematosus/Sjögren’s syndrome combination or a rheumatoid arthritis/autoimmune thyroiditis combination. The combination of three or more autoimmune diseases is called multiple autoimmune syndrome (MAS), and it, too, is surprisingly common. That Ramey et al. associates multiple autoimmune disorders with AD raises the highly speculative possibility that AD may itself be an autoimmune disease occurring in combination with one or more of these other well-recognized and established autoimmune diseases. Understandably, the authors are very careful and do not speculate about this.
Nonetheless, it is interesting to hypothesize that AD is another autoimmune disease in its own right, occurring in a setting of polyautoimmunity. For papers on this, see Weaver, 2023; Meier-Stephenson et al., 2022).
We are still searching for better ways to diagnose AD. Blood biomarker tests are gaining in popularity. Does this study suggest new possible biomarkers for autoimmunity that could be used in a battery of blood tests for detecting AD?
Cautionary Comment
As a practising neurologist, I’ve been seeing people with AD for decades. Over the past five-10 years, papers appeared suggesting a role for the immune system (including autoimmunity) in AD. Patients follow the medical literature because they are anxious for solutions that are slow in coming. Many have asked me why they cannot be treated with standard medications used to treat immune diseases, such as autoimmune diseases. Ramey et al. clearly indicates that autoimmunity is a risk factor for AD. However, this does NOT lead to the conclusion that agents used to treat autoimmune diseases (like steroids or certain biologics) should be repurposed for AD. There is nothing to suggest this.
I think this study fits in very nicely with prior work linking immune diseases and neurodegeneration. It makes a strong case for better exploring the contributory role of adaptive immunity to the pathogenesis of AD.
References:
Weaver DF. The Immunopathy of Alzheimer's Disease: Innate or Adaptive?. Curr Alzheimer Res. 2023;20(2):63-70. PubMed.
Weaver DF. Alzheimer's disease as an innate autoimmune disease (AD2 ): A new molecular paradigm. Alzheimers Dement. 2022 Sep 27; PubMed.
Meier-Stephenson FS, Meier-Stephenson VC, Carter MD, Meek AR, Wang Y, Pan L, Chen Q, Jacobo S, Wu F, Lu E, Simms GA, Fisher L, McGrath AJ, Fermo V, Barden CJ, Clair HD, Galloway TN, Yadav A, Campágna-Slater V, Hadden M, Reed M, Taylor M, Kelly B, Diez-Cecilia E, Kolaj I, Santos C, Liyanage I, Sweeting B, Stafford P, Boudreau R, Reid GA, Noyce RS, Stevens L, Staniszewski A, Zhang H, Murty MR, Lemaire P, Chardonnet S, Richardson CD, Gabelica V, DePauw E, Brown R, Darvesh S, Arancio O, Weaver DF. Alzheimer's disease as an autoimmune disorder of innate immunity endogenously modulated by tryptophan metabolites. Alzheimers Dement (N Y). 2022;8(1):e12283. Epub 2022 Apr 6 PubMed.
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