Is Alzheimer’s an autoimmune disease?

A recent study sheds more light on the autoimmune origins of Alzheimer’s disease (AD) and, quite possibly, other forms of neurodegenerative disease as well through the interplay of genetics and the environment. We have ample evidence that chronic neuroinflammation driven by multiple mechanisms leads to the breakdown of our blood-brain barrier and subsequent neurodegeneration. But now we have additional insight into these cellular activities that can hopefully lead us to more targeted responses and enhanced treatment protocols.

In this study1, scientists examined how CD8 +T cells infiltrate Alzheimer's brains and regulate neuronal- and synapse-related gene expression in APP-PS1 transgenic mice the authors conclude "that CD8+ T-cells infiltrate the aged and AD brain and that brain CD8+ T-cells might directly contribute to neuronal dysfunction in modulating synaptic plasticity.”
In a certain subset of patients with the “right” (or wrong) genetics, this can indeed set the stage for autoimmune dysfunction and disease initiation.

The Foot Soldiers of Immunity.
CD8 + T cells have been called the “foot soldiers of immunity”2, referring to their role in our immune system processes. Resting naive CD8+ T cells have an exceptional capacity to react to pathogens by massive expansion and differentiation into cytotoxic effector cells that migrate to all corners of the body to clear the infection. But we also know that CD8+ T cells play an essential part in the progression of cell and tissue-specific autoimmune disease.

What factors drive autoimmune disease?  
Autoimmune diseases occur when self-reactive T cells become activated by deregulated presentation of self-peptides in the presence of inflammatory co-stimulatory molecules.  The involvement of CD4+ (helper) and CD8+ (cytotoxic) T cells in autoimmune disorders leads to autoantibody production and self-reactive cytotoxicity, respectively.3 It is our toxic world and environment that is in essence turning on a switch that instigates an abnormal immune response in all segments of our population including both the young and the old. We have only to look at the rise of chronic disease among all ages to recognize that there is more going on here than genetics alone.

Neuronal antibodies and role in neurodegenerative disease.

Whatever brings the brain down (infectious triggers, chemicals, toxins, EMFs, etc.) in a subset of patients triggers an immune-mediated response in the form of neuro-inflammation and the production of autoantibodies directed to antigen-specific targets and the breach of the BBB.

Alzheimer’s disease is significantly more common in most types of autoimmune disease, and genome-wide association studies also have demonstrated numerous shared loci between Parkinson’s disease and autoimmunity.    

Researchers recently published findings from a study that examined the role of neuronal antibodies and encephalopathy syndromes.

Key study points reported include: 4

1.  Neuronal surface autoantibodies have also been detected in patient populations outside the context of encephalitis, and particularly for IgA/IgM NMDAR antibodies, seroprevalence appears to be greater in older populations, although the clinical consequences of this are not yet known.   

(Note: for these patients, I think it could be especially valuable and telling to look closely too at Cunningham panels.)

2.   The clinical profile of antibody-mediated cognitive impairment has led to particular interest in the potential pathogenicity of neuronal autoantibodies in neurodegenerative dementias.

3.  Autoantibodies have recently been suggested to play a causative role in the pathogenesis of Alzheimer’s disease

4.  Both IgG and IgM or IgA NMDAR serum antibodies were found to be more common in ‘atypical’ dementia vs healthy control. This study found more NMDAR autoantibodies in atypical dementia.  IgA NMDAR antibodies have been associated with ‘atypical dementia’ in older adults, characterized by a slowly progressive cognitive impairment, which is reversible with immunotherapy.

Perhaps we should model our treatment protocols toward neurodegenerative disease through autoimmune-directed strategies and consider a complete autoimmune encephalopathy workup for these patients as well.

IVIG for autoimmune disease including Alzheimer’s.
Thankfully, scientists have moved away from the single amyloid hypothesis3 and are considering a wide range of contributing pathways including: prion transmission; cerebral vasoconstriction related to underlying vascular disease; oxidative stress; excitotoxicity; iron overload; chemicals; toxins; unhealthy gut microbiome; and infectious triggers. It is crucial to note that there is only a weak association between amyloid plaques and AD symptoms.

One of the most striking discoveries with this disease is how very much it involves the white matter of our brain whereas in years past it as thought that only the cortical gray matter was involved. I describe the white matter as the “super highway” of lines of communication connecting everything in our central nervous system (CNS).  Gray matter is where all our neuronal cells are located. White matter abnormalities, and in particular myelin and oligodendrocytes, could be mechanistically important in AD pathology and could be potential treatment targets. Soon we may be utilizing treatments used in multiple sclerosis (MS) to treat AD while continuing to address vascular risk factors as well.

The clinical trials using IVIg in AD done few years ago were not successful, but many in the medical community believe this was because too low a dose was administered as part of the study. The dose used in the clinical trials was .6grams/ kg vs. the recommended 2 grams/kg dosage.

How can IVIg help the immune system and our brain?

IVIg has many helpful mechanisms of action, but in this study findings indicated that IVIg directly interferes with or interrupts the cytotoxicity of activated CD8+ T cells.
Other significant mechanisms include:
1. Binding of natural antibodies contained in IVIg to cytokines and cell surface receptors.
2. Binding to surface receptors on B-cells and down-regulate antibody production.
3. Inhibiting complement activation, neutralizing inflammatory cytokines, and modulating chemokine expression.
4.  IVIg contains anti-idiotypic antibodies that may neutralize circulating autoantibodies; autoantibodies are the principle cause for autoimmune disease like MS , lupus, rheumatoid arthritis and others.  IVIg also down-regulates autoantibody production by anti-idiotypic antibodies interacting with B cells.
5.  Blocking Fc receptors, which are important for antigen presentation.
6.  IVIg is capable of neutralizing bacterial and viral super-antigens that may cause activation of myelin-specific encephalitogenic T-cells.
7.   IVIg promotes remyelination not only by abrogation of the autoimmune attack, but also by an effect on glial cells.5

I continually emphasize (because it’s true) that it is never just one thing that brings down the body or brain, nor is there one simple solution in treatment. It may be that this need for multimodality in patient care is what contributed in part to the unsuccessful use of IVIg in AD trials. Truly, we have yet to fully explore this and I do believe that for every neurodegenerative disease it is imperative to address the foundations of health and wellness so that we can address as many drivers of systemic and CNS inflammation as possible. As part of our comprehensive program we often employ the Bredesen Protocol, which you can find in our Medical Resources section along with other helpful materials and links for many disease-specific support organizations.

We should all be implementing a “Brain Recovery” protocol as part of our everyday lives - and starting at a very young age - to ideally reduce our systemic inflammatory responses. Let us know if we can explain more about what that comprises and answer any questions regarding our integrative approaches or about the many conditions we treat.

In health and hope,
Dr. Suzanne Gazda

References and additional reading:

1 CD8+ T-cells infiltrate Alzheimer’s disease brains and regulate neuronal- and synapse-related gene expression in APP-PS1 transgenic mice.
https://www.sciencedirect.com/science/article/pii/S0889159119315739

2 CD8+ T Cells: Foot Soldiers of the Immune System
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3303224/

3 Is the Amyloid Hypothesis of Alzheimer's disease therapeutically relevant?
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3686157/

4 Gibson, L.L., McKeever, A., Cullen, A.E. et al. Neuronal surface autoantibodies in dementia: a systematic review and meta-analysis. Journal of Neurology (2020).
https://doi.org/10.1007/s00415-020-09825-0

5 Immunomodulation and Remyelination: Two Aspects of Human Polyclonal Immunoglobulin Treatment in Immune Mediated Neuropathies?
https://pubmed.ncbi.nlm.nih.gov/9291162/