, , , , , ,

Rather than incontrovertible evidence, what triggers Alzheimer’s disease (AD) is still very much a mystery. As Ruth F. Itzhaki and Matthew A. Wozniak state in a 2006 review, ‘until fairly recently, the only known risk factors were age, Down’s syndrome and head injury’ for Alzheimers‘ (1).

Genetics as in familial AD accounts for <3% of total AD. Mutations in 3 genes, APP, PS1 and PS2 are implicated. However, genetics alone doesn’t explain AD since identical twin AD risk is estimated to be 59% (2, 3). Thus far, apolipoprotein E4 (ApoE4) is the one consensus risk factor for AD (4).

Since genetics alone can’t explain AD, at least not so far, infectious agents and/or response to them have been suggested as AD triggers since at least 1982 when Melvyn J. Ball asked if herpes simplex virus 1 (HSV1) was an AD trigger (5). As for bacteria, a recent meta-analysis concluded strong associations between Spirochaete and Chlamydophila pneumoniae infections and AD (6).

Ruth F. Itzhaki and others at the Faculty of Life Sciences at the University of Manchester, UK, suspected a viral role and ‘discovered that HSV1 DNA is present in brain of a high proportion of elderly people and that in combination with APOE-e4 it confers a high risk of AD‘ (1). Viral infection in combination with a genetic risk factor, namely the type 4 allele of apolipoprotein E (ApoE4). APOE is also implicated as a modulator of cardiovascular disease (7), where infectious disease agents such as HSV and Chlamydia pneumoniae have been implicated as risk factors (1). Cytomegalovirus (CMV) is another virus implicated in AD (8).

The news article referenced in the question quotes several AD investigators who pooh-pooh the role of infectious disease agents as AD triggers.

‘Prof John Hardy, Professor of Neuroscience, UCL, said: “This is a minority view in Alzheimer research. There had been no convincing proof of infections causing Alzheimer disease. We need always to keep an open mind but this editorial does not reflect what most researchers think about Alzheimer disease.”

Dr Simon Ridley, Director of Research at Alzheimer’s Research UK, said: “There is growing evidence for the role of the immune system in Alzheimer’s and active ongoing research looking at how an inflammatory response might contribute to the disease. There is some evidence to suggest that infections in general could ramp up the immune system and contribute to the progression of Alzheimer’s, but there isn’t conclusive evidence to suggest that a particular infectious agent or microbe could be directly responsible for causing the disease.

“There are many avenues being explored to understand the initial events that trigger the development of Alzheimer’s and this is an important part of the research process for ruling in and out particular hypotheses. There is no evidence that Alzheimer’s can be passed from person to person like a virus. Continued research funding into diseases like Alzheimer’s is important to build a clearer picture of the genetic and lifestyle risk factors for the disease and use this knowledge to develop preventions or treatments.” ‘

However, Itzhaki states (9) that since 1991, ~37 studies by several labs including hers have published data supporting a role for HSV1 in AD.

HSV1 belongs to the herpes virus family that includes viruses that cause genital herpes, shingles and glandular fever. HSV1 can cause a variety of diseases, the most recognized of which is cold sores, i.e., herpes labialis. It’s ubiquitous in that >80% of >65 year olds are estimated to harbor it (10). A neurotrophic double-stranded DNA virus, it largely infects oral and nasal mucosal epithelial cells and replicates. Idea is newly replicated viral particles enter sensory neurons and reach the Trigeminal ganglion where they reside as a latent infection. Trigeminal ganglion neurons project to the brainstem trigeminal nuclei and thalamus to reach the sensory cortex. So HSV1 can travel this route and establish latent infection in CNS (10).

Idea linking long-lived latent HSV1 infection in CNS to AD is virus reactivation. Why should AD be an outcome of latent virus reactivation? Aging-associated immune response dysregulation or Immunosenescence or ‘inflammaging’, i.e., inappropriate inflammatory immune responses associated with aging. Problem is this is conjecture. Where’s the incontrovertible evidence? That’s where the rubber needs to meet the road but hasn’t yet, probably because infection trigger for AD is an idea not yet mainstream among AD researchers. Incontrovertible evidence would be antiviral Rx halting or even reversing cognitive decline.

However, Itzhaki points out in her 2014 review (9),

‘so far there has been no clinical trial of antiviral treatment for AD patients, the reason being that applications for funding have been refused by grant-giving bodies and pharmaceutical companies (the latter presumably because VCV [valacyclovir] is off-patent’

This brings us slap bang against a structural flaw in mainstream science enterprise, in this case how to fund an idea mainstream AD research considers too risky and unorthodox to even fund? Rather than simply bemoan an odious status quo, this is where private funding has a net opportunity to not just make a difference that has inherent value but in doing so effect much-needed restructuring in scientific research funding.


1. Itzhaki, Ruth F., and Matthew A. Wozniak. “Herpes simplex virus type 1, apolipoprotein E, and cholesterol: a dangerous liaison in Alzheimer’s disease and other disorders.” Progress in lipid research 45.1 (2006): 73-90.

2. Gatz, Margaret, et al. “Complete ascertainment of dementia in the Swedish Twin Registry: the HARMONY study.” Neurobiology of aging 26.4 (2005): 439-447.

3. Iacono, Diego, et al. “Neuropathologic assessment of dementia markers in identical and fraternal twins.” Brain Pathology 24.4 (2014): 317-333. https://www.researchgate.net/pro…

4. Xu, He, David I. Finkelstein, and Paul A. Adlard. “Interactions of metals and Apolipoprotein E in Alzheimer’s disease.” Front Aging Neurosci 6 (2014): 121. http://citeseerx.ist.psu.edu/vie…

5. Ball, Melvyn J. “Limbic predilection in Alzheimer dementia: is reactivated herpesvirus involved?.” Canadian Journal of Neurological Sciences/Journal Canadien des Sciences Neurologiques 9.03 (1982): 303-306. http://journals.cambridge.org/do…

6. Maheshwari, Priya, and Guy D. Eslick. “Bacterial infection and Alzheimer’s disease: a meta-analysis.” Journal of Alzheimer’s Disease 43.3 (2015): 957-966.

7. Martins, I. J., et al. “Apolipoprotein E, cholesterol metabolism, diabetes, and the convergence of risk factors for Alzheimer’s disease and cardiovascular disease.” Molecular psychiatry 11.8 (2006): 721-736. https://www.researchgate.net/pro…

8. Barnes, Lisa L., et al. “Cytomegalovirus infection and risk of Alzheimer disease in older black and white individuals.” Journal of Infectious Diseases (2014): jiu437. Cytomegalovirus Infection and Risk of Alzheimer Disease in Older Black and White Individuals

9. Itzhaki, Ruth F. “Herpes simplex virus type 1 and Alzheimer’s disease: increasing evidence for a major role of the virus.” Frontiers in aging neuroscience 6 (2014). Herpes simplex virus type 1 and Alzheimer’s disease: increasing evidence for a major role of the virus

10. Monastero, Roberto, Calogero Caruso, and Sonya Vasto. “Alzheimer’s disease and infections, where we stand and where we go.” Immunity & Ageing 11.1 (2014): 1. Immunity & Ageing