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Epidemiological trends may help clarify the role of infection in etiology of Alzheimer’s disease

7 June 2016

The editorial paper by Itzhaki et al. [1] addresses critically important questions about the role of infection in etiology of Alzheimer's disease (AD). We believe that in addition to the evidence of infectious nature of AD that have been described in the paper, one more type of the evidence must be taken into account and routinely included in consideration of AD mechanisms.

That is, any hypothesis about the mechanism of AD development should be consistent with the observed epidemiological trends in AD risk. Suppose we know that AD is related to infection but do not know exact mechanism of such relationship. We also know that AD risk globally increased over time and is also generally higher in more affluent societies [2-7]. So any proposed mechanism of AD should explain not only how this disease could develop in brain of an individual, but also why it is spreading across populations and times in the observed way.

For example, there may be two different types of relationships between microbial involvement in AD and current epidemiological trends in AD risk. First, exposure to a microbe could favor an increase in disease risk over time simply because respective infection is contagious and may result in epidemic. Second, the infection may not be contagious per se, but disease risk could still increase over time as result of increasing vulnerability to such infection in populations.

The latter scenario may happen, for example, for this reason (there are may be other reasons as well): The exposure to challenging microbes in the more developed countries is overall reduced due to better living and health care conditions; this may lead to insufficiently trained immune system in individuals who live in such countries and, as result, favor chronic inflammation and increased blood-brain barrier permeability; this in turn may increase brain vulnerability to infection and contribute to an increase in AD risk linked to that infection. The fact that the risk of AD is generally higher in the more affluent societies [3, 5] indirectly supports a possibility of such scenario.

These two above mechanisms, connecting brain infection and population risk of AD, imply potentially different strategies of AD prevention. In the first case, some specific microbe (e.g., a herpes virus) may need to be targeted. In the second case, a broader vaccination program might be a more reasonable strategy. In sum, incorporating epidemiological information and biological hypothesis is of vital importance for better understanding of AD etiology and developing its prevention and treatment.

Svetlana Ukraintseva, PhD*; Anatoliy Yashin, PhD; Igor Akushevich, PhD; Konstantin Arbeev
Duke University, Durham, NC 27708, USA
*E-mail: svo@duke.edu

References
[1] Itzhaki RF, Lathe R, Balin BJ, Ball MJ, Bearer EL, Braak H, Bullido MJ, Carter C, Clerici M, Cosby SL, Del Tredici K, Field H, Fulop T, Grassi C, Griffin WS, Haas J, Hudson AP, Kamer AR, Kell DB, Licastro F, Letenneur L, Lövheim H, Mancuso R, Miklossy J, Otth C, Palamara AT, Perry G, Preston C, Pretorius E, Strandberg T, Tabet N, Taylor-Robinson SD, Whittum-Hudson JA (2016) Microbes and Alzheimer's Disease. J Alzheimers Dis 51, 979-984.
[2] Akushevich I, Kravchenko J, Ukraintseva S, Arbeev K, Yashin AI (2013) Time trends of incidence of age-associated diseases in the US elderly population: Medicare-based analysis. Age Ageing 42, 494-500.
[3] Hendrie HC, Ogunniyi A, Hall KS, Baiyewu O, Unverzagt FW, Gureje O, Gao S, Evans RM, Ogunseyinde AO, Adeyinka AO, Musick B, Hui SL (2001) Incidence of dementia and Alzheimer disease in 2 communities: Yoruba residing in Ibadan, Nigeria, and African Americans residing in Indianapolis, Indiana. JAMA 285, 739-747.
[4] Honda H, Sasaki K, Hamasaki H, Shijo M, Koyama S, Ohara T, Ninomiya T, Kiyohara Y, Suzuki SO, Iwaki T (2016) Trends in autopsy-verified dementia prevalence over 29 years of the Hisayama study. Neuropathology, doi: 10.1111/neup.12298.
[5] Mathers C, Leonardi M (2003) Global burden of dementia in the year 2000. World Health Organization (WHO), 2003. http://www.who.int/entity/healthinfo/statistics/bod_dementia.pdf, Accessed May,2016.
[6] Qiu C, Kivipelto M, von Strauss E (2009) Epidemiology of Alzheimer's disease: occurrence, determinants, and strategies toward intervention. Dialogues Clin Neurosci 11, 111-128.
[7] Ukraintseva S, Sloan F, Arbeev K, Yashin A (2006) Increasing rates of dementia at time of declining mortality from stroke. Stroke 37, 1155-1159.

Comments

Submitted by JAD Admin on

I appreciate the interesting comments on our Editorial made by Ukrainseva et al. In response, it is relevant to mention that most, if not all, populations worldwide are infected with HSV1, and that by the age of 60, the proportion infected is very high—80-90% (values of seropositivity, reflecting PNS infection). The age of primary infection has risen with increasing socio-economic level: a century ago most people were infected in infancy, but now in developed countries, it is usually in the teenage or adult years. In the case of the AD patients and age-matched controls whose brain samples we examined in the 1990s [1-3], the average age was 79 years, and we discovered that the majority, around 60-70% of both groups, harbored HSV1 in brain. A high proportion of those in the AD group carried an APOE-ε4 allele, the data indicating that HSV1 in brain of APOE-ε4 carriers confers a high risk of AD, accounting for about 60% of the patients [3].

Ukrainseva et al. state that "AD risk globally increased over time". However, the progressive increase in number of sufferers presumably results from the improvements in diagnosis and the dramatic rise in longevity over the past and present century: after all, aging is one of the very few known risks for AD. (Intriguingly though, studies in Europe and the US suggest that the incidence of cognitive impairment and dementia might actually be decreasing, but more data are needed over longer periods to confirm this, see, e.g., [4]). That the "AD risk is higher in more affluent societies" presumably again results from the better facilities for diagnosis in such societies, compared to less affluent ones. Also, in some societies (generally low affluence ones), it would be regarded as shameful to divulge that a family member is an AD sufferer, and so the risks would very probably be under-estimated.

The possibility that in very affluent societies the higher prevalence of AD is caused by a poorer immune system because of lesser exposure to microbes, through better conditions of life and health care, seems unlikely: the similar levels of HSV1 infection in the brain of AD and age-matched controls indicate that the virus reaches the brain irrespective of whether or not the subjects develop AD. In fact we suggested that it reaches the brain because of the age-related decrease in the immune system [3]. Nonetheless, the proposal that the relevant microbe should be targeted, or a vaccination program set up, is most welcome; one can only hope that these measures will soon be implemented.

Ruth Itzhaki
University of Manchester, Faculty of Life Sciences, Manchester M13 9PT, UK
Current Address: University of Oxford, Nuffield Dept. of Clinical Neurosciences, John Radcliffe Hospital, Oxford, OX3 9DU, UK

References
[1] Jamieson G a, Maitland NJ, Wilcock GK, Craske J, Itzhaki RF (1991) Latent herpes simplex virus type 1 in normal and Alzheimer’s disease brains. J Med Virol 33, 224–227.
[2] Jamieson GA, Maitland NJ, Wilcock GK, Yates CM, Itzhaki RF (1992) Herpes simplex virus type 1 DNA is present in specific regions of brain from aged people with and without senile dementia of the Alzheimer type. J Pathol 167, 365–368.
[3] Itzhaki RF, Lin W-R, Shang D, Wilcock GK, Faragher B, Jamieson GA (1997) Herpes simplex virus type 1 in brain and risk of Alzheimer’s disease. Lancet 349, 241–244.
[4] Rocca W, Petersen RC, Knopman DS, Hebert LE (2012) Trends in the incidence and prevalence of Alzheimer’s disease, dementia and cognitive impairment in the United States. Alzheimers Dement 7, 80–93.