7 June 2016
The editorial paper by Itzhaki et al.  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
 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.
 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.
 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.
 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.
 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.
 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.
 Ukraintseva S, Sloan F, Arbeev K, Yashin A (2006) Increasing rates of dementia at time of declining mortality from stroke. Stroke 37, 1155-1159.