Despite the best efforts of pharmaceutical industry and academia, no new drugs against Alzheimer's Disease (AD) have been developed since 2003 
. Moreover, currently available drugs (acetylcholinesterase inhibitors and/or N-metyle D-aspartate (NMDA) antagonists) only treat/mask AD symptoms for about one year, if at all - none of them directly slow or lessen AD pathogenesis itself. In view of the universal failure of every major drug trial to alter the course of AD, it is time to think outside the “pharmaceutical box" by considering non-pharmaceutical approaches that are safe, disease modifying, and can be expeditiously explored to treat AD. We propose high frequency electromagnetic field (EMF) treatment could be that approach, based on several epidemiologic studies 
and our recently completed EMF studies in Alzheimer's transgenic (Tg) mice 
In humans, high frequency EMF exposure/treatment studies have essentially involved “cell phone level" EMF parameters (pulsed, modulated and primarily GSM), in large part because of initial concerns that high frequency EMF exposure may induce health problems such as brain cancer 
. However, the recent 13-nation INTERPHONE study 
, as well as analytic findings from NIEHS 
and numerous epidemiologic studies 
, all collectively conclude that there is no consistent evidence that long-term exposure of adults or children/adolescents to cell phone level EMFs causes brain tumors, or very likely any other health problems for that matter. In concert with these studies alleviating safety issues related to high frequency EMF exposure, dozens of studies have investigated potential cognitive and physiologic (i.e., EEG, cerebral blood flow, and auditory processing) effects of cell phone level EMF exposure. With rare exception 
, these studies only involved brief (3–120 minute), single EMF exposure at GMS, CW, or UMTS cell phone parameters given to normal subjects. Not surprisingly, recent reviews/meta-analyses find these “acute" exposure studies to result in no significant beneficial or impairing effects on cognitive performance 
. Nonetheless, several PET studies have reported that acute, single-exposure EMF treatment can affect regional cerebral blood flow 
and increase brain glucose utilization 
, thus suggesting that even acute high frequency EMF treatment can affect brain neuronal activity.
Although results from acute, single EMF exposure studies are insightful, they are most probably not indicative of the physiologic and cognitive effects of long-term/daily EMF exposure (i.e. the EMF exposure typical of cell phone users or the repeated EMF treatments almost certainly required for any clinical EMF applications). In this context, no controlled human studies have investigated the “long-term" effects of high frequency EMF treatment in normal or AD subjects over weeks, months, or years. Nonetheless, two epidemiologic studies have provided initial human evidence that years of high frequency EMF exposure are associated with cognitive benefit. One of these studies found that heavy cell phone use over several years resulted in better performance of normal subjects on a word interference test 
, while the other study reported that long-term cell phone users (>10 years) had a 30–40% decreased risk of hospitalization due to AD and vascular dementia 
The lack of controlled human studies investigating cognitive effects of “long-term" EMF exposure/treatment has at least been partially negated by our highly controlled EMF treatment studies in AD Tg mice and littermate non-transgenic (NT) mice 
. In the first long-term, high frequency EMF treatment study evaluating cognition in adult humans or animals 
, we reported that treatment (at cell phone levels of 918 MHz/0.25–1.05 W/kg; pulsed and modulated) over 7–9 months prevented or reversed cognitive impairment in AD Tg mice bearing the APPsw mutation. Even normal mice showed EMF-induced cognitive enhancement in that initial study. For AD mice, the primary mechanism of cognitive benefit appears to be a suppression of brain Aβ aggregation into neuritic plaques, presumably resulting in greater Aβ efflux from the brain 
. Moreover, the cognitive benefits of long-term EMF treatment to both AD mice and normal mice occurs without any evidence of tissue abnormalities in either the brain or peripheral tissues, without any evidence of increased oxidative stress in the brain, and without any increase in DNA damage to circulating blood cells. Thus, long-term EMF treatment in mice appears safe in having no deleterious side effects across multiple sensitive markers of brain/body function.
In a second study that involved AD Tg mice bearing the APPsw+PS1 double mutation, we reported that daily EMF treatment for one month enhances the impaired brain mitochondrial function of these AD mice, as well as the brain mitochondrial function of normal mice 
. These EMF-induced mitochondrial enhancements occurred through “non-thermal" mechanisms because brain temperatures were either stable or decreased during and after daily high frequency EMF treatments. Since this EMF-induced mitochondrial enhancement in AD mice was linked to dramatic 5–10 fold elevations in soluble Aβ within the same mitochondria, EMF treatment disaggregated toxic Aβ oligomers therein, apparently resulting in very high monomeric Aβ levels (which are innocuous to mitochondrial function). Our mitochondrial function results in Dragicevic et al. 
collectively suggest that brain mitochondrial enhancement may be a primary mechanism through which long-term EMF treatment provides cognitive benefit to both AD mice and NT mice.
In a third study, we have most recently reported that two months of daily EMF treatment enhances neuronal activity in the entorhinal cortex of aged Alzheimer's Tg mice and littermate NT mice 
. This EMF-induced enhancement of neuronal activity was temporally linked to cognitive benefit in the same animals. Based on these results, we have suggested that EMF treatment could be a viable approach to counter the neuronal hypo-activity that occurs very early in AD pathogenesis 
It is noteworthy that our prior EMF studies 
identified the first biologic mechanisms that could explain the EMF-induced cognitive benefits, which we also reported in normal and Alzheimer's Tg mice (i.e., anti-Aβ aggregation, mitochondrial enhancement, and enhanced neuronal activity). The fact that our long-term EMF treatment involves pulsed, modulated GSM signal is important because a recent, comprehensive review concluded that EMF-induction of biologic effects occurs primarily with GSM-type modulation and a pulsed signal - not continuous wave or UMTS fields 
Our initial behavioral study in AD Tg mice involved long-term EMF treatment to young adult APPsw mice (from 2–7.5 months of age), as well as to older APPsw adults (from 5–13.5 months of age) 
. Inasmuch as Aβ pathology was not yet well established when treatment began for these mice, the beneficial effects reported were most relevant to human EMF treatment in pre-symptomatic/prodromal AD or in mild cognitive impairment (MCI), the prelude to AD. The present study extends our earlier findings by evaluating the impact of long-term EMF treatment given to very old 21–26 month-old APPsw and APPsw+PS1 mice, both of which bear much heavier brain Aβ burdens/Aβ levels than the APPsw mice in our initial work. In these aged mice with advanced Aβ pathology, we evaluated an array of behavioral, neuropathologic, and physiologic measures to get a clearer understanding of how long-term EMF treatment might impact the aged and heavily Aβ-burdened brain. We report a profound ability of long-term EMF treatment to reverse brain Aβ deposition, induce changes in regional cerebral blood flow, and provide selected cognitive benefits - all without induction of brain hyperthermia.