by Carl Sherman
February 6, 2019
viruses from the Herpesviridae family (seen using an electron micrograph),
including varicella-zoster (chickenpox), and herpes simplex type 1 and
2 (HSV-1, HSV-2) Source: CDC
Suddenly, it seems, Alzheimer’s research is
crawling with microbes.
An outlandish metaphor, perhaps, but the
growing attention to viruses (and to a lesser extent bacteria) in the search
for the origins of Alzheimer’s disease (AD) is hard to ignore. On the cellular,
molecular, and population level, recent research has aroused excitement.
Clinical trials are underway.
The concept is not new. More
than a century ago, Alois Alzheimer considered a role for infection in the
disease that bears his name. In the 1990s, Ruth Itzhaki of Oxford and University of
Manchester in Britain demonstrated the presence of herpesvirus DNA in the
post-mortem brains of the elderly and of people with AD, especially around
Other investigators have found
evidence implicating bacteria, particularly spirochetes (including
the pathogen responsible for Lyme disease) and chlamydia pneumoniae. One recent paper
suggested a pathogen involved in chronic gum disease plays
Still, “Everyone laughed at the idea or was
hostile,” says Itzhaki. “It’s been a constant battle for over 25 years.”
Researchers have resisted the challenge to the
long-dominant amyloid cascade hypothesis of AD because it questions their own
work, she believes. “And most don’t know much about viruses, particularly the
concept of viral latency—that people can be infected but not affected.”
Such latency is evident in herpesviruses, the
microbes for which AD-link evidence is strongest. Almost everyone is infected
with HSV1, which is responsible for cold sores, and the virus is present
in normal as well as AD brains. The difference, Itzhaki conjectures, lies in
periodic reactivation due to stress or immunosuppression, which allows HSV to
kill brain cells. “Damage accumulates,” she says, “and leads to AD.” Carriers
of ApoE4, the strongest genetic risk factor for AD, seem particularly prone to
HSV1 reactivation, she observes.
Lately, however, “far more
people have come into the field [of microbe-AD research],” Itzhaki says. “It
started happening about eight years ago, and the number of researchers has
increased gradually.” In 2017 and 2018, papers from Taiwan provided “the first population-level evidence for a link between
herpes infection and senile dementia,” she wrote in a commentary in the Journal
of Alzheimer’s Disease. “And last June, two papers that augment some of our
data caught the public eye.”
Neuroscientists whose AD
research is unrelated to microbes see a similar trajectory. “I remember hearing
about this work back in the late 1990s,” recalls Robert Vassar, professor of cellular and
molecular biology at Northwestern University. “I didn’t think much of it at the
time. It seemed farfetched.”
More recent research, he says, is “pretty
compelling…. In retrospect, if you look at the progression of these studies,
there’s certainly a lot of circumstantial evidence supporting the microbial
hypothesis.” Although much more research needs to be done, “it’s
paradigm-shifting work,” he says.
To Eliezer Masliah, director of the division of
neuroscience at the National Institute of Aging (NIA) and a member of the Dana
Alliance for Brain Initiatives, growing interest in microbes reflects, in part,
“more intense questioning of traditional amyloid-tau cascade hypotheses.
There’s a search for alternatives.”
There is also “new, very
provocative data coming out in recent years, which has contributed to
heightened interest,” he says. He, like Itzhaki, points to two papers published
in Neuron in July 2018.
“All the other studies were more
correlational, descriptive, equivocal,” says Masliah. “These are looking at the
issue in a more mechanistic way.”
In one paper, which was funded by the NIA,
researchers at Icahn School of Medicine at Mt. Sinai and at Arizona State
University analyzed genomic, transcriptomic, proteomic, and histopathological
data from postmortem brains of people with signs of AD and others without.
Applying advanced computation methods to tissue from three large brain banks,
they explored the interaction of viral DNA and RNA fragments with neuronal
They found that human herpesviruses 6 and
7(HHV6,7) were more common in brains that had signs of AD than in non-AD
brains, and that viral levels correlated with the severity of dementia. These
viruses, moreover, appeared to have an effect on molecular processes in
neurons. In particular, they altered the expression of genes that have been
implicated in AD, and influenced pathways involved in amyloid production.
Of note, points out Mack Mackiewicz of NIA, the investigators
used an “unbiased approach”: they were not testing a hypothesis involving a
specific virus, but looking more widely for clues to molecular processes
underlying AD neuropathology that might suggest new drug targets. The HHV6-7
connection emerged from the data.
Studies reported in the other paper demonstrated that
introducing herpesviruses into lab dishes of neurons and into the brains of
genetically modified mice triggers the formation and deposition of beta-amyloid
(Aβ), in forms resembling the characteristic plaques of AD.
Additional experiments described the
subcellular process by which Aβ protected the mice against HSV1-related
encephalitis and inhibited viral growth in cell culture.
The study came out of the
Harvard laboratories of Rudolph Tanzi and Robert Moir, adding a new chapter to
10 years of research that gave rise to what they call the antimicrobial protection hypothesis of
Tanzi and Moir have accumulated
evidence that Aβ, long thought to be a “functionless” protein, is actually an
antimicrobial peptide (AMP), one of a class of molecules important in innate
immunity. Against certain pathogens, “Aβ is more powerful than penicillin,”
says Tanzi, professor of neurology at Harvard and
also a member of the Dana Alliance.
AMPs, “the most primitive, ancient immune host
response,” protect against unwelcome organisms and substances by forming
extracellular traps to bind and sequester them. “That’s what plaques are in the
brain,” he says.
The hypothesis accords microbes a key if
limited role in AD; their presence triggers the generation of beta amyloid as a
defensive measure. Amyloid induces the production of neurofibrillary tangles,
which kill neurons and activate microglia. As neuroinflammation gathers steam, neurons
die. “Amyloid is the match, tangles are brush fires, neuroinflammation is a
forest fire,” says Tanzi. “Microbes are what’s lighting the match.”
In this formulation, says Tanzi, AD is an
“auto-innate immune disorder,” in which amyloid takes the place of antibodies
in conventional autoimmune disorders.
The 2018 Neuron paper provides a clear, graphic
instance of the “seeding” process that begins the cascade.
The theory can account for the
fact that a broad spectrum of bacteria and viruses have emerged as possible AD
factors. “We don’t have a favorite microbe; we’re saying a bunch of different
ones may be involved,” Tanzi says. There’s a place for the amyloid cascade
hypothesis as well, as one step along the road to AD. Since innate immunity is
a general reaction to foreign material, the theory suggests a mechanism by
which other factors might raise AD risk, such as fine particulate air
pollution. (see “Air Pollution Linked to Higher Risk of Dementia”)
Even as the evidence for an AD-microbe link
grows stronger, “we are still struggling with ideas of cause and effect,”
cautions Mackiewicz. “It is not known whether microbes are causative or a
passenger of the AD process.” Long-dormant viruses may be activated by a
disease process already underway, in other words, rather than a factor in
The role of viruses and other microbes,
ultimately, must be understood in the context of other factors, Masliah says.
“Aging, neuropathology, the amyloid cascade, certain genotypes—what we’ve
learned is that all things leading to the pathogenic process of AD are
synergistic; that multiple hits, multiple steps are involved in an interactive