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NerveCenter New AD diagnostic criteria being developed.

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We heard in May that they
were having some problems
with skin cancer, but this
one came out of the blue.
—Adam S. Fleisher, MD
Aβ-lowering therapy, after years or decades
of use, might well cause a rebound, as is true
with sudden withdrawal of many drugs,” he
says. “Such a rebound might translate into
sudden excess levels of Aβ that could aggregate, oligomerize, and deposit in the brain as
an acute event, undoing the years or decades
of prophylaxis.” However, it is also possible
that such rebound could be manageable with
concomitant anti-Aβ antibody treatment “so
that there is an accelerated clearance mechanism-in-waiting,” he says.
The bottom line is that many questions about novel treatments are yet to have
answers—especially the question of whether
treatment will have any effect if amyloid deposits already exist. “Few studies have used
mouse models that have weeks or months of
amyloidosis for just this reason,” he says. “Even
total genetic silencing of APP metabolism in a
mouse with extensive cerebral amyloidosis is
followed by long persistence of pathology,” according to an editorial he wrote in response to
a study published in PloS Medicine.5
Gandy, too, says the increase in skin cancers suggests that semagacestat may have a
deleterious effect on Notch signaling. “This
particular GSI was known to inhibit processing of Notch, and I would attribute the skin
cancers to that known action and risk. However, the acceleration of cognitive decline is
difficult to judge in the absence of plaque
New AD Diagnostic Criteria
Being Developed
At this year’s Alzheimer’s Association International Conference on Alzheimer’s
Disease—which took place July 10–15 in Honolulu, Hawaii—initial draft reports from
3 workgroups convened by the National Institute on Aging (NIA) and the Alzheimer’s
Association presented recommendations for updating diagnostic criteria for Alzheimer disease (AD). The criteria have not had a major update in 25 years.
According to the official announcement of the plan, the proposed changes
should better reflect the various stages of the disease, as well as include recommendations on the use of disease biomarkers. William Thies, MD, Chief Medical and
Scientific Officer of the Alzheimer’s Association, notes that the utility of biomarkers
differs at each of the 3 recognized stages of the disease, although their reliability and
validity in diagnosis will require additional research.
Further input will be solicited by the NIA and the Alzheimer’s Association at a new
website, Once comments and suggestions
from the scientific community have been considered, draft criteria will be published
in a peer-reviewed journal and systematically validated.
According to the announcement, among the most important advances since the
1984 Alzheimer criteria were approved are recognition that AD-driven changes in the
brain, together with associated cognitive deficits, develop slowly, over many years,
with dementia coming only at the end stage. Therefore, the criteria will acknowledge
that brain changes associated with AD can occur long before dementia symptoms,
among other important advances
The foci of the 3 working groups mirror the 3 stages of AD: preclinical disease,
mild cognitive impairment, and Alzheimer dementia. Their agendas include:
• Developing a research agenda focusing on identifying methods of assessment
that can help predict a person’s risk for the disease, including possible biomarkers to identify early cognitive decline before symptoms appear.
• Developing criteria to identify mild cognitive changes prior to dementia and
better differentiation between mild cognitive impairment and AD.
• Revising the current criteria for AD diagnosis.—KS
DOI: 10.1002/ana.22250
load data with PiB or AV45.”
New evidence for sequential cleavage at
Aβ 42 and Aβ 40 might suggest that certain
GSI dosing strategies may actually increase
Aβ 42 if the GSI blocks the second cut but
not the first, he says.6 Other new data show
that semagacestat has deleterious effects on
dendritic spine structure in a mouse model
of AD, which in turn impair cognition.7
“I don’t see the failure of the Lilly GSI as
a fatal blow to either the amyloid hypothesis
or to GSIs, although this re-emphasizes the
likely superiority of gamma-secretase modulators over GSIs,” Gandy concludes.
mum—at the stage of mild cognitive impairment. If these high-risk populations turn out
to be the key target populations for intervention, then many of them will be healthy at
the time intervention begins, and intervention will need to be sustained over years, decades, or even for life.”
Even if Aβ rebound does not prove to
be dangerous when GSI treatment is interrupted or discontinued, there could be other
risks, he notes. “Acute withdrawal of any
1. Cook JJ, Wildsmith KR, Gilberto DB, et al.
Acute gamma-secretase inhibition of nonhuman primate CNS shifts amyloid precursor
protein (APP) metabolism from amyloid-beta
production to alternative APP fragments
without amyloid-beta rebound. J Neurosci
2. Bateman RJ, Siemers ER, Mawuenyega KG,
et al. A gamma-secretase inhibitor decreases
amyloid-beta production in the central nervous
system. Ann Neurol 2009;66:48–54.
3. Portelius E, Zhang B, Gustavsson M, et al. Effects
of γ-secretase inhibition on the amyloid β isoform
pattern in a mouse model of Alzheimer’s disease.
Neurodegenerative Dis 2009;6:258–262.
4. Rinne JO, Brooks DJ, Rossor, MN, et al. C-PiB
PET assessment of change in fibrillar amyloid-β
load in patients with Alzheimer’s disease treated with bapineuzumab: a phase 2, doubleblind, placebo-controlled, ascending-dose
study. Lancet Neurol 2010;9:363–372.
5. Gandy S, Heppner FL. Breaking up (amyloid) is
hard to do. PLoS Med 2005;2(12):e417.
6. Fukumori A, Fluhrer R, Steiner H, Haass C.
Three-amino acid spacing of presenilin endoproteolysis suggests a general stepwise
cleavage of gamma-secretase-mediated intramembrane proteolysis. J Neurosci 2010;30:
7. Bittner T, Fuhrmann, Burgold S, et al. Gammasecretase inhibition reduces spine density in vivo
via an amyloid precursor protein-dependent
pathway. J Neurosci. 2009;29:10405–10409.
DOI: 10.1002/ana.22249
Volume 68, No. 4
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