Writing in the December 30, 2019
online issue of Neurology, researchers at University of California San
Diego School of Medicine and Veterans Affairs San Diego Healthcare System
report that accumulating amyloid — an abnormal protein linked to
neurodegenerative conditions such as Alzheimer’s disease (AD) — occurred faster
among persons deemed to have “objectively-defined subtle cognitive
difficulties” (Obj-SCD) than among persons considered to be “cognitively
normal.”
Classification
of Obj-SCD, which has been previously shown to predict progression to mild
cognitive impairment (MCI) and dementia, is determined using non-invasive but
sensitive neuropsychological measures, including measures of how efficiently
someone learns and retains new information or makes certain types of errors.
The new
findings, say authors, suggest that Obj-SCD can be detected during the
preclinical state of AD when amyloid plaques are accumulating in the brain,
neurodegeneration is just starting, but symptoms of impairment on total scores
on thinking and memory tests have not yet been recorded.
“The scientific
community has long thought that amyloid drives the neurodegeneration and
cognitive impairment associated with Alzheimer’s disease,” said senior author
Mark W. Bondi, PhD, professor of psychiatry at UC San Diego School of Medicine
and the VA San Diego Healthcare System. “These findings, in addition to other
work in our lab, suggest that this is likely not the case for everyone and that
sensitive neuropsychological measurement strategies capture subtle cognitive
changes much earlier in the disease process than previously thought possible.
“This work, led
by Dr. Kelsey Thomas, has important implications for research on treatment
targets for AD, as it suggests that cognitive changes may be occurring before
significant levels of amyloid have accumulated. It seems like we may need to
focus on treatment targets of pathologies other than amyloid, such as tau, that
are more highly associated with the thinking and memory difficulties that
impact people’s lives.”
Study participants
were enrolled in the Alzheimer’s Disease Neuroimaging Initiative (ADNI), an
on-going effort (launched in 2003) to test whether regular, repeated brain
imaging, combined with other biological markers and clinical assessments, can
measure the progression of MCI and early AD. Seven hundred and forty-seven
persons were involved in this study: 305 deemed cognitively normal, 153 with
Obj-SCD and 289 MCI. All underwent neuropsychological testing and both PET and
MRI scans.
The research
team found that amyloid accumulation was faster in persons classified with
Obj-SCD than in the cognitively normal group. Those classified as Obj-SCD also
experienced selective thinning of the entorhinal cortex, a region of the brain
impacted very early in Alzheimer’s disease and associated with memory,
navigation and perception of time. Persons with MCI had more amyloid in their
brain at the start of the study, but they did not have faster accumulation of
amyloid compared to those with normal cognition. However, those with MCI had
more widespread temporal lobe atrophy, including the hippocampus.
Broadly
speaking, scientists believe that for most people, AD is likely caused by a
combination of genetic, lifestyle and environmental factors. Increasing age is
a primary, known risk factor. The amyloid hypothesis or amyloid cascade model
posits that accumulating amyloid protein plaques in the brain kill neurons and
gradually impair specific cognitive functions, such as memory, resulting in AD
dementia. However, many scientists are now questioning the amyloid hypothesis
given the large number of clinical trials in which drugs targeted and
successfully cleared amyloid from the brain but did not impact the trajectory
of cognitive decline.
The ability to
identify those at risk for AD before significant impairment and before or
during the phase of faster amyloid accumulation would be a clinical boon, said
authors, providing both a way to monitor disease progression and a window of
opportunity to apply potential preventive or treatment strategies.
Currently, both
approaches are limited. Some risk factors for Alzheimer’s can be minimized,
such as not smoking, managing vascular risk factors such as hypertension or
following a healthy diet with regular exercise. There are a handful of
medications approved for treating symptoms of AD, but as yet, there is no cure.
“While the
emergence of biomarkers of Alzheimer’s disease has revolutionized research and
our understanding of how the disease progresses, many of these biomarkers
continue to be highly expensive, inaccessible for clinical use or not available
to those with certain medical conditions,” said first author Thomas, PhD,
assistant professor of psychiatry at UC San Diego School of Medicine and
research health scientist at the VA San Diego Healthcare System.
“A method of
identifying individuals at risk for progression to AD using neuropsychological
measures has the potential to improve early detection in those who may
otherwise not be eligible for more expensive or invasive screening.”
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