What is “Alzheimer’s Dementia”?

• Alzheimer’s disease is a degenerative brain

disease and the most common cause of
dementia. Dementia is a syndrome—a group
of symptoms—that has a number of causes.
 Characteristics

• Most common cause of dementia; accounts for an estimated 60

percent to 80 percent of cases. Autopsy studies show that about
half of these cases involve solely Alzheimer’s pathology; many of
the remaining cases have evidence of additional pathologic
changes related to other dementias. This is called mixed
pathology and if recognized during life is called mixed dementia.
• Difficulty remembering recent conversations, names or events is
often an early clinical symptom; apathy and depression are also
often early symptoms. Later symptoms include impaired
communication, disorientation, confusion, poor judgment,
behavior changes and, ultimately, difficulty speaking, swallowing
and walking.
• Revised guidelines for diagnosing Alzheimer’s were
proposed and published in 2011. They recommend that
Alzheimer’s bconsidered a slowly progressive brain
disease that begins well before clinical symptoms emerge.
• The hallmark pathologies of Alzheimer’s are the
progressive accumulation of the protein fragment beta-
amyloid (plaques) outside neurons in the brain and
twisted strands of the protein tau (tangles) inside
neurons. These changes are eventually accompanied by
the damage and death of neurons.
Signs!!
Signs!!
Signs!!
 Prevalence

Ages of people with Alzheimer’s disease in the United States, 2017.

Percentages do not total 100 because of rounding. Created from
data from Hebert and colleagues
 Growth of the oldest-old population

Projected number of people age 65 and older (total and by age group) in the
U.S. population with Alzheimer’s dementia, 2010 to 2050. Created from data
from Hebert and colleague
Research Update A of Alzheimer’s Dementia
 Recent
publications from the Alzheimer's Disease Neuro
imaging Initiative
:
Reviewing progress toward improved AD clinical
trials
The Alzheimer's Disease Neuroimaging Initiative
(ADNI) has continued development and
standardization of methodologies for biomarkers
and has provided an increased depth and
breadth of data available to qualified
researchers. This review summarizes the over
400 publications using ADNI data during 2014
and 2015.
 Results
Structural and functional changes, including subtle changes to
hippocampal shape and texture, atrophy in areas outside of
hippocampus, and disruption to functional networks, are detectable
in presymptomatic subjects before hippocampal atrophy

• In subjects with abnormal β-amyloid deposition (Aβ+), biomarkers

become abnormal in the order predicted by the amyloid cascade
hypothesis;
Cerebrovascular risk factors may interact with Aβ to increase white-
matter (WM) abnormalities which may accelerate Alzheimer's disease
(AD) progression in conjunction with tau abnormalities;

• Cognitive decline is more closely linked to tau than Aβ deposition;

>Different patterns of atrophy are associated with
impairment of memory and executive function and
may underlie psychiatric symptoms;
• Structural, functional, and metabolic network connectivities are
disrupted as AD progresses. Models of prion-like spreading of Aβ
pathology along WM tracts predict known patterns of cortical Aβ
deposition and declines in glucose metabolism;

>New AD risk and protective gene loci have been

identified using biologically informed approaches;

• Cognitively normal and mild cognitive impairment (MCI) subjects

are heterogeneous and include groups typified not only by
“classic” AD pathology but also by normal biomarkers,
accelerated decline, and suspected non-Alzheimer's pathology;
Selection of subjects at risk of imminent decline on the
basis of one or more pathologies improves the power of
clinical trials;
• Sensitivity of cognitive outcome measures to early changes in cognition
has been improved and surrogate outcome measures using longitudinal
structural magnetic resonance imaging may further reduce clinical trial
cost and duration;
Advances in machine learning techniques such as neural
networks have improved diagnostic and prognostic
accuracy especially in challenges involving MCI subjects;
and
• (Network connectivity measures and genetic variants show promise in
multimodal classification and some classifiers using single modalities are
rivaling multimodal classifiers.
Amyloid tracers binding sites in autosomal dominant and sporadic Alzheimer's disease

• Amyloid imaging has been integrated into diagnostic

criteria for Alzheimer's disease (AD). How amyloid
tracers binding differ for different tracer structures
and amyloid-β aggregates in autosomal dominant AD
(ADAD) and sporadic AD is unclear.
Methods
• Binding properties of different amyloid tracers were
examined in brain homogenates from six ADAD
with APPswe, PS1 M146V, and PS1 EΔ9 mutations, 13
sporadic AD, and 14 control cases.
• Result
3H-PIB, 3H-florbetaben, 3H-AZD2184, and BTA-1 shared a high- and a

varying low-affinity binding site in the frontal cortex of sporadic AD.

AZD2184 detected another binding site (affinity 33 nM) in the frontal
cortex of ADAD. The 3H-AZD2184 and 3H-PIB binding were significantly
higher in the striatum of ADAD compared to sporadic AD and control.
Polyphenol resveratrol showed strongest inhibition on 3H-AZD84
binding followed by 3H-florbetaben and minimal on 3H-PIB.

• Discussion
This study implies amyloid tracers of different structures detect
different sites on amyloid-β fibrils or conformations.
 Molecular markers of neuropsychological functioning
and Alzheimer’s disease
• Background: The current project sought to examine molecular
markers of neuropsychological functioning among elders with and
without Alzheimer’s disease (AD) and determine the predictive
ability of combined molecular markers and select
neuropsychological tests in detecting disease presence.
• Methods: Data were analyzed from 300 participants (n 5150, AD and
n 5150, controls) enrolled in the Texas Alzheimer’s Research and
Care Consortium. Linear regression models were created to examine
the link between the top five molecular markers from our AD blood
profile and neuropsychological test scores. Logistical regressions
were used to predict AD presence using serum biomarkers in
combination with select neuropsychological measures.
• Results:
Using the neuropsychological test with the least amount of
variance overlap with the molecular markers, the combined
neuropsychological test and molecular markers was highly
accurate in detecting AD presence.
 Conclusion
• A combination of blood-based biomarkers 1 cognitive measure
1demographics has yielded excellent diagnostic accuracyin detecting the
presence of AD even in early stages. The current project sought to further
refine prior research examining the strength of the relationship of the top
five molecular markers from our recently published Adalgorithm with
neuropsychological test scores. The molecular markers accounted for a
significant amount of variance in neuropsychological test scores,
specifically with measures related to memory. This finding is not
surprising given that the bloodbased biomarker algorithmis highly
accurate in detecting AD where memory deficits are the core cognitive
feature. Among the neuropsychological measures, the COWAT a measure
of phonemic fluency had the least amount of shared variance with the
molecular markers. Combining five molecular markers with this single
neuropsychological test yielded an excellent overall accuracy of 91%.