Dementia and Alzheimers Flashcards
1
Q
Dementia
A
A serious loss of global cognitive abilities which is significant enough
to interfere with independent, daily functioning and is markedly more
than what is caused by normal aging
2
Q
Common Kinds of
Dementia
A
- Alzheimer’s disease (AD): hallmark
accumulation of beta-amyloid plaques and
twisted strands of the protein tau (tangles)
inside neurons in the brain. Followed by
neuronal death and brain tissue atrophy.
Most common cause of dementia,
estimated to be 60% to 80% of all cases. - Vascular dementia: occurs commonly from
blood vessel blockage, e.g., stroke, leading
to areas of dead tissue. - Lewy body disease: abnormal aggregations
(or clumps) of the protein alpha-synuclein in
neurons. Such clumps leads to dementia
with Lewy bodies (DLB). About 5% of older
individuals with dementia have DLB alone,
but most with DLB also have AD pathology. - Creutzfeldt-Jacob dementia (CJD):abnormal
misfolded prion protein. Gets worst fast. - Frontotemporal dementia (FTD): second
most common form of dementia in those
younger than 65 years.
3
Q
Pathological
progression of AD
A
- Stage A: Pre-clinical. Subtle changes
in the brain, biomarkers (e.g., Aβ 1-42,
phospho-Tau) in CSF and blood, No
symptoms or memory loss yet. - Stage B: Mild Cognitive Impairment.
Noticeable impairments in memory
and cognitive functions. Daily
functions intact. - Stage C: Dementia. Severe
symptoms, major mood and
personality changes, paranoia. Loss
of independence. Decreased or
inability to control bodily functions,
loss of speech
4
Q
Neuroimaging
Dementing Brain
A
- AD brains undergo severe atrophy.
- AD diagnosis was dependent on post-
mortem examination of the brain
morphology. - Now, PET imaging is used to look for
markers of AD in living people. This
has transformed AD diagnosis. - Tau radiotracers (e.g., [ 18F]Flortaucipir)
are utilized to image neurofibrillary
tangles. - Several radiotracers are available for
detection of amyloid plaques (e.g.,
[ 18F]Florbetapir)
5
Q
Genetic Risk Factors
A
- Early-onset AD: onset of dementia
symptoms before the age of 65. The main
cause: one’s genetic predisposition
facilitated by familial inheritance of
mutations in specific genes: amyloid
precursor protein (APP), presenilin 1
(PSEN1), and presenilin 2 (PSEN2). Both
PSEN1 and PSEN2 are part of γ-secretase,
an enzyme that processes APP. - Late-onset AD: Common form where
symptoms manifest after 65 years of age.
No specific genes. Several risk genes. E.g.,
risk increases in carriers with at least one
copy of the APOE4 allele of the
Apolipoprotein E (APOE4) gene.
6
Q
Tangles
A
- Under pathological conditions, tau
protein is hyperphosphorylated at an
abnormal levels. - The hyperphosphorylated tau proteins
polymerized into paired helical
filaments (PHF) and straight filaments
(SF) referred as neurofibrillary tangles. - The loss of normal tau function leads
to pathological disruptions in
structural and regulatory functions of
the neuronal cytoskeleton. - Abnormal cytoskeleton affects normal
cellular functions of neurons such as
maintenance of appropriate
morphology, and axonal transport
leading to Wallerian degeneration,
causing synaptic dysfunction and
neurodegeneration.
Structure of microtubule binding domain of tau protein with phosphorylation sites
(Inset). The hyperphosphorylation of tau by glycogen synthase kinase 3β (GSK-
3β), cyclin-dependent kinase (cdk5) results in microtubules destabilization
followed by detachment of tau and self-aggregation into paired helical filament.
7
Q
So, what’s amiss? Tau!
A
- Soluble Ab causes neuronal hyperexcitability, leading to
impaired network oscillations, and overt seizures (multiple
mechanisms: impaired glutamate reuptake, inhibitory
GABAergic interneuron dysfunction, abnormal ion channel
modulation, and structural dendritic degeneration). - Genetic deficiency of tau confers protection against the
above-mentioned phenotypes. This suggests tau is
downstream of Ab in the pathogenic cascade. - Soluble Tau suppresses neuronal activity independently of
tangle formation. Tau binds to synaptogyrin-3 and reduces
synaptic neurotransmitter release. It also suppresses
nuclear transcription and protein translation. - From the perspective of neural circuit activation, tau and
Ab have antagonistic effects. This relationship has not been
explored therapeutically. Most efficacious approach to slow
AD may be to combine anti-Ab and anti-tau therapies.
8
Q
APOE isoforms
in Alzheimer’s Disease
A
- Studies show a link between APOE genotype
and multiple proteinopathies, including that of
Ab in Alzheimer’s disease. - APOE*ε4 is consistently associated with
greater Ab deposition in the brains of
cognitively healthy elderly individuals,
individuals with mild cognitive impairment,
and individuals with AD. - APOEε2 is associated with reduced
cognitive decline during ageing (protective),
but APOEε4 is dominant when present. - Insufficient Ab clearance from the brain leads
to Ab accumulation. This accumulation initiates
Ab oligomerization and accelerates
subsequent aggregation and fibrillogenesis,
leading to deposition of insoluble Ab in the
brain parenchyma (amyloid plaques) and in the
vascular wall (cerebral amyloid angiopathy).
9
Q
Down’s syndrome and Dementia
A
- Most people with Down syndrome (DS) end
up with Alzheimer disease (AD) pathology by
40 years of age. - Chromosome 21 carries the APP gene.
- This association provides an opportunity to
understand the temporal progression of AD
pathogenesis and provides unique insights for
AD in the general population. - Understanding the role of amyloid precursor
protein in DS might lead to a greater
understanding of its role in both sporadic AD
and familial AD in the general population. - The study of neuroinflammation in DS might
provide unique insights into AD in the
general population.
