Alzheimer’s Disease Flashcards
Alzheimer’s disease
- Definition
- Prevalence of cases of dementia
- Age
Neurodegenerative disorder characterized by memory loss, impairment in thinking and reasoning, changes in behavs
60-70%
After 65 years old, doubling in risk every 5 years
DSM-5 criteria for Alzheimer’s
- Mild neurocognitive disorder (MCI) due to AD
- Major neurocognitive disorder (dementia) due to AD
- Appears slowly + gradual progression
- MCI: 1+ cog domains impaired; intact ability to complete daily activities
- Dementia: 2+ cog domains impaired; impaired ability to complete daily activities
Probable vs Possible Alzheimer’s
Probable:
- Evidence of AD genetic mutation
- OR impairment in memory + one other cog domain, progressive gradual decline in cognition, no other possible etiology
- Otherwise, possible AD diagnosed
Diagnostic evaluation of AD:
- Detailed clinical history
- Neurological evaluation
- Neuropsychological evaluation
- Biomarker studies
- Memory loss as earliest and most prominent symptom; insidious onset and gradual progression
— - Physician evaluates for possible causes of cognitive decline (mild impairment on mental status screening if AD)
— - Longitudinal examinations at 6 month or 1 year intervals; reveal gradually progressive decline if AD)
— - PET imaging, MRI structural imaging, CSF, blood tests to rule out other possible causes
CSF biomarkers of Alzheimer’s:
- Amyloid plaques (what, how it’s formed, how it’s hydrolyzed/cleaved, in abnormal conditions)
- Neurofibrillary tangles (tau protein, how tangles form, what they do)
Result of this?
- Insoluble deposits of beta-amyloid (AB) peptides
- Formed when amyloid precursor protein (APP) is cleaved by proteases beta-secretase and gamma-secretase
- Cleaved by beta-pathway (b-secretase and y-secretase produce insoluble AB) or alpha-pathway (a-secretase and b-secretase do not produce insoluble AB)
- Under abnormal conditions, b-pathway happens more and AB misfolds, aggregating into amyloid plaques which weaken communication at synapses
—— - Tau are in microtubules to stabilize them
- Tangles form through hyperphosphorylated tau which move from axons to cell bodies and form paired helical filaments; Aggregates misfolded tau and propagates across synapses into neurons to make healthy tau misfold
— - Build up of amyloid plaques and neurofibrillary tangles leads to breakdown of synapses and neuronal death
- Microglia activated by amyloid plaques can trigger inflammatory cytokines which damage neurons; can also remove synapses thru phagocytosis, leading neurons to die and synapse malfunction
Where does amyloid pathology start + where does it spread to?
How many years does it happen before symptoms of Alzheimer’s?
How about tau pathology?
- Begin in medial prefrontal cortex (mPFC) and posterior medial regions (PCC/MPC)
- Spreads to association cortices before primary and sensory cortices (frontal, temporal, parietal), brainstem, then cerebellum
- 10-20 years before symptoms of AD, tapers off before MCI; appears before tau pathology and facilitates it
— - Begins in entorhinal cortex (ERC) in medial temporal lobe (MTL)
- Spreads thru hippocampus and other MTL regions, then ventral temporal cortex (VTC) and cingulate cortex (CC), then neocortex and medial prefrontal cortex (cPFX)
- Doesn’t taper off; linked to brain atrophy
Where is early atrophy seen in Alzheimer’s disease? (5)
What function is reduced?
Entorhinal cortex
Hippocampus
Medial parietal cortex
Lateral parietal cortex
Inferior temporal cortex
—
Cholinergic function (acetylcholine), caused by basal forebrain cell loss
- Involved in attention, learning, memory
Stages of Alzheimer’s disease:
- Preclinical
- Mild cognitive impairment (MCI)
- Mild dementia
- Moderate dementia
- Severe dementia
PRECLINICAL:
- Amyloid and tau pathology begin
- Usually asymptomatic or only subtle cog decline
—
MCI:
- Decline in 1+ cog areas but can still perform daily activities
- High risk if developing dementia
—
MILD:
- Usually when AD diagnosed
- Impaired memory for recent events, judgment and problem solving, and difficulty organizing and expressing thoughts
- Impacts daily functioning but only require minor help
—
MODERATE:
- Greater memory loss (personal details, filling in gaps with made up stories), poorer judgment and deepening confusion (confusing family, surroundings), changes in personality and behav (agitated, delusion/hallucinations)
- Need help with daily activities, including self-care
—
SEVERE:
- Impaired communication (words that don’t make sense), motor function (unable to walk without assistance, unable to sit/hold head up without support, muscles rigid and reflexes abnormal, loss of ability to swallow and control bladder/bowel)
- Limb and whole body contractures until eventual fetal position
- Need assistance with personal care
- Death from pneumonia or aspiration
Protective factors (3)
Risk factors (5)
(Alzheimer’s)
High education attainment
Physical exercise
Dietary factors (low saturated fats)
—
Age
Genetics (early onset familial AD, ApoE4)
Low education attainment
Cardiovascular disease and risk factors (hypertension and obesity)
Traumatic brain injury
Cognitive reserve hypothesis
(Alzheimer’s)
Ability to make flexible and efficient use of available brain reserve when performing tasks
- Having cognitively active lifestyles increases connections between neurons, enabling the brain to compensate for pathological changes by using alt networks to complete cognitive tasks
- Higher reserve means can tolerate more AD pathology before clinical symptoms become apparent
Sporadic vs Familial Alzheimer’s disease
Sporadic - Occurs irregularly without inherited pattern
Familial:
- Early onset - Mutations in amyloid precursor protein (APP) gene, presenilin 1 (PSEN1) gene, presenilin 2 (PSEN2) gene
- Late onset - E4 allele of apolipoprotein E (ApoE) gene, transports cholesterol between cells in nervous system but assoc with accumulation of AB
Alzheimer’s disease memory impairment:
- Declarative vs Procedural
- Recent vs Remote info
- Declarative most impaired, procedural better preserved
- Recent memory impaired, remote preserved (esp emotionally toned memories) until late stages
Orientation (4)
(Alzheimer’s)
To person: Awareness of name, age, date of birth
To place: Awareness of city, building, address
To time: Awareness of day, year, season
To situation/circumstances: Awareness that an event has taken place and the impact of that event
First to last impacted: Time, place, pwrson
Language impairment in Alzheimer’s:
- Anomia
- Global aphasia
Starts w/ tip of tongue exp that become severe enough to interrupt flow of speech
- Leads to anomia (word-finding difficulty)
—
Reading skill and verbal comprehension worsen, prosody (rhythm, melody, emotional intonation) affected in late stage
- Global aphasia = Severe impairment across all aspects of language
Executive dysfunction and impaired higher-order visual processing in Alzheimer’s disease
- Problems w/ judgment, problem solving, planning, abstract reasoning
- Manifests as failure to manage complex tasks and poor task persistence + behavioural disinhibition (maybe from disorientation)
— - Agnosia: Impaired recognition (may evolve into prosopagnosia, impaired facial recognition)
- Impaired spatial processing: Spatial disorientation
- Impaired visual attention: Impaired visual exploration
