Aging & neurodegeneration

Question 1

Common socioemotional changes of aging (2)

Answer 1

• Smaller but more intentionally chosen social networks with a higher proportion of emotionally close partners
• Greater emotional stability and emotional complexity (positive and negative together) in daily life

Question 2

Normal cognitive changes of aging

Answer 2

• Differential impacts on some cognitive domains over others
• Processing speed also declines: decreases in long-term and working memory

Question 3

Do age-related cognitive changes impact everyone in the same way?

Answer 3

• NO - considerable variation between individuals

Question 4

Evidence for compensation

Activity in younger vs. older

Answer 4

older brains can show larger activity than younger for the same task

Question 5

Normal brain aging (4)

Answer 5

1. Volume loss: Overall volume shrinks by 5% per decade after 40, accelerating after 70; Varies across structures: frontal cortex > basal ganglia > temporal lobe > other
2. Neurotransmitter depletion: dopamine and serotonin levels decline
3. Decreased cerebral blood flow
4. Accumulation of white matter damage (linked to hypertension)

Question 6

When are brain changes considered “normal”?

Answer 6

• Normal = small degree of Alzheimer’s pathology (amyloid plaques and neurofibrillary tangles), neuronal loss

Question 7

When are brain changes considered “beyond normal”?

Answer 7

• Mild cognitive impairment - MCI
• Dementia
• Alzheimer’s disease

Question 8

Mild cognitive impairment - MCI

When are brain changes considered “beyond normal”?

Answer 8

• Changes in attention and memory serious enough to be noticed by the person, friends, and family
• Cognitive difficulties in excess of normal aging; preserved activities of daily living
• Conversion rate to dementia diagnosis = 5-15% per year
• 12-20% of individuals 65+

Question 9

Clinical Testing for MCI?

When are brain changes considered “beyond normal”?

Answer 9

• patient history
• mental status exam (e.g., MoCA)
• maybe imaging?

Question 10

Dementia

When are brain changes considered “beyond normal”?

Answer 10

• Impairment of multiple cognitive functions and activities of daily living
• Progressive decline
• Dementia is a syndrome that can be caused by multiple diseases
• Onset in middle-to-late adulthood (usually)

Question 11

Dementia - vocabulary do’s and don’ts

When are brain changes considered “beyond normal”?

Answer 11

• Avoid: sufferer, victim, burden
• Use: person with dementia, person with lived experience

Question 12

Alzheimer’s Disease - early symptoms:

When are brain changes considered “beyond normal”?

Answer 12

• Confusion
• Irritability
• Anxiety
• Deterioration of speech

Question 13

Alzheimer’s Disease - late symptoms:

When are brain changes considered “beyond normal”?

Answer 13

• Difficulties with even simple responses or behaviours (e.g., swallowing, speech)

Question 14

Causes of alzheimer’s - genes?

Answer 14

No single gene cause of Alzheimer’s disease - only rare, but can do a post-mortem exam

Question 15

What predicts progression from MCI to AD?

Answer 15

• Older age
• APOE ε4 status
• Medial temporal lobe atrophy on MRI
• Positive amyloid on PET scan
• Molecular markers in CSF (low Aβ, elevated total tau and phosphorylated tau)

Question 16

What is Apo-E?

What predicts progression from MCI to AD?

Answer 16

• ApoE, the protein, plays a role in cholesterol (fat) transport and is involved in normal metabolism of amyloid beta
• There are multiple forms of this gene (alleles) - ε2, ε3, ε4
• Everyone carries two Apo-E (apolipoprotein E) genes - whichever combination of alleles people have can determine their potential for alzheimer’s
• A non-carrier has NO ε4 allele on either Apo-E genes

Question 17

For someone with one of two alleles being ε4, what’s their potentiality for alzheimer’s?

Answer 17

47% (heterozygous)

Question 18

For someone with two of two alleles being ε4, what’s their potentiality for alzheimer’s?

Answer 18

91% (homozygous)

Question 19

Defining characteristics of AD

Answer 19

1. Neurofibrillary tangles
2. Amyloid plaques
3. Volume loss

Question 20

Neurofibrillary tangles

Defining characteristics of AD

Answer 20

• A tauopathy: tau proteins (similar to CTE) have the role of giving a cell its shape
• However, become hyperphosphorylated and misfolded
• Left unable to be broken down and be removed from the cell like usual
• This leads to a build up
• Additionally, act as prions (= proteins are misfolded, causing disease)
• Meaning once some tau starts to misfold, other “normal” tau becomes misfolded too
• Intracellular (happens inside the cell)

Question 21

Amyloid plaques

Defining characteristics of AD

Answer 21

• Aβ (= “beta amyloid”) proteins build up and take on large, collapsed forms and take up extracellular space
• Starts first in the medial temporal lobe and interferes with regular cell processes, ultimately resulting in the loss of synapses

Question 22

Volume loss

Defining characteristics of AD

Answer 22

• (linked to tauopathy and amyloid plaques)
• Progressive loss of both cells and synapses, appearing first in medial temporal lobe structures – entorhinal cortex-amygdala, hippocampus – involved in memory

Question 23

AD Theories

Answer 23

1. Amyloid cascade hypothesis (dominant theory)
2. Neurofibrillary (tau) hypothesis

Question 24

Amyloid cascade hypothesis (dominant theory)

AD Theories

Answer 24

Holds that amyloid plaques are the primary symptom and cause all other symptoms (basically step 0)

• Evidence: Trisomy 21 (Down’s Syndrome)
• These individuals have 3 copies of chromosome 21, including the gene for Aβ
• Will most likely develop alzheimer’s in later life
• Problems: 100% will develop amyloid plaques (loss of synapses), BUT not all develop alzheimer’s; amyloid drugs keep failing

Question 25

Neurofibrillary (tau) hypothesis ## Footnote AD Theories

Answer 25

* Holds that misfolded tau is the causal agent (tau first) * Evidence: tau pathology correlates with cognitive impairment better than Aβ * Problem: tau mutation alone does not seem to cause Aβ plaques * i.e. we can find people who have tau mutation who don't have Aβ

Question 26

Treatments for AD

Answer 26

1. **Cholinergic agonists** (i.e., cholinesterase inhibitors, prevent breakdown of ACh); **Can help prevent decline in learning and memory** 2. **NMDA receptor antagonist** (reduces actions of glutamate); **Can prevent damage to neurons** 3. Target modifiable risk factors: depression, smoking, social isolation

Question 27

Biomarkers

Answer 27

* CSF biomarkers for AD are related to amyloid and tau are helpful but not 100% definitive * Can inform diagnostic, treatment, and referral decisions * Return of biomarker results must be done with care: “knowing that it wasn’t all in my head, that there is something going on, gave me relief.”