Lecture 4: Forebrain/Dementia & Alzheimer’s Disease - Professor Bettina Platt

Question 1

Limbic System

Answer 1

Part of the medial temporal lobe, includes cingulate gyrus, olfactory cortex, amygdala (fear), hippocampus (memory), and mammillary bodies of the hypothalamus. Regulates emotions and memory formation.

Question 2

Hippocampus Structure

Answer 2

The hippocampus consists of cornu ammonis (CA1-CA3), dentate gyrus, and subiculum. Adjacent cortical areas include the entorhinal cortex, perirhinal cortex, and parahippocampal gyrus.

Question 3

Alzheimer’s Disease

Answer 3

Most common cause of dementia. Key pathologies include beta-amyloid plaques (extracellular) and tau tangles (intracellular). Cholinergic hypothesis suggests the loss of limbic and neocortical cholinergic innervation.

Question 3

Beta Amyloid Theory

Answer 3

Stemming from misprocessing of beta-amyloid precursor, leading to the formation of toxic beta-amyloid plaques. Associated with Alzheimer’s disease.

Question 4

Dementia

Answer 4

An umbrella term for cognitive/memory impairment/brain degeneration diseases. Neurodegenerative diseases, including movement disorders (e.g., Parkinson’s) and PNS diseases (e.g., motor neuron disease), fall under this category. Key risk factor is age.

Question 5

Tau Protein

Answer 5

Microtubule-associated protein stabilizing the cytoskeleton. Hyperphosphorylated in Alzheimer’s disease by GSK3β, leading to the formation of intracellular neurofibrillary tangles.

Question 6

Amyloid Precursor Protein

Answer 6

Sits in the pre-synaptic membrane and is cleaved by secretases. Cleavage by sAPPβ in Alzheimer’s disease releases beta-amyloid fragments, assumed to cause oxidative stress, cellular damage, and inflammation.

Question 7

Genetic Factors in Alzheimer’s

Answer 7

Familial Alzheimer’s disease associated with mutations in amyloid precursor protein, Presenilin 1, and Presenilin 2. Down’s syndrome (trisomy of chromosome 21) increases the risk of early-onset AD.

Question 8

Alzheimer’s Risk Factors

Answer 8

Majority of cases involve a combination of genetic and environmental factors. No direct genetic link between Alzheimer’s disease and tau.

Question 9

Genetic Factors in Alzheimer’s Disease

Answer 9

Purely genetic factors contribute to about 5% of Alzheimer’s disease cases. The ApoE gene, involved in lipid transport and inflammatory/glial function, is associated with varying risks (E2/E2: 40% less likely, E4/E4: 14.9 times more likely).

Question 10

Genetic Risk Score for AD

Answer 10

A Nature Genetics journal paper proposed a genetic risk score for Alzheimer’s disease based on risk genes. Higher scores are associated with an increased risk of AD. However, the study has limitations and provides limited insight.

Question 11

Tau Pathology in AD

Answer 11

Tau pathology is crucial in determining AD. Braak staging associates different Braak stages with cognitive impairment severity. The ABC score combines amyloid deposition, Braak stage, and neuritic plaque score, but tau pathology remains the decisive factor.

Question 12

Mixed Pathology in AD

Answer 12

Most AD cases exhibit mixed pathology, involving tau/amyloid pathology and other toxic proteins. Different neurodegenerative diseases have specific proteins associated and distinct regional brain patterns.

Question 13

Amyloid Cascade Hypothesis Critique

Answer 13

Amyloid cascade hypothesis faces challenges. Studies on aging and Alzheimer’s in nuns showed that plaques and tangles are not causative. Beta-amyloid does not satisfy criteria to be a sole cause; there’s no dose response, and AD symptoms can be present without beta-amyloid.

Question 14

New Treatments for AD

Answer 14

New treatments (monoclonal antibody drugs) targeting amyloid pathology from 2023 show limited effectiveness, only slowing down progression. Side effects include brain bleeding and swelling due to the abundance of beta-amyloid in blood vessels

Question 15

Challenges in Alzheimer’s Treatment

Answer 15

Current Alzheimer’s treatments require regular costly brain scans, making it impractical. Early treatment initiation is crucial, but distinguishing AD patients from controls based on beta amyloid is challenging

Question 16

Finger-Prick Blood Test for AD

Answer 16

In 2023, a new finger-prick blood test for AD focused on markers for neuronal death (excluding Aβ). It demonstrated 80% accuracy, offering a more accessible option for testing, especially for home use.

Question 17

Lifestyle Factors and Dementia

Answer 17

Around 40% of dementia cases may result from factors such as high blood pressure, heart disease, obesity, diabetes, lack of exercise, poor diet, high alcohol consumption, low cognitive engagement, stroke, and smoking.

Question 18

Dementia Risk Reduction

Answer 18

Dementia risk can be reduced through physical activity, a healthy diet, cognitive challenges, heart care, and social engagement. The CAIDE dementia risk score app estimates risk based on age, hypertension, hypercholesterolemia, physical inactivity, obesity, and educational level.

Question 19

Trauma and Inflammation in Dementia

Answer 19

Trauma and inflammation likely increase dementia risk. Lancet (2020) suggests that 40% of dementia cases can be prevented by addressing neuropathological damage and cognitive reserve.

Question 20

Complexity of Alzheimer’s Disease

Answer 20

Alzheimer’s is a diverse, multi-factorial disease with potential inducers beyond traditional protein misfolding pathways. Ionic dyshomeostasis, oxidative stress, and enzyme dysregulation may play crucial roles.

Question 21

AI Tools in Dementia Research

Answer 21

AI tools could effectively analyze multiparameter data in dementia research, providing a deeper understanding of multifactorial parameters and their role in increasing disease risk.

Question 22

Resilience to Alzheimer’s

Answer 22

Some individuals may present with end-stage AD pathology yet retain cognitive function. Investigating this resilience is crucial for a better understanding of Alzheimer’s.