Glutamate is the brain's primary excitatory neurotransmitter. In a healthy brain, it is quickly cleared away by surrounding glial cells after transmitting a signal. But amyloid-beta plaques impair this clearance gumming up the glial cells. The toxic overload of glutamate in the synaptic cleft overstimulates and locks open glutamate receptors, triggering excitotoxicity and cell death. 

most cells in our body are relatively short-lived but
neurons have evolved to survive a long time so they
must constantly maintain and repair themselves.
neurons also continuously “remodel” their synaptic connections depending on how much stimulation they receive from other neurons. they may strengthen or weaken synaptic connections, or even break down connections with one group of neurons and build new connections with a different group. 

 cells require oxygen and glucose supplied by blood circulating through the brain. our  brains consume 20% of these requirements. with Alzheimer’s, there's a reduction in glucose entering the brain = a decrease in energy production = decrease in metabolic health.

"prevention"

also...starved cells activate their stress pathways causing Tau proteins to collapse and tangle. tau tangles block neurons from transporting nutrients which kills them. causing them to wither and die. 

our brain contains tens of billions of neurons...

microglia, "nursemaid" cells which normally are protective, become hyper-reactive and release cytokines and ROSs = oxidative stress.

the science of aging:
Alzheimers Disease

1. family history: risk increases if a first-degree relative was                                   diagnosed; this risk factor is largely not                                       understood. 

2. Symptom-Relieving Medications
 drugs designed to boost acetylcholine to help brain chemicals to temporarily preserve thinking, memory, and communication skills. 

1.  mutations in the APP gene or the genes for the enzyme                     components alter the enzymes' ability to cleave the                       protein correctly. 
2. aging decreases the activity and efficiency of the protective             α-secretase enzyme. With less α-secretase available to                 safely cut APP, a higher volume of the protein becomes               available for the β- and γ-secretase enzymes to process.
3. as we age, certain other enzymes (Delta-secretase) are 
         overactivated which pre-cuts APP so that the aggressive
         β-secretase can slice up the fragments.

what happens? enzymes known as kinases add excess phosphate groups to Tau proteins. Tau proteins normally stabilize the cell's microtubules. But hyperphosphorylated Tau clump together into the neurofibrillary tangles (NFTs) seen with AD.  

what about  neurotransmitter toxicity?  

remodeling of synaptic connections are important for learning and memory. in AD there is evidence suggesting decreased remodeling in areas of the brain involved in memory and learning.

Cholinesterase Inhibitors: slow the breakdown of the key memory neurotransmitter acetylcholine by blocking the enzyme that typically destroys it allowing acetylcholine to remain active in the brain for longer periods.

                         language & visual difficulties:
 1. trouble following a conversation, stopping mid-thought,
              struggling to find the right words
 2. visual/spatial issues: difficulty reading, judging distance,
              recognizing colors/contrast (driving!)
              confused, suspicious, depressed, anxious

13. lifelong learning and social engagement stimulate the mind reducing risk. low education levels may be a risk factor.

                       disruptive loss of memory:
 1. frequently forgetting recently learned information,                            important dates, repeating questions or stories.
 2. planning/problem solving:
              trouble managing a budget, balancing a checkbook,                or following a familiar recipe.
 3. time/place confusion:
              forgetting the day/season/year or getting lost in                      familiar area
 4. misplacing items:
              hiding or putting items in unusual places and being                unable to retrace steps to find them

there are networks of brain cells...
one neuron may have 7,000 synaptic connections with other neurons!

4. protection from pathogens and toxins

monoclonal antibodies are lab-engineered immune proteins that bind to beta-amyloid plaques then
signal immune cells (microglia) to consume and clear the toxic amyloids, delaying disease progression.

high blood pressure, diabetes, and stroke
damage blood vessels and reduce the flow of oxygen and nutrients to brain tissue. reduced blood flow may lead to the breakdown of the blood-brain barrier. 

 9. Poor sleep patterns like apnea, trouble falling asleep or staying asleep are risk factors. 

although not fully understood, Alzheimer's is believed to be a combination of genetic, environmental, and lifestyle factors.
 primary risk factors include:

AD

our Blood-Brain Barrier is a VERY selective, semi-permeable membrane that separates your circulating blood from the brain's extracellular fluid. it's made up of  specialized cells that shield the central nervous system from pathogens and toxins while regulating essential nutrient and gas exchange

1. communication

4. Non-Drug Management & Lifestyle
exercise, heart-healthy diet, consistent sleep routine,

active social and cognitive engagement

2025 US population
> 65 ​= 61.2 million 

Alzheimer’s disease
is the most common cause of dementia.

It is a progressive, neurological disorder that slowly diminishes memory, thinking skills, and the ability to carry out basic tasks.

the loss of synaptic connections is one of the main hallmarks of cognitive decline.

IDE = insulin degrading enzyme

​Memantine: regulates glutamate by acting as a sort of
 gatekeeper to prevent excitotoxicity, helping protect brain cells from damage and improve daily functioning

besides messing up synapse function, Aβ proteins trigger a
sustained, localized immune response. 

plaques??

2. genetics: inheriting the apolipoprotein E (APOE) gene e4                        does increase risk.
 25% to 30% of the population carries APOE e4 BUT not everyone with this form of the gene develops the disease. Having two copies of APOE e4 increases risk vs one copy.

btw...there are three alleles:
ε2: Rare; sometimes offers a protective effect  
ε3: The most common allele; neutral risk.
ε4: Inheriting one copy increases your risk 3X;
       carrying two copies increases your risk by 10-15X 

neurons are constantly in touch with neighboring brain cells via neurotransmitters that traverse a teeny gap between the cells called a synapse. each neurotransmitter molecule binds to specific receptor on the nearby neuron which triggers chemical/electrical signals that stimulate OR inhibit activity in the receiving neuron. 

APP is supposed to be processed by α-secretase and
​γ-secretase. But when β-secretase (BACE1) cleaves APP first, followed by γ-secretase, Aβ peptides of varying lengths are made which are sticky. they misfold and aggregate into neurotoxic amyloids which eventually
mature into the large plaques found in brain tissue.

      each year there were:
      4 new diagnoses per   
   1,000 people ages 65 to 74

      32 new diagnoses per           1,000 people ages 75-84
     
      76 new diagnoses per                1,000 people ages >85

in our brain, there's an enzyme that has two jobs:
1. breaks down insulin
2. clears out toxic beta-amyloid proteins.
when insulin levels are really high due to blood sugar imbalances, this enzyme spends all its time breaking down surplus insulin, leaving the beta-amyloid to accumulate and form damaging plaques.

1. Disease-Modifying Immunotherapies
monoclonal antibodies target and clear amyloid plaques in the brain, slowing cognitive and functional decline in early-stage patients
(IV) infusion. cost roughly = $30K annually
covered by Medicare for qualified patients.

Alzheimer's is characterized by the build up of abnormal protein clumps called plaques.
Plaques (and tangles) damage and kill nerve cells in the brain. 

researchers  refer to Alzheimer's as "Type 3 diabetes." 

3. people with Down Syndrome disproportionately develop the disease and exhibit symptoms earlier.
probably due to 3 x chromosome 21 which contains a gene involved in the production the beta-amyloid protein          associated with plaques in the brain.

  6. people age 50 or older who had a traumatic brain injury (TBI) are at higher risk. risk increases with serious/many TBIs.

 @7.4 million Americans >65
have Alzheimer's (1 in 9)
projections = 13.8 million by 2060 unless science triumphs

4. neurobiology!

3.  repair/remodeling/regeneration

  5. individuals with mild cognitive impairment (MCI)
are at increased risk. 

 11. hearing loss: the worse the hearing loss, the higher the risk BUT
wearing hearing aids offer protection

1. prevelance    

Alzheimer's and vascular issues 

theAPOE gene codes for apolipoprotein E protein. this protein combines with fats in the body to form lipoproteins which play a critical role in brain lipid transport and nerve injury repair

  7. air pollution particulates can speed the breakdown of the nervous system.
exposure to traffic exhaust and burning wood is linked to a higher risk.

why does this amyloidogenic pathway occur?

 10. the same risk factors for heart disease also may increase
       the risk of dementia (due to brain blood vessel changes)
       *obesity  *smoking  *high blood pressure 
              *high cholesterol  *poorly managed type 2 diabetes
                     *high levels of LDL

the proper function and the survival of neurons depends on:

4. Sex assigned at birth:  more women develop the disease because they tend to live longer than men.

2. risk factors    

​ which process and transmit information via electrical and chemical signals to other neurons and to muscles and organs of the body. Alzheimer's disease disrupts this communication as many neurons stop working properly and eventually die.

AD treatment

treatments focus on managing symptoms and targeting the biology of the disease: 

our BBB

3. Treatments for Behavioral Symptoms
targeted medications to alleviate depression, agitation, anxiety, sleep disturbances

btw...
healthy Tau proteins help sustain normal brain insulin signaling. When Tau becomes tangled and loses its normal function, the brain's ability to respond to insulin worsens so it's a vicious cycle. 

   8. alcohol misuse is linked to risk especially early-onset dementia.

amyloid plaques are insoluble aggregates of beta-amyloid (Aβ) proteins that form between nerve cells in the brain. they develop when the bigger Amyloid Precursor Protein (APP) is incorrectly cut by enzymes.

2. efficient metabolism

research

  12. vision loss that is not treated 

today we'll explore:
1. prevelance     2. risk factors     3. symptoms
4. neurobiology 5. treatments   6. "prevention"

because APP cleavage leads to plaques, therapies targeting these pathways are a major focus of clinical research:
1. inhibiting Beta/Gamma-Secretases:
drugs designed to block BACE1 or gamma-secretase, the enzymes that improperly cut APP, aim to stop Aβ production at the source.
2. stimulating Alpha-Secretase:
boost alpha-secretase activity, steering APP processing into the harmless non-amyloidogenic pathway

​https://www.alz.org/research

neurons become resistant to insulin so they can't absorb and utilizing sugar effectively.
brain cells starve. 

3. symptoms:

why? in type 2 diabetes, cells lose their sensitivity to insulin which blocks glucose from entering the cell.

                   behavioral & personality shifts:
 1. poor judgment/decreased ability to make sound                                    decisions (falling for scams)
 2. social withdrawal/loss of interest in hobbies, work                                projects, or social activities
 3. mood swings/uncharacteristically confused, suspicious,                     depressed, anxious, or easily upset