The Subtypes of Alzheimer's Disease
There are currently 5 million Americans living with Alzheimer’s Disease and there are estimated to be as many as 16 million by 2050 (1). This increase in disease prevalence is largely due to brain complexity, environmental factors, and an outdated and over simplistic standard of care. The work of Dr. Dale Bredesen has been crucial in understanding the development and effective treatment of Alzheimer's disease (2). Although many understand Alzheimer’s to be the most common form of dementia, very few recognize that the Alzhiemer’s has various subtypes which are linked to specific root causes.
These subtypes as identified by Dr. Bredesen are:
- Type 1: Inflammatory
- Type 1.5: Glycotoxic
- Type 2: Atrophic
- Type 3: Toxic
- Type 4: Vascular
- Type 5: Traumatic
Type 1: Inflammatory or “Hot” Alzheimer’s Disease
Inflammation is the native action of our immune system. It is a normal, healthy and necessary biological process for defending against foreign invaders and acute diseases. When uncontrolled, however, such as with chronic diseases, it can become harmful. Inflammation occurs whenever the body detects a threat, and thus triggers an influx of white blood cells and other chemicals to defend the body against this threat. Inflammation is commonly associated with injury, such as a cut or wound, but also when it comes to chronic diseases such as cardiovascular disease, diabetes, aging and Alzheimer’s Disease. Our physiological defense process (immune system) is constantly in communication with how we live (including where we live, what we eat etc.). Certain foods and other environmental factors can contribute to inflammation. For example, too many saturated fats, omega-6 unsaturated fats and sugars can increase inflammatory markers such as CRP, Interleukin-6 and Homocysteine which can lead to disease (3)(4). Type 1 Alzheimer’s Disease is consistently seen with inflammatory markers such as these.
Characteristics of Type 1
- Type 1 tends to run in families as it is common in people who carry one or two ApoE4 alleles (ApoE in itself is considered an inflammatory gene)
- Individuals begin to lose the ability to store new information in the hippocampus – for individuals who carry two copies of ApoE4 this tends to begin in the late fifties or sixties. For those with no copies of ApoE4, symptoms present typically in the sixties or seventies.
- A reduction in hippocampal volume – the chronic inflammation encourages the brain to destroy synapses faster than it creates them.
Biochemical Markers of Type 1
- An increase in C-reactive protein (CRP), which is made by the liver in response to inflammation. Normal Hs-CRP levels should be below 0.9 mg/L
- A decrease in the ratio of albumin to globulin. Normal levels should be at least 1.8:1
- An increase in interleukin-6. Normal levels should be less than 3 pg/ml
- An increase in tumor necrosis factor. TNFa levels should be lower than 6.0 pg/ml.
- Additional metabolic and hormonal abnormalities such as insulin resistance (as we know is commonly seen in diabetes)
Type 1 AD responds the most quickly to Dr. Bredesen’s ReCODE protocol.
Type 1.5: Glycotoxic or “Sweet” Alzheimer’s Disease
Type 1 and Type 2 Alzheimer’s Disease can occur together – often seen with neural inflammation in addition to the reduced support for brain synapses. A commonly seen combination of type 1 and type 2 AD is known as Type 1.5 or glycotoxic Alzheimer’s Disease.
Characteristics & Biochemical Markers of Type 1.5
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Although characteristics are similar to those found in Type 1 and Type 2 AD, blood glucose levels and hemoglobin A1c are chronically high in Type 1.5 which results in inflammation.
- Normal fasting blood glucose levels should be between 70-90 mg/dL.
- Normal hemoglobin A1c levels should be 4.0-5.3%
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High levels of insulin that is secreted in response to this high blood glucose level leads to insulin resistance. This results in a loss of trophic support.
- Trophic factors, such as NGF and BDNF, control the development and survival of specific groups of neurons, as mentioned above (8).
- Normal fasting insulin levels are 4.0-5.0 μIU/mL.
Type 1, Type 1.5 and Type 2 Alzheimer’s Disease lead to the imbalance between the production and destruction of neural synapses.
Type 2: Atrophic or “Cold” Alzheimer’s Disease
The word atrophy refers to cells and systems physically degenerating. In this case, the overall support for brain synapses “dries up” and the brain begins destroying synapses faster than it can create them. Trophic factors, such as NGF (Nerve Growth Factor) and BDNF (Brain-Derived Neurotrophic Factor) are crucial proteins for neural maintenance and regeneration (5). Since BDNF plays a crucial role in cognition, learning and memory formation, lower levels of BDNF in the brain have been associated with higher incidences of Alzheimer’s Disease (6). Low levels of BDNF are often seen with impaired glucose metabolism, thus chronic insulin resistance results in a loss of trophic support (7). This atrophy, or reduction in trophic support, is consistently seen in Type 2 Alzheimer’s Disease.
Characteristics of Type 2
- Type 2 also occurs more frequently in those who carry one or two copies of the ApoE4 allele, but the symptoms tend to initiate about a decade later than the inflammatory Type 1.
- Individuals begin to lose the ability to store new information (form new memories) in the hippocampus (Also seen in Type 1).
- No evidence of inflammation – sometimes inflammatory markers may actually be lower than normal.
Biochemical Markers of Type 2
- Levels of hormones such as thyroid, adrenal, estrogen, progesterone, testosterone and pregnenolone tend to be suboptimal
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The optimal hormone ranges are:
- TSH: less than 2.0 mIU/L
- Free T3: 3.2-4.2 pg/mL
- Free T4: 1.3-1.8 ng/dL
- Reverse T3: less than 20 ng/dL
- AM Cortisol: 10-18 mcg/dL
- Pregnenolone: 100-250 ng/dL
- Estradiol: 50– 250 pg/ mL (women, age dependent)
- Progesterone: 1-20 ng/mL (women, age dependent)
- Testosterone: 500-1,000 ng/dL (men) 25-70 ng/dL (women)
- A decrease in serum Vitamin D levels. Normal Vitamin D levels should be 50-80 ng/mL
- An increase in homocysteine levels can occur. Normal homocysteine levels should be less than or equal to 7 μmol/ L (homocysteine is also seen to increase in Type 1)
- Insulin resistance can occur OR insulin levels may be too low
Type 2 usually responds slower than Type 1 to the ReCODE or Bredesen protocol.
Type 3: Toxic or “Vile” Alzheimer’s Disease
Similar to how carcinogens are known as compounds that can cause cancer, dementogens are possible toxins that lead to cognitive decline. According to Dr. Bredesen’s research and experience, all patients with Type 3 Alzheimer’s disease have histories of toxic exposures (2).
Characteristics of Type 3
- Type 3 tends to occur in those who have the ApoE3 allele rather than ApoE4 and thus does not typically run in families.
- Type 3 hits individuals at younger ages, typically late forties to early sixties.
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Symptoms do not begin with memory loss but rather with cognitive difficulties involving numbers, speech or organization. Individuals will start seeing difficulties with:
- Math, such as calculating tips or bills.
- Speech, such as finding the right words, or spelling or reading correctly.
- Rules of games, such as poker or bridge.
- Depression and attention deficits are common.
- The brain ultimately loses recent and old memories
- Patients with Type 3 are often diagnosed initially with something other than Alzheimer’s Disease such as depression or frontotemporal dementia.
Biochemical Markers of Type 3
- Low triglyceride levels as compared to cholesterol levels.
- MRI scans show shrinkage of the hippocampus.
- Neuroinflammation and vascular leaks, which are presented on a specific MRI called FLAIR (Fluid-attenuated inversion recovery) as white spots.
- Decreased zinc levels. Normal levels are between 90-110 mcg/dL.
- Elevated copper levels. Normal copper levels are between 90-110 mcg/dL.
- High blood levels of toxic chemicals such as mercury or mycotoxins (caused by molds).
- The pituitary gland and adrenal glands become dysfunctional, which can show up in lab tests as hormonal abnormalities.
Type 4: Vascular or "Pale" Alzheimer's Disease
Type 4 or Vascular AD, is caused by a reduction of blood flow to the brain, which ultimately deprives the brain of essential oxygen and nutrients. The brain is an extremely vascularized tissue, meaning it requires large amounts of oxygen. A lack of oxygen to the brain leads to hypoperfusion (low blood flow) and compromises the blood-brain barrier which allows for harmful substances to leak in and damage neurons (9). Cerebral vasculature is extremely important as it is one way the body clears the accumulation of amyloid-beta.
Characteristics & Biochemical Markers of Type 4
- “Leakiness” present in vascular tissues.
- Individuals with cardiovascular disease have high risk for Type 4 Alzheimer’s.
- These individuals do best when they prioritize healing underlying insulin resistance.
Type 5: Traumatic or “Dazed” Alzheimer’s Disease
Type 5 or trauma induced Alzheimer’s, results from traumatic brain injuries (TBI) which disrupt normal brain function, including learning and thinking skills. Certain types of TBI’s may increase the risk of developing Alzheimer’s disease years after the injury takes place (1). One of the most impactful studies showed that those with a history of moderate TBI had a 2.3 times greater risk of developing Alzheimer’s than older adults with no history of a head injury and those with a history of severe TBI had a 4.5 times greater risk (10). Additional research is needed however to fully understand the relationship between TBI’s and Alzheimer’s disease.
The Importance of the Subtypes
Between 2000 and 2018 the deaths from heart disease have gone down 7.8%, while the deaths from Alzheimer’s disease have increased by 146% (1). This is largely due to our increased knowledge regarding how to treat and reverse heart disease yet various unknowns when it comes to the brain and how to treat Alzheimer’s disease. The recognition of various subtypes of Alzheimer’s disease allow for individualized treatment that addresses the root cause of the disease. Evidence-based interventions with an individualized approach to treatment is essential when seeking the proper remedy for any ailment – Alzheimer’s Disease is no exception. Working with clinicians such as those at the Amos Institute, who are not only experts at identifying Alzheimer’s Disease subtypes but also in the nutritional treatment of the disease, is absolutely critical to the prevention of Alzheimer’s pathology and reversal of symptoms.