Most people in the U.S. are affected by Alzheimer’s disease (AD)—they either have it themselves, or know someone who is, said Dale Bredesen, MD, an internationally recognized as an expert in the mechanisms of neurodegenerative diseases, who spoke at the Institute for Functional Medicine’s 2017 Annual International Conference in Los Angeles, California earlier today.

The general assumption is that there is no way to prevent or reverse Alzheimer’s. While there may not be a cure for the disease, Bredesen is spearheading efforts that help reverse cognitive decline in AD patients, based on the idea that a lack of nutrients impair cognition. Part of his efforts include identifying subtypes of the disease to target treatment efforts.

Several different metabolic syndromes are called "Alzheimer’s disease," which can be broken down into six subtypes:

• Type 1: Inflammatory (“Hot”)
• Type 2: Atrophic (“Cold”)
• Type 1.5: Glycotoxic (“Sweet")
• Type 3: Toxic (“Vile”)
• Type 4: Vascular (“Pale”)
• Type 5: Traumatic (“Dazed”)

The following will explore four types of AD as well as characteristics practitioners can use to identify them.

Type 1: Inflammatory (“Hot”)

Characteristics of this AD subtype include:

• Inflammatory (Ayurvedic pitta)
• Increase in hs-CRP and/or other inflammatory markers (e.g., increases in IL-6, IL-8, TNFα, etc.)
• Reduction in A/G ratio
•  Increase in M1/M2 ratio; reduction in MFI
• ApoE4 is important risk factor
• Presentation is typically amnestic
• Hippocampal atrophy is common
• Seek cause(s) of inflammation (e.g., gut leak, AGEs, diet,
  poor oral hygiene, etc.)

A 66 year-old man is experiencing "senior moments". There's a family history of AD in both parents.

• ApoE3/4, amyloid PET is markedly positive, FDG-PET typical for AD, hippocampal volume reduced, neuropsych testing MCI
• Hs-CRP 9.9
•  Homocysteine 15.1
• Vitamin D 21
• Testosterone 264, free T3 2.4, TSH 2.21

The patient responded metabolically, cognitively, and volumetrically to ReCODE. Neurologist said he is now “normal.” Metabolism and cognition go hand-in-hand, says Bredesen.

Type 2: Atrophic (“Cold”)

Characteristics of this AD subtype include:

• Atrophic (“cold;” Ayurvedic vata)
  Patients tend to be older than type 1
  Typically amnestic presentation; patients often protest that nothing is wrong
  Reductions in trophic support (e.g., estradiol, progesterone, testosterone, vitamin D, pregnenolone, thyroid, NGF, BDNF)
• ApoE4 is risk factor
• Rapid reductions in support are most concerning (cf.
  oophorectomy at <41 without HRT), c/w depR mismatch
• Hippocampal atrophy is common
• Optimizing support may be complicated by receptor response, HRT controversy, trophic factor delivery (intranasal vs. peptides vs. indirect, etc.)

A 75 year-old psychiatrist has a two-year history of memory loss. She has severe difficulty retaining new information, but no problem organizing, calculating, dressing, or speaking:

• ApoE3/3
• FDG-PET c/w Alzheimer’s. MRI with HC volume 16th percentile
• On-line cognitive assessment 9th percentile for age
• Low vit D, pregnenolone, progesterone, estradiol, fT3, B12
• Diagnosis of mild cognitive impairment (MCI)

The patient began the protocol but left out several parts. Her cognitive assessment went from the 9th percentile to the 97th percentile over 12 months. Her significant other said her memory went from disastrous to lousy, and is now "normal."

The patient noted marked improvement in her memory. Tests show improvements in vitamin D, pregnenolone, progesterone, estradiol, fT3, and B12.

Type 1.5: Glycotoxic (“Sweet”)—Combines 1 and 2

Characteristics of this AD subtype include:

• Glycotoxic (“sweet”)
•  Inflammatory part from AGEs (via RAGE, glyoxals, etc.)
  and related
• Atrophic part from insulin resistance (e.g., IRS1 S/T
  phos.)
• Goetzl noted insulin resistance in 100% of the neural
  exosomes from AD patients (measured via IRS1).
• ApoE4 is an important risk factor
• Amnestic presentation is common
• Hippocampal atrophy is common
• Paradox of insulin sensitization and trophic requirement

A 69 year-old businessman has a three-year history of poor memory and orientation. His MRI reads as normal without volumetrics:

• Fasting insulin 14, hemoglobin A1c 5.8, fbs 102
• hs-CRP 0.1
• ApoE3/3
• BMI 33
• Normal Cu:Zn, Mg, vit D, Hg, hormones

His diagnosis is type 1.5 AD.

Type 3: Toxic (“Vile”)—A fundamentally different problem

Characteristics of this AD subtype include:

• Age at symptom onset < 65
•  ApoE4-negative (often)
• Negative family history (or only older)
• Low triglycerides and/or zinc
• HPA dysfunction
• Depression
• Problems with math or organization or word finding
• Exposure to toxins (mercury, mycotoxins, CIRS-related such as Lyme, MARCoNS, surgical implants, chronic viral infections)
•  Precipitation or exacerbation by stress.
• “Atypical Alzheimer’s,” often with frontal effects and imaging.
• High C4a (>2800), TGF-beta-1 (>2380); low MSH (<35)
• HLA-DR/DQ with “dreaded” multiple biotoxin sensitive or
  pathogen-specific (4-3-53, 11-3-52B, 12-3-52B, 14-5-52B)
• MARCoNS (multiple-antibiotic resistant coagulase-negative
  Staphylococcus, deep nasopharyngeal culture)—biofilm
  assessment
• Visual contrast sensitivity abnormalities
• Surprisingly, most do NOT have allergic symptoms
• Most do not fulfill criteria for CIRS, yet have laboratory values
  compatible with CIRS—thus “ISIS” (innate system immune
  stimulation)
• Potential relationship to Lewy body disease
• Most difficult type of AD to treat successfully

A 50 year-old woman is experiencing depression following a hysterectomy. Over the ensuing four years, she developed word-finding difficulty, disorientation, difficulty following recipes, and difficulty driving. She declined markedly with stress, sleep deprivation, and viral illness. She experienced poor semantic fluency, paucity of speech, confabulation; frontal, temporal, and parietal deficits:

• FDG-PET: temporal and parietal > frontal reduced glucose utilization, compatible with Alzheimer’s disease.
• Seen at university dementia center, started on antidepressant and donepezil
• ApoE3/3, negative family history, hs-CRP 0.2, C4a 5547, TGF-α1 7037, VCS failed, anti-Lyme negative, anti-thyroglobulin antibodies 1:2000.

She was treated with ReCODE, intranasal VIP, and experienced improvements in memory, interaction, and following directions.

Closing the complexity gap

Cognitive decline in early Alzheimer’s disease and its forerunners, MCI (mild cognitive impairment) and SCI (subjective cognitive impairment), is reversible, and improvement sustainable, using a programmatic approach rather than a monotherapy.

We can reduce the global burden of dementia markedly, and increase the global cognitive ability, through metabolic profiling, larger data sets, prevention and early reversal, and personalized, programmatic approaches to cognitive and overall health. This could be a highly efficient use of practitioner time and healthcare finances.

Editor’s note: Integrative Practitioner is reporting live from the Institute for Functional Medicine’s annual conference. For live updates and complete show coverage, click here.