Alzheimer’s disease: The Three Subtypes


Welcome to my blog ‘The Three Subtypes Of Alzheimer’s disease’.

I am starting a series of blogs on Alzheimer’s disease (AD), you may like to check out the blog series click here. Posts include:

The cause of AD is incompletely defined, and no truly effective therapy exists.

However, accumulating data suggest important contributions from metabolic abnormalities such as insulin resistance, metabolic syndrome, chronic inflammation, low vitamin D, hormonal deficiencies, and elevated homocysteine, among others

Optimising metabolic parameters in a comprehensive way has yielded cognitive improvement, both in symptomatic and asymptomatic individuals. Therefore, expanding the standard laboratory evaluation in patients with dementia may be revealing. (1)

Recent results…support the notion that metabolic abnormalities are present in patients with cognitive decline, often years prior to diagnosis (1)

The Three Types Of Alzheimer’s

Alzheimer’s disease is one of the most significant healthcare problems today, with a dire need for effective treatment. Identifying subtypes may aid in the development of therapeutics, and recently three different subtypes have been described:

  1. Type 1: Characterised by systemic inflammation, reflected in such laboratory results as a high hs-CRP (high-sensitivity C-reactive protein), low albumin:globulin ratio, and high cytokine levels such as interleukin-1 and interleukin-6.
  2. Type 2: Characterised by an atrophic profile, with reduced support from molecules such as estradiol, progesterone, testosterone, insulin, and vitamin D, often accompanied by increased homocysteine and insulin resistance.
  3. Type 3: Is very dissimilar to the other two types, and may be mediated by a fundamentally different disease process (although, by definition, still β-amyloid positive and phospho-tau positive): the onset is typically younger (late 40s to early 60s); ApoE genotype is usually 3/3 instead of 4/4 or 3/4; the family history is typically negative (or positive only at much greater age); symptom onset usually follows a period of great stress, sleep loss, anesthesia, or menopause/andropause.

Type 1 Alzheimer’s Disease

The first is inflammatory, in which markers such as hs‐CRP and globulin:albumin ratio are increased.

Type 2 Alzheimer’s Disease

The second type is non‐inflammatory, in which these markers are not increased, but other metabolic abnormalities are present.

Type 3 Alzheimer’s Disease

The third type is a very distinctive clinical entity that affects relatively young individuals, extends beyond the typical Alzheimer’s disease initial distribution to affect the cortex widely, is characterized by early non‐amnestic features such as dyscalculia and aphasia, is often misdiagnosed or labeled atypical Alzheimer’s disease, typically affects ApoE4‐negative individuals, and is associated with striking zinc deficiency.

Why Does Subtype Matter?

The classification of the disease into subtypes may be useful for therapeutic studies. Since increasing evidence supports an important role for metabolic abnormalities such as insulin resistance in Alzheimer’s disease pathophysiology, it is of interest to determine whether metabolic profiling may be useful clinically, both in classification and, ultimately, in therapeutic trials.


In summary, metabolic profiling of patients with cognitive decline, as described previously, reveals three readily distinguishable subtypes of Alzheimer’s: inflammatory, non-inflammatory, and cortical. The distinctive features, presentation, lack of association with ApoE4, and marked hypozincemia, together suggest that the cortical subtype of Alzheimer’s disease is a fundamentally different disease than the other two subtypes. This subtype deserves further genetic, epigenetic, and metabolomic studies.


  1. Metabolic profiling distinguishes three subtypes of A.D (click here)
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