Metabolic profiling distinguishes three subtypes of Alzheimer's disease

Introduction

Alzheimer's disease represents a major healthcare problem, with over five million Americans estimated to suffer from this disease, and a recent study showing that AD has now become the third leading cause of death, trailing only cardiovascular disease and neoplasia [1]. The cause(s) of AD remain incompletely determined, and there is currently no truly effective treatment. However, accumulating data suggest important contributions from metabolic abnormalities such as insulin resistance, metabolic syndrome, chronic inflammation, hypovitaminosis D, hormonal deficiencies, and hyperhomocysteinemia, among others [2]. Despite this, most clinical evaluations of patients with cognitive decline do not include extensive metabolic or genomic evaluations. Furthermore, given the perceived poor prognosis for AD, in patients with evidence of amyloid-β accumulation by amyloid PET imaging or, indirectly, by cerebrospinal fluid profile, there has been little incentive to perform extensive evaluations of hormonal status, nutritional status, toxicity status, metal status, gastrointestinal permeability, or other laboratory evaluations perceived by healthcare systems as “non-standard.” However, studies such as the recent FINGER study [3] suggest that metabolic factors may play important roles in the neurodegenerative process, at least early in the pathogenetic process. Recent results from the evaluation of neural exosomes and nanosomes support the notion that metabolic abnormalities are present in patients with cognitive decline, often years prior to diagnosis of AD [4]. Therefore, it may be productive, both from the standpoint of identifying novel biomarkers and from the standpoint of identifying treatable metabolic abnormalities, to perform metabolic profiling of patients with cognitive decline and those at risk for such decline.

I recently described a protocol for metabolic enhancement in neurodegeneration [5]. Evaluating these same metabolic parameters in patients with cognitive decline revealed three subtypes of Alzheimer's disease, which are described in greater detail below. Such metabolic subtyping may provide novel insights into the pathogenesis in specific patients, as well as suggesting therapeutic approaches that may be effective only in specific subgroups of patients.

Results

Discussion

The classification of Alzheimer's 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.

Here it is shown that clinical metabolic testing reveals three readily distinguishable subtypes of Alzheimer's disease. The first type, inflammatory, is associated with markers of systemic inflammation, such as high hs-CRP, low albumin:globulin ratio, and high interleukin-6. Additional metabolic abnormalities may also be present, such as insulin resistance, metabolic syndrome, hyperhomocysteinemia, hypovitaminosis D, hypo-thyroidism, and hypercortisolemia. ApoE4, which exerts pro-inflammatory effects, is associated with this subtype of Alzheimer's disease. The presentation is typically amnestic, and imaging studies are compatible with such a presentation, showing hippocampal atrophy in the absence of widespread cerebral atrophy.

The second type, non-inflammatory, is associated with other metabolic abnormalities such as insulin resistance, hypovitaminosis D, hyperhomocysteinemia, and reductions in hormonal support. Indicators of systemic inflammation, such as high hs-CRP, reduced albumin:globulin ratio, and high interleukin-6, are by definition absent, but of course this does not exclude the possibility of intra-CNS inflammation. The patients with this second subtype of AD tend to be slightly older than those in the first, often in the eighth instead of seventh decade. Interestingly, Fiala's studies have shown that both inflammatory and non-inflammatory subtypes display phagocytic defects for amyloid-β in their peripheral blood mononuclear cells [17]. This second subtype is also associated with ApoE4, and, as for the inflammatory subtype, tends to present with an amnestic syndrome and FDG-PET showing temporal-parietal reductions in glucose utilization.

In contrast to the profiles for the first two subtypes, the profile of the third subtype argues that it is a fundamentally different disease process than the first two: instead of losing the ability to form new memories as the initial presentation, in this subtype there is an initial loss of long-term memory maintenance, resulting in problems such as dyscalculia and aphasia, with an initial retention of new memory formation and retrieval. A recurring feature was the patients' ability to describe recent events in detail, but frequent inability to keep their trains of thought. In some cases, the presentation was associated with a history of depression. However, none had the visual hallucinations, delusions, REM behavioral disturbance, or autonomic disorders that would suggest Lewy body dementia. Some of the patients were also noted to become passive, simple-minded, or childlike, often in marked contrast to their earlier, highly-accomplished, hard-driving personalities. There was widespread cerebral atrophy (sometimes along with cerebellar atrophy), and early symptom onset in the fifth, sixth, or early seventh decades, but no ApoE4-related over-representation and typically no family history of Alzheimer's disease. Surprisingly, all had very low serum zinc, typically 50-60mcg/dl. It should be noted that serum zinc is a relatively insensitive test for zinc deficiency, so that low serum zinc is strongly suggestive of relatively severe zinc deficiency, but a normal serum zinc does not necessarily exclude some degree of zinc deficiency.

Zinc is the second most abundant trace metal in the human body, following only iron. Over 300 enzymes utilize zinc as a co-factor, either for catalysis (in which it functions as a Lewis acid) or structure, and it typically sits in a distorted tetrahedral structure, coordinated with three or four protein side chains and interacting directly with a cysteine sulfur and/or histidine nitrogen and/or glutamate or aspartate oxygen [18]. Zinc deficiency, which is common in aging individuals, affects many functions that are directly or indirectly related to cognitive performance and Alzheimer's disease. For example, zinc deficiency induces insulin resistance, a known risk factor for AD. Zinc deficiency also increases inflammation, and reduces the finely tuned nature of the immune response, resulting in a reduced specific response (and thus loss of resistance to infectious agents) and a greater autoimmune response. Zinc is also involved in wound healing, DNA repair, and oxidative damage. Zinc deficiency is associated with increased aging, increased susceptibility to toxins, increased susceptibility to infections, increased production of reactive oxygen species, reduced hormonal function, reduced adrenal support, increased susceptibility to copper toxicity, and gastrointestinal hyperpermeability. Furthermore, zinc treatment has been shown to mitigate cognitive decline [19]. Therefore, zinc deficiency is a concern as a potential contributor to cognitive decline.

Zinc deficiency is relatively common, and may be associated with poor absorption due to reduced gastric acidity (e.g., due to H. pylori and/or the use of proton pump inhibitors), a zinc-deficient diet (e.g., due to vegetarianism without supplementation), adrenal stress, diabetes, alcohol use, toxic exposure, intestinal parasites, or aging. As noted above, serum zinc represents a relatively insensitive test for zinc; RBC zinc provides a more accurate assessment. Thus by the time that serum zinc is low, the body's zinc deficiency is likely to be quite severe.

The cause(s) of zinc deficiency in the six patients reported here is unknown, as is the potential relationship of the zinc deficiency to the distinctive neurodegenerative process. Given the relationship between zinc deficiency and susceptibility to toxins and infectious agents, historical data were obtained from all patients on potential toxic exposure. Whether or not causally related, all had histories of toxic exposures: one had grown up in Tom's River, New Jersey, a well documented area of extreme chemical toxicity; another had a sibling with childhood leukemia (which may suggest exposure to chemical toxins) and himself had worked for a chemical company for years, describing the difficulty with dealing with the severe chemical odors. Two others had lived in a home heavily contaminated with molds for years, another had worked with sewage for many years, and another had had unusually extensive dental amalgam work over the years.

In summary, metabolic profiling of patients with cognitive decline, as described previously [5], reveals three readily distinguishable subtypes of Alzheimer's disease: 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.