Journal of Alzheimer’s Disease

This team takes the position that what is commonly referred to as non-familial Alzheimer’s disease (AD) is predominantly due to genetic factors. Population-based studies suggest that genetic factors cause the majority of cases that begin after age 60. There are several lines of evidence supporting this position:

Data from the Nun Study suggest that the risk for AD is largely established by early adulthood, implying that later adult exposures likely play only a small role in causation.

The proposition that environmental agents, such as diet, aluminum, and viruses, are as important as genetic factors in the etiology of Alzheimer's disease (AD) was advanced by the authors at the Challenging Views of Alzheimer's Disease meeting held in Cincinnati on July 28 and 29, 2001. Diet, dietary fat, and to a lesser extent, total energy (caloric intake), were found to be significant risk factors for the development of AD in a dozen countries, while fish consumption was found to be a significant risk reduction factor. An acid-forming diet, such as one high in dietary fat or total energy, can lead to increased serum and brain concentrations of aluminum and transition metal ions, which are implicated in oxidative stress potentially leading to the neurological damage characteristic of AD. Many of the risk factors for AD, such as cholesterol and fat, and risk reduction factors, such as whole grain cereals and vegetables, are shared with ischemic heart disease. Aluminum may cause neurological damage and a number of studies have linked aluminum to an increased risk for developing AD. The evidence for viral agents playing a role in AD is the strong association between the presence of HSV1 in brain and carriage of an apoE-ε4 allele in the case of AD patients but not of controls; statistical analysis shows the association is causal. Diet, aluminum, and viral infections may increase the prevalence of AD by eliciting inflammation, which may cause the neurological damage that results in AD.

Alzheimer's disease (AD) brain is characterized by excess deposition of amyloid β-peptide (Aβ), particularly the 42-amino acid peptide [Aβ(1-42)] and by extensive oxidative stress. Several sources of the oxidative stress and inflammatory cascades are likely, including that induced by advanced glycation end products, microglial activation, and by Aβ(1-42) and its sequelae. This review briefly examines each of these sources of oxidative stress and inflammation in AD brain and discusses their potential roles in the clinical progression of AD dementia.

Neuronal cell death is the primary underlying pathogenic lesion in Alzheimer's disease (AD). Despite intense research efforts, the mechanisms that contribute to neuronal cell death have not been clarified. In this debate we address the question, Is AD a vascular or metabolic disorder? Here we defend the hypothesis that the cerebromicrovasculature is a key player in the pathogenesis of AD. Evidence is presented that vascular amyloid β (Aβ) is more closely associated with tau pathology than the distribution of diffuse or neuritic plaque Aβ. Furthermore, brain endothelial cells are identified as important regulators of the neuronal microenvironment, including Aβ levels. Finally, evidence is presented that brain endothelial cells undergo cellular and biochemical changes in AD and that the release of neurotoxic factors from these dysfunctional cells contributes to the neuronal cell loss characteristic of AD.

This paper discusses the hypothesis that the cerebrometabolic deficiency in Alzheimer's disease(AD) is the proximate cause of the clinical disability. Several sets of observations support this hypothesis. (1) Impaired brain metabolism essentially always occurs in clinically significant AD, and the degree of clinical disability is proportional to the degree of metabolic impairment. The earliest, mildest changes in brain metabolism occur even before the onset of measurable cognitive impairment or atrophy. This observation disproves the now outdated assumption that the decreased metabolism is simply a consequence of decreased mental function or of atrophy. One of the important mechanisms reducing brain metabolism in AD appears to be damage to key mitochondrial components. Another appears to relate to inappropriate responses to insulin, i.e. to diabetes of the brain. (2) Inducing impairments of brain metabolism causes changes in mentation that mimic the clinical disabilities in AD, in both humans and experimental animals. (3) Preliminary results from several units suggest that treatment directed at the impairment of brain metabolism can improve neuropsychological functions in AD patients.

The hypothesis presented here in no way negates the importance of other mechanisms in AD, such as amyloid accumulation, vascular compromise, and free radical action. However, those other abnormalities including amyloidosis can occur in people whose mentation is still clinically unimpaired. In contrast, once significant decrease in the rate of brain metabolism occurs, mentation becomes defective.