Epidemiological evidence indicates that Alzheimer's disease is initiated by the precipitation of aluminosilicates in the extracellular fluid of the brain. The resulting miniscule, charged particulates serve as nidi for amyloid deposition and induce tangle formation in neurons. The frequency and severity of these precipitation events is dependent upon blood levels of silicic acid and aluminum which in turn is directly related to the intake of silicic acid in drinking water and the prevalence of aluminum in the diet, especially aluminum-containing leavening agents. Longevity increases the probability of precipitations and facilitates the unremitting aggregation of amyloid.

View all comments by Colin Meyer

My pet theory is accumulation of inappropriate protein conformations

View all comments by Paul Coleman

Redundancy exhaustion for biological systems probably can contribute as one of the main aging components.

On the level of a brain, it is the rate of atrophy, or fraction of brain left with capacity to redundancy.

View all comments by Svetlana Egorova

There is maybe an unknown aging mechanism that causes amyloid peptide to form oligomers and despoit easier.Then neuron cell die further...

View all comments by shen chengyong

I think as we age our cells, including nerves, become less flexible or less able to change modes/states properly. Consider the possiblility that cells could have modes/states of function: growth mode, function mode, hormone secretion mode, etc. If the function-state is the normal stable mode, then one could invision a cell shifting into a risk-mode to accomplish a task then shifting back to function-mode when it is done. I am suggesting that: as we age this ability to change gears becomes problematic. As we age a variety of factors could hinder the cells ability to change gears or shift back into function mode, but all of these different factors would point to one set of keys, a family of proteins. I think SERPINS & serine proteases are the keys. (I have a theory on the hypothesis factory page) Does this make sense? I hope it inspires new ideas. Angela Biggs

View all comments by Biggs Angela

My pet theory is primary cholesterol and other membrane lipid abnormalities. See ARF hypothesis for futher details ( URL: http://www.alzforum.org/res/adh/cur/koudinov/default.asp )

View all comments by Alexei R. Koudinov

The role of cell-specific carbonic anhydrase enzymes in cellular death in aging, which includes Alzheimer's disease
The mechanism and the functions of carbonic anhydrase enzymes have been poorly understood by the medical community until now. Carbonic anhydrase enzymes in humans are further divided into CA1, 2, 3, 4, 5, 6, and 7, which are cell-specific, meaning that they are produced by specific types of cells in the human body.

Aside from carbon dioxide hydration, maintaining the acid base balance, PO2/CO2 ratio, ionic transport process, ester hydrolysis, and phosphatase, the newly discovered function is that these enzymes produce hydrogen ions, which are acted upon the cytochrome system and utilized as fuel (ATP) for the ion pump that maintains the integrity of the cell wall membrane, and also as fuel (ATP) for other cellular functions. Disruption of this process leads to dying and dead cells.

Carbonic anhydrase enzymes are zinc enzymes. Any disease or condition that alters the blood-brain barrier that seeks the displacement of zinc from carbonic anhydrase...  Read more

The role of cell-specific carbonic anhydrase enzymes in cellular death in aging, which includes Alzheimer's disease
The mechanism and the functions of carbonic anhydrase enzymes have been poorly understood by the medical community until now. Carbonic anhydrase enzymes in humans are further divided into CA1, 2, 3, 4, 5, 6, and 7, which are cell-specific, meaning that they are produced by specific types of cells in the human body.

Aside from carbon dioxide hydration, maintaining the acid base balance, PO2/CO2 ratio, ionic transport process, ester hydrolysis, and phosphatase, the newly discovered function is that these enzymes produce hydrogen ions, which are acted upon the cytochrome system and utilized as fuel (ATP) for the ion pump that maintains the integrity of the cell wall membrane, and also as fuel (ATP) for other cellular functions. Disruption of this process leads to dying and dead cells.

Carbonic anhydrase enzymes are zinc enzymes. Any disease or condition that alters the blood-brain barrier that seeks the displacement of zinc from carbonic anhydrase enzymes leads to deficiencies of carbonic anhydrase, including lead, copper, mercury, aluminum, and other neurotoxic materials.

Defective gene-linked carbonic anhydrase also causes deficiencies of cell-specific CA.

Deficiencies of intracellular zinc (found in cell-specific carbonic anhydrase enzymes) induce apoptosis, which leads to dead and dying brain cells. Elemental zinc does not cross the blood-brain barrier in humans, but deposits in the plaques.

Dead brain cell—tau proteins and neurofibrillary tangles—serves as nidus for the formation of plaques.

Carbonic anhydrase enzymes are produced by hormones such as growth hormone, sex hormones, DHEA, and others. In aging there is a loss of hormonal activity.

In summary, in aging there is progressive deficiency of cell-specific carbonic anhydrase enzymes, leading to progressive gradual death of cells such as that found in Alzheimer's disease.

For further information kindly refer to: WIPO World Intellectual Property Organization, publication# 03070167A3. Click News and Information, then click Patents, then click All, then search IN/"Rodriguez Victorio" or BME/"03070167A3.

References:
Chai F, Truong-Tran AQ, Evdokiou A, Young GP, Zalewski PD. Intracellular zinc depletion induces caspase activation and p21 Waf1/Cip1 cleavage in human epithelial cell lines. J Infect Dis. 2000 Sep;182 Suppl 1:S85-92. Abstract

Ermini M, Moret ML, Reichlmeier K, Dunne T. Age-dependent structural changes in human neuronal chromatin. Aktuelle Gerontol. 1978 Dec;8(12):675-80. Abstract

U.S. Patent # 5,972,684, Badman et al.

View all comments by Victorio Rodriguez

Comment by Roy O. Weller, Roxana Carare-Nnadi, and James A.R. Nicoll
Hypothesis:

Cerebrovascular disease impedes the drainage of Aβ from the brain and this is a major factor in the pathogenesis of Alzheimer’s disease (1, 2).

Such failure of elimination of Aβ is a major factor in the accumulation of insoluble Aβ in blood vessel walls as cerebral amyloid angiopathy and as plaques in brain parenchyma with increasing age (3, 4). Ultimately, drainage of soluble Aβ and other soluble metabolites fails and dementia ensues (5, 6).

The evidence for this working hypothesis is to be found in an expanded form on the ARF Live Discussion Vascular Factors in Alzheimer’s Disease, near the end of the discussion entitled “The hypothesis of Aβ drainage.”

References:
1. Weller RO, Massey A, Kuo YM, Roher AE. Cerebral amyloid angiopathy: accumulation of A beta in interstitial fluid drainage pathways in Alzheimer's disease. Ann N Y Acad Sci 2000,903:110-7.   Read more

Comment by Roy O. Weller, Roxana Carare-Nnadi, and James A.R. Nicoll
Hypothesis:

Cerebrovascular disease impedes the drainage of Aβ from the brain and this is a major factor in the pathogenesis of Alzheimer’s disease (1, 2).

Such failure of elimination of Aβ is a major factor in the accumulation of insoluble Aβ in blood vessel walls as cerebral amyloid angiopathy and as plaques in brain parenchyma with increasing age (3, 4). Ultimately, drainage of soluble Aβ and other soluble metabolites fails and dementia ensues (5, 6).

The evidence for this working hypothesis is to be found in an expanded form on the ARF Live Discussion Vascular Factors in Alzheimer’s Disease, near the end of the discussion entitled “The hypothesis of Aβ drainage.”

References:
1. Weller RO, Massey A, Kuo YM, Roher AE. Cerebral amyloid angiopathy: accumulation of A beta in interstitial fluid drainage pathways in Alzheimer's disease. Ann N Y Acad Sci 2000,903:110-7. Abstract

2. Weller RO, Massey A, Newman TA, Hutchings M, Kuo YM, Roher AE. Cerebral amyloid angiopathy: amyloid beta accumulates in putative interstitial fluid drainage pathways in Alzheimer's disease. Am J Pathol 1998,153:725-33. Abstract

3. Preston S D, Steart PV, Wilkinson A, Nicoll JAR, Weller RO. Capillary and Arterial Amyloid Angiopathy: Deliniation of the Perivasular Route for Elimination of Amyloid-beta from the Human Brain. Neuropathology and Applied Neurobiology 2003,29:106-117. Abstract

4. Weller RO, Nicoll JAR. Cerebral Amyloid Angiopathy: Pathogenesis and effects on the ageing and Alzheimer brain. Neurological Research 2003,25:611-616. Abstract

5. Lue LF, Kuo YM, Roher AE, Brachova L, Shen Y, Sue L, Beach T, Kurth JH, Rydel RE, Rogers J. Soluble amyloid beta peptide concentration as a predictor of synaptic change in Alzheimer's disease. Am J Pathol 1999,155:853-62. Abstract

6. McLean CA, Cherny RA, Fraser FW, Fuller SJ, Smith MJ, Beyreuther K, Bush AI, Masters CL. Soluble pool of Abeta amyloid as a determinant of severity of neurodegeneration in Alzheimer's disease. Ann Neurol 1999,46:860-6. Abstract

View all comments by Roxana O. Carare
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Sex, Aging and Alzheimer’s Disease
Results from a previous poll on the Alzheimer Research Forum (What New Year Resolutions have you made in hopes of reducing your risk of Alzheimer's?) show a strong majority favor (“More Sex”). While perhaps revealing more than one might want to know about the lives (or lack thereof) of researchers in the field, sex may also provide the answer to this month's teaser (What is the most likely mechanism by which aging contributes to AD pathogenesis?). Specifically, in a futile effort to reignite the aged reproductive system, we propose that age-related increases in constituents of the hypothalamic pituitary gonadal (HPG) axis (Smith et al., 2003), such as luteinizing hormone, play a fundamental role in disease pathogenesis (reviewed in Webber et al., 2004). In support of this, we have shown that luteinizing hormone is significantly elevated in both the sera (Bowen et al., 2000) and brain tissue (Bowen et al., 2002) of patients with Alzheimer’s disease and leads to an...  Read more

Sex, Aging and Alzheimer’s Disease
Results from a previous poll on the Alzheimer Research Forum (What New Year Resolutions have you made in hopes of reducing your risk of Alzheimer's?) show a strong majority favor (“More Sex”). While perhaps revealing more than one might want to know about the lives (or lack thereof) of researchers in the field, sex may also provide the answer to this month's teaser (What is the most likely mechanism by which aging contributes to AD pathogenesis?). Specifically, in a futile effort to reignite the aged reproductive system, we propose that age-related increases in constituents of the hypothalamic pituitary gonadal (HPG) axis (Smith et al., 2003), such as luteinizing hormone, play a fundamental role in disease pathogenesis (reviewed in Webber et al., 2004). In support of this, we have shown that luteinizing hormone is significantly elevated in both the sera (Bowen et al., 2000) and brain tissue (Bowen et al., 2002) of patients with Alzheimer’s disease and leads to an increased production of amyloid-β in vitro (Bowen et al., 2004). A key role in the disease process is further bolstered by the parallel distribution of neuronal receptors for luteinizing hormone with populations of neurons that degenerate during the course of the disease (Lei and Rao, 2001). Based on these factors, the effects of agents that abolish luteinizing hormone, such as leuprolide acetate, are currently being evaluated in (Phase II clinical trials) for the treatment of Alzheimer’s disease.

References:
Bowen RL, Isley JP, Atkinson RL (2000) An association of elevated serum gonadotropin concentrations and Alzheimer disease? J Neuroendocrinol 12, 351-354. Abstract

Bowen RL, Smith MA, Harris PL, Kubat Z, Martins RN, Castellani RJ, Perry G, Atwood CS (2002) Elevated luteinizing hormone expression colocalizes with neurons vulnerable to Alzheimer's disease pathology. J Neurosci Res 70, 514-518. Abstract

Bowen RL, Verdile G, Liu T, Parlow AF, Perry G, Smith MA, Martins RN, Atwood CS (2004) Luteinizing hormone, a reproductive regulator that modulates the processing of amyloid-beta precursor protein and amyloid-beta deposition. J Biol Chem, Feb 9 [Epub ahead of print] Abstract

Lei ZM, Rao CV (2001) Neural actions of luteinizing hormone and human chorionic gonadotropin. Semin Reprod Med 19, 103-109. Abstract

Smith MA, Perry G, Atwood CS, Bowen RL (2003) Estrogen replacement and risk of Alzheimer disease. JAMA 289, 1100. Abstract

Webber KM, Bowen R, Casadesus G, Perry G, Atwood CS, Smith MA (2004) Gonadotropins and Alzheimer’s disease: the link between estrogen replacement therapy and neuroprotection. Acta Neurobiol Exp 64, 113-118.

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