. Stages of the pathologic process in Alzheimer disease: age categories from 1 to 100 years. J Neuropathol Exp Neurol. 2011 Nov;70(11):960-9. PubMed.


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  1. This is one of the very few large-sample cohort studies on aged-related stages of the pathological process in Alzheimer's disease among the European population. Of a total of 2,332 cases from one to 100 years old, 1,031 (44.2 percent) of them had β amyloid plaques. These plaques were generally found to develop in the forties in 4 percent of these cases, peaking in the tenth decade (75 percent). Neurofibrillary tangles (NFTs) are aggregates of hyperphosphorylated tau protein that are most commonly known as a primary marker of Alzheimer's disease. In this study, β amyloid plaques and argyrophilic neurofibrillary tangles were significantly correlated (p There have been some suggestions that the formation of NFTs is not a causal relationship with disease; rather, that NFTs may be produced in response to a variety of conditions and may be a compensatory response against oxidative stress and serve a protective function. Nevertheless, recent research has suggested that the degree of cognitive impairment in diseases such as AD is significantly correlated with the presence of neurofibrillary tangles (Braskie et al., 2010). In addition, a recent study looked for correlation between the quantitative aspects of Alzheimer's disease (neuron loss, neuritic plaque, and neurofibrillary tangle load) and aggression frequently found in Alzheimer's patients (Lai et al., 2010). It was found that only an increase in neurofibrillary tangle load was associated with severity of aggression and chronic aggression in Alzheimer's patients.

    Hence, further large-scale epidemiological or biological research should be conducted to investigate the causative or predictive factors of Alzheimer's disease at different age categories and sociodemographic backgrounds.


    . Accumulation of abnormally phosphorylated tau precedes the formation of neurofibrillary tangles in Alzheimer's disease. Brain Res. 1989 Jan 16;477(1-2):90-9. PubMed.

    . Plaque and tangle imaging and cognition in normal aging and Alzheimer's disease. Neurobiol Aging. 2010 Oct;31(10):1669-78. PubMed.

    . Hippocampal neurofibrillary tangle changes and aggressive behaviour in dementia. Neuroreport. 2010 Dec 8;21(17):1111-5. PubMed.

  2. Anatomy Leads the Way, But Not Without Physiology
    In their remarkable paper, Braak et al. present a detailed neuroanatomical and temporal map of the appearance and development of pathology associated with Alzheimer's disease in 2,332 non-selected brains from individuals age one to 100 (1). This is an extraordinary study, not only because of the sheer number of brains and brain sections, and state-of-the-art staining and immunohistochemistry procedures, but because it challenges much of the previous work and thinking in the AD pathology field:

    1. Based on the results showing that AD-associated tau lesions are present in the brains of the majority of adolescents and young adults, Braak et al. suggest that the pathologic process underlying sporadic AD is not age dependent.

    2. Based on their finding that “the pre-tangle material that purportedly occurs in axons originates from normal tau proteins bound to axonal microtubules,” the authors challenge the tau microtubule hypothesis, which claims that “hyperphosphorylated tau becomes detached from microtubules and induces failed microtubule transport owing to the accumulation of improperly transported material.”

    3. By showing that “nerve cell nuclei or somatodendritic compartments of affected neurons did not display signs of acute reactive responses that would have indicated a life-threatening event,” the authors question the common assumption that the soluble pre-tangle material is toxic.

    4. The finding that “the pathologic process associated with AD commences with intraneuritic formation of pre-tangle material in the lower brainstem,” primarily in the locus coeruleus, challenges the current thinking that sporadic AD begins in the transentorhinal region of the brain.

    5. Based on the finding that “abnormal tau protein occurred in pre-tangle stages or early NFT stages without the presence of insoluble β amyloid plaques (1,291/2,332 cases),” the authors conclude that the current neuropathological staging NFT categories for AD, and the hypothesis that β amyloid drives AD pathogenesis and secondarily induces the formation of abnormal tau protein, need to be revised.

    Overall, the major paradigm shift promoted by the study by Braak et al. is that the pathological process in sporadic AD “may commence before puberty or in early young adulthood.” This paradigm shift would have profound implications not only for understanding and defining AD, both conceptually and clinically, but also for the diagnostic, prevention, and therapeutic approaches, which, as pointed out by the authors, would need to start during the first decades of life. Clearly, this is an extraordinary development that should attract full attention and a timely response from researchers in the AD and related fields, and, I’m not aware of a better forum for an open evaluation than Alzforum.

    However, the work of Braak et al. has a major weakness, a weakness that it shares with much of the thinking and research on AD and other devastating neurodegenerative disorders, including Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis, and Creutzfeldt-Jakob disease. Because of the old dogma that amyloids are "misfolded proteins," and that these disorders are "protein misfolding diseases," their etiology and the putative pathological mechanisms by which tau, Aβ, α-synuclein, huntingtin, TDP-43, and PrP induce pathology have been disconnected from the normal philological function of these proteins.

    Recently, I proposed a unifying hypothesis on the function of tau, β amyloid, and other primary proteins implicated in neurodegenerative and systemic amyloid disorders in innate immunity (2). In the context of this hypothesis, “the stages of the pathological process” mapped by Braak et al., such as the "intraneuronal formation of abnormal tau protein," are normal events associated with physiological function of this protein and its various isomeric conformers in immunity, which explains their presence early in life. Interestingly, this hypothesis is consistent with the new finding by Braak et al. regarding the incipient formation of tau pre-tangle material in the locus ceruleus and other nuclei of the lower brainstem, which represent putative portals for the entry of neurotropic pathogens into cortical regions.

    References: See also Bandea, C.I. October 19, 2011. AD, PD, HD, ALS, FTLD-U, CJD and RSA are autoimmune disorders: a unifying hypothesis on the function of Aβ, Tau, α-Synuclein, Huntingtin, TDP-43, PrP and AA in innate immunity. ARF Current Hypotheses.


    . Stages of the pathologic process in Alzheimer disease: age categories from 1 to 100 years. J Neuropathol Exp Neurol. 2011 Nov;70(11):960-9. PubMed.

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  1. In Pursuit of Toxic Tau