Historic evidence to support a causal relationship between spirochetal infections and Alzheimer's disease

Abstract

Following previous observations a statistically significant association between various types of spirochetes and Alzheimer's disease (AD) fulfilled Hill's criteria in favor of a causal relationship. If spirochetal infections can indeed cause AD, the pathological and biological hallmarks of AD should also occur in syphilitic dementia. To answer this question, observations and illustrations on the detection of spirochetes in the atrophic form of general paresis, which is known to be associated with slowly progressive dementia, were reviewed and compared with the characteristic pathology of AD. Historic observations and illustrations published in the first half of the 20th Century indeed confirm that the pathological hallmarks, which define AD, are also present in syphilitic dementia. Cortical spirochetal colonies are made up by innumerable tightly spiraled Treponema pallidum spirochetes, which are morphologically indistinguishable from senile plaques, using conventional light microscopy. Local brain amyloidosis also occurs in general paresis and, as in AD, corresponds to amyloid beta. These historic observations enable us to conclude that chronic spirochetal infections can cause dementia and reproduce the defining hallmarks of AD. They represent further evidence in support a causal relationship between various spirochetal infections and AD. They also indicate that local invasion of the brain by these helically shaped bacteria reproduce the filamentous pathology characteristic of AD. Chronic infection by spirochetes, and co-infection with other bacteria and viruses should be included in our current view on the etiology of AD. Prompt action is needed as AD might be prevented.

Keywords: Alzheimer’s disease; Borrelia burgdorferi; Treponema pallidum; Treponema spirochetes; dementia; general paresis; oral spirochetes; syphilis.

Figure 1

Reproduction of illustrations published by Pacheco e Silva (1926–1927) showing plaque-like spirochetal colonies in the cerebral cortex of patients suffering from the atrophic form of general paresis. (A) Argyrophilic spirochetal colonies are visible in the parietal cortex, morphologically similar to senile plaques. The legend used by the author himself: “Colonias de espirochetas em torno dos capillares periphericos do cerebro. Lobo parietal. Caso de paralysia geral. Meth. Jahnel. Pequeno augmento.” (B) At higher magnification the colonies are made up by individual spirochetes. (C) Further magnification of part of panel (B) showing the typical spiral appearance (arrow) of T. pallidum spirochetes. (D,E) Cortical spirochetal colonies morphologically undistinguishable from argyrophilic immature and perivascular senile plaques. These illustrations were reproduced from the original Figures 14A; 11B, C; 5/IID and 7E of Pacheco e Silva (1926–1927).

Figure 2

Comparison of the morphology of senile plaques and spirochetal colonies in general paresis. (A,B) Early (A) and degenerated (B) spirochetal colonies in the atrophic form of general paresis. (C,D): Immature (C) and mature (D) senile plaques in Alzheimer’s disease (AD). Cortical paraffin sections of an AD case stained with Bosma-Steiner silver impregnation technique for the detection of spirochetes. Spirochetal colonies in (A,B) show the same morphological features as senile plaques in (C,D). Panels (A,B) were reproduced from Figure 1 of Steiner (1940) who noticed with respect to (A) “Note the spread of spirochetes from the center and the peripheral liquefaction of tissue” and with respect to (B): “A yellow center is shown, and the peripheral zones consist of a black ring with degenerating spirochetes and granules of spirochetal debris.” Permission for the reproduction was kindly provided by the American Medical Association (Copyright 1940). Bar: is the same for (A–D) and corresponds to 40 μm.

Figure 3

Morphological similarity of perivascular spirochetal accumulation in general paresis with a small perivascular plaque in the cerebral cortex in AD. Compare (A), showing perivascular accumulation of spirochetes in general paresis with (B) where an amorphous perivascular cortical plaque is illustrated in AD stained with Bosma-Steiner silver technique. Panel (A) is reproduced from Figure 4 of Hauptmann (1920). Bar: 5 μm.

Figure 4

Disseminated form of cortical spirochetosis in general paresis showing striking similarity to disseminated curly fibers in AD. Compare (A), where each filament corresponds to individual Treponema pallidum spirochete in general paresis, with (B), where Gallyas silver impregnation technique shows disseminated curly fibers in the frontal cortex of an AD patient. (A) is reproduction of part of Figure 6 of Hauptmann (1920). Bars: 15 μm.

Figure 5

The brain amyloid deposits in general paresis, as in AD, corresponds to beta amyloid. (A) Cortical amyloid deposits in the brain in syphilitic dementia showing positive immunoreaction with anti-Aβ 8–17 (6F/3D, DakoCytomation) antibody. (B) Beta amyloid deposition similar to immature and mature plaques was observed. (C) Beta amyloid deposits in the wall of leptomeningeal arteries in the same case as (A). For the immunohistochemical analysis of Aβ, the avidin-biotine-peroxidase technique was used and the paraffin sections were pre-treated with 80% formic acid for 20 min. Bar: 50 μm. Panels (A) and (C) were reproduced form Figure 2 of Miklossy et al. (2006b).