While the etiopathogenesis of Alzheimer’s disease (AD) still remains unresolved, a growing body of evidence indicates the involvement of the immune system. Yet, both character and the significance of the observed alterations are matter of dispute.
During the seventies and eighties of the 20th century a high amount of literature accumulated dealing with the impact of immunological factors on neurobehavioral pathology associated with aging and AD (Richartz et al. 2004).
The putative relevance of inflammatory processes is shown by over 20 epide-miological studies suggesting a potential benefit of antiinflammatory intervention (Akiyama et al. 2000; McGeer and McGeer 1999). Further indication of a patho-physiological role of inflammation in AD is given by the presence of inflammatory mediators in the AD brain, including proinflammatory cytokines, acute phase pro-teins and the full complement cascade (Hüll et al. 1996; Mrak et al. 1995; Tarkowski et al. 1999). In summary, data available suggest that the AD brain undergoes chronic inflammatory process mediated by activated glial cells, targeted on the destruction of senile plaques, but lethal to surrounding neurons (McGeer & McGeer 2003).
The understanding that the brain is not that immunologically privileged site that it has been considered before is the result of modern psychoneuroimmunologi-cal research. There is an active and highly regulated communication between the
Decline of Immune Responsiveness: A Pathogenetic Factor in Alzheimer’s Disease?Elke Richartz-Salzburger and Niklas Koehler
3.1 In Vivo Concentrations of Cytokines and Soluble Receptors in CSF and Serum. . 12793.2 Production of Cytokines in Stimulated Blood Cell Cultures (Figs. 1, 2) . . . . . . . . 1279
E. Richartz-Salzburger ( ) · N. KoehlerDepartment of Psychiatry and PsychotherapyUniversity of TübingenOsianderstrasse 24DE-72076 Tübingen, GermanyE-mail: [email protected]
1276 E. Richartz-Salzburger and N. Koehler
brain and the immune system, and consequently, peripheral reactions can influence the cerebral immune response. Vice versa, cerebral immune processes can lead to peripheral immune alterations.
Against this background, numerous studies have been carried out focusing peripheral immunological alterations in AD.
In particular, the occurrence of brain—reactive autoantibodies in serum of patients with AD has raised the question of whether autoimmune processes could contribute to the clinical syndrome. Experimental animal studies have suggested a relationship between autoimmune status and age-associated cognitive decline (Richartz et al. 2004). In demented patients, serum autoantibodies against several self-antigens have been observed. However, the increase of autoantibody concentra-tions in the serum is not specific, but rather reflects age-dependant effects on the immune status of the patients (Schott et al. 1996, 1997).
Further studies did not confirm the presence of increased antibodies concen-trations in AD. Antibodies against CD95 are increased in other neurodegenerative disease such as ALS or Parkinson’s disease, but are decreased in AD (Appel and Sengun 2003). As to organ specific CNS antigens, a decreased incidence of autoan-tibodies against gm1 gangiliosides in CSF was observed (Richartz et al. 2004]). Moreoever, the natural antibodies against amyloid protein supporting the degrada-tion of cerebral ß-amyloid, are decreased in AD patients (Du et al. 2001; Weksler et al. 2002).
Taken together, investigations of autoantibodies remained contradictory. The results did not sustain the neuroautoimmune model (Aisen and Davies 1994; Singh 1997) suggesting that neurodegeneration in AD is a consequence of classical autoimmune processes.
Rather, recent findings point to a decrease instead of an increase of antibody concentrations (Richartz et al. 2004).
With the development of more sophisticated techniques, the investigation of cytokines as essential immune mediators advanced, and studies on cytokine altera-tions of cytokines seemed more promising.
As to their origin, it seemed reasonable to postulate a link between the cytokine profile in the blood stream and that in the brain, because there is an active and highly regulated communication between the brain and the immune system (Huberman et al. 1994). On this background, several studies on inflammatory markers in serum and CSF in AD patients have been carried out, in attempt to find a premortem diagnostic marker for AD. First, it seemed consequent that the local inflammatory processes would be associated with systemic inflammatory signs. However, data remained inconsistent and, hitherto, do not allow drawing definite conclusions. Guided by cerebral findings, numerous studies focused on the peripheral secretion of proin-flammatory cytokines. In CSF, increased levels of proinflammatory cytokines (Bagli et al. 2003; Blum-Degen et al. 1995), unchanged levels (Lanzrein et al. 1998; März et al. 1997; Tarkowski et al. 1999) and decreased levels (Singh 1994; Yamada et al. 1995) have been found in AD. Of similar inconsistence are the findings in serum: Some working groups report elevated levels of proinflammatory cytokines (Kalman
Decline of Immune Responsiveness: A Pathogenetic Factor in Alzheimer’s Disease? 1277
et al. 1997; Licastro et al. 2000; Lombardi et al. 1999; Singh and Ghutikonda 1997), other do not see any changes (Androsova et al. 1995; Esumi et al. 1991; Lanzrein et al. 1998), while several find a decrease of proinflammatory cytokine secretion (Cacabelos et al. 1994; De Luigi et al. 2001; Paganelli et al. 2002; Sala et al. 2004). These discrepancies have mostly been attributed to technically different approaches and to different criteria to choose patient groups as well as control groups. Moreo-ver, most of the studies report very low cytokines levels nearby their detection limit, so that statistical evaluation is restricted. However, within the confusing variety of systemic findings it is becoming increasingly substantiated that AD patients exhibit systemic immunological alterations, which do not just reflect the inflammatory proc-esses in the brain. It has been stated that the neuroinflammatory events found in the brain and CSF of AD patients seem to be limited to the CNS without direct associa-tion of a peripheral inflammation (Blum-Degen et al. 1995).
Own studies were carried out on the hypothesis that AD patients display sys-temic immunological alterations in terms of a dysregulation or impairment of the immune response, which do not only reflect an epiphenomenon, but may causally be related to the Alzheimer’s pathology (Richartz et al. 2005). On the assump-tion that various immune functions, not only of the proinflammatory response, are hampered in AD, we investigated the cytokine secretion of TH 1 cells, TH 2 cells, as well as of the macrophage/moncyte system. In a preliminary study, we measured the concentrations of the proinflammatory cytokines IL-1ß, IL-2, IL-6, and TNF- α, as well as of the soluble receptors sIL-2r, sIL-6r, and sTNF-αr in cerebrospinal fluid (CSF) and in serum of Alzheimer patients and controls. With respect to the low concentration values, we then stimulated whole blood cell cultures with mitogens, leading to higher cytokine levels. After mitogenous stimulation, we measured the increase of cytokine levels above basal levels of the proinflammatory cytokines IL-6, IL-12, IFN-y and TNF-α, and of the antiinflam-matory cytokines IL-5 and IL-13.
2 Subjects and Methods
Recruitment of AD patients was done at the University Clinic for Psychiatry Tue-bingen, Germany. The diagnosis of probable AD was performed according to the NINCDS-ADRDA criteria (McKhann et al. 1984). Control subjects for CSF and serum investigations were chosen from the Department of Neurology, Goettingen, Germany. Lumbar punction was carried out either in patients with questionable disc prolapse, who underwent radiological examination with contrast medium, or in patients suspected of having an inflammatory or other CNS disease. Their CSF sta-tus was normal as regards cell count, albumin and IgG, as were all measured serum parameters. Any organic CNS disease was excluded in all of these persons. For cell cultures, control blood was gained by healthy aged persons, who were recruited through advertisement in the local press.
1278 E. Richartz-Salzburger and N. Koehler
A comprehensive somatic, psychiatric, and socio-demographic history was taken of all persons. All subjects underwent thorough psychiatric and neurological examination including EEG and neuroimaging (CT or NMR). Cognitive decline was measured by the Mini Mental State Test (MMST, Folstein et al. 1974). Total blood count and blood chemistry including C reactive protein, thyroid function, vitamin B12, Folic acid, Borrelia and Lues serology was evaluated. Patients with a psychiatric, neurological, inflammatory or infectious disease or with a history of immunological or malignant disease were excluded, as well as persons with abnormal white blood cell count, C reactive protein or signs of malnutrition. Further exclusion criteria were the intake of immunologically relevant or psy-chotropic drugs and a positive family history for dementia. All control subjects underwent the same clinical examinations including MMST and laboratory tests as the AD patients. The same exclusion criteria were applied. MMST of controls had to be normal.
In vivo concentrations of cytokines and soluble receptors in CSF and serum were determined in twenty patients with probable AD (16 female and 4 male, 60–88 years, median 72 years). The MMST score was in the range of 10–23, with a median of 16. As controls, we investigated CSF and serum samples from 21 subjects (7 female, 14 male, 59–82 years, median 68 years). For studying cytokine production in stimulated blood cell cultures, further 27 patients, 18 of them females, 9 males, with probable AD and 23 healthy aged volunteers, 16 females and 7 males, were included. The median age of the Alzheimer patients was 70 years (63–84 years), of the control persons 68 years (59–77 years). The MMSE score ranged between 11 and 21 in the patient group (Median: 17.3). Mean of Alzheimer disease duration was 2.5 years (1.5–3.4 years). The groups for native and stimulated cytokine investigations were comparable with respect to age and disease duration.
The investigation was carried out in accordance with the Declaration of Helsinki. Written informed consent was given from all subjects or their relatives following full explanation of the procedure. The study was carried out after approval by the local ethics committee.
Samples were collected at routine venipuncture between 8:00 and 9:00 am in order to take in account the circadian rhythm. For in vivo cytokine measurement, blood samples were centrifuged and the serum frozen at–20° C until analysis. CSF was obtained by lumbar punction, centrifuged and frozen at–20° C until analy-sis. For blood cell stimulation, whole blood samples were cultured following the Lubeck protocol (Kirchner et al. 1982). Peripheral blood cells were stimulated with LPS and PHA, for 48 and 96 h, respectively. After centrifugation supernatants were stored at –80° C until measurement. Cytokine concentrations were determined using commercially available ELISA kits (IL-1ß, IL-6, TNF-α, IFN-γ, sIL-2r:Mile-nia, Bad Nauheim, Germany; IL-5, IL-12, IL-13, sIL-6r, sTNF-αr:R&D Systems, Wiesbaden, Germany). Based on preliminary experiments, for each cytokine the time of stimulation was chosen according to the time of maximal induction. IL-5, IL-6, IL-13, and TNF-α were measured after 48 h of stimulation, IL-12 after 72 h, IFN-γ after 96 h of stimulation.
Decline of Immune Responsiveness: A Pathogenetic Factor in Alzheimer’s Disease? 1279
For statistical analysis, the differences between the patients and control groups were analyzed by Wilcoxon rank sum test and χ 2 test. The Bonferroni adjustment for multiple comparisons was applied.
3 Results
3.1 In Vivo Concentrations of Cytokines and Soluble Receptors in CSF and Serum
The data of this study are compiled in Table 1. The concentration of IL-2 in CSF as well as serum levels of IL-1ß, IL-2 and TNF-α were too low to reach detection limit. Regarding the other values, we found a decrease of all parameters in CSF and serum of the AD patients compared with the control group. Considering a p-value of less than 0.005 (n=10), Bonferroni adjustment showed a statistically significant decrease of TNF-α in CSF ( p <0.0001) and of IL-6 in serum ( p <0.0012) of the AD patients. There was no effect of gender (Kendall tau b correlation) and age (Pear-son correlation). The diminished levels were not correlated with disease duration (MMST values) or severity.
3.2 Production of Cytokines in Stimulated Blood Cell Cultures (Figs. 1, 2)
We determined the ability of blood cells to produce the proinflammatory cytokines IL-6, IL-12, TNF-α and IFN- , and the T-helper (TH)-2-cell derived antiinflam-matory cytokines IL-5 and IL-13. As illustrated in figs. 1, 2, the AD group shows reduced levels of all cytokines after mitogen-induced whole blood stimulation in comparison with the control group. On account of Bonferroni adjustment, a p value
Table 1 Cytokine concentrations in CSF and serum (pg/ml): mean and standard error of the mean (S.E.M.) (in parentheses); (*) = p < 0,005 (Bonferroni adjustment); “-“: levels under detec-tion limit
Fig. 1 Release of proinflammatory cytokines (in pg/ml, with SEM) in mitogen-stimulated whole-blood cell cultures from AD-patients (AD) and controls (Ctrl)
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Fig. 2 Release of antiinflammatory cytokines (in pg/ml, with SEM) by mitogen-stimulated whole-blood cell cultures from AD-patients (AD) and controls (Ctrl)
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Decline of Immune Responsiveness: A Pathogenetic Factor in Alzheimer’s Disease? 1281
of less than 0,008 (n=6) was considered statistically significant. Thus, a high sig-nificance was shown for the decrease of IL-6 ( p <0.001), IFN- ( p <0.0002), TNF-α ( p <0.0005) and of IL-5 ( p <0.001). IL-12 was decreased with p<0.019, IL-13 with p<0.023. The results remained significant also after stepwise regression control to exclude the possible influence of age and sex. No correlation was found between the cytokine levels and duration of disease or severity of disease, respectively.
4 Discussion
The role of the immune system in the pathogenesis of AD has been widely dis-cussed. Since AD is no longer regarded as a single unified condition but as a complex syndrome, it has been postulated that the presence of different clinical subgroups may imply a differential involvement of the immune system (Huberman et al. 1994; Licastro et al. 2000).
4.1 Cytokine Measurement in AD
The literature on peripheral cytokine secretion in AD is various, and findings remain inconsistent and intricate to interprete. Obvious methodological differences among studies, including inclusion criteria and differences in the techniques used to meas-ure cytokines contribute to the great variability of data. Sample sizes show consid-erable differences, and the patient groups differ with respect to stage of dementia, further pathological conditions and drug intake. Moreover, varying cytokine levels may also be due to genetic polymorphisms (Bagli et al. 2003). Therefore, the meas-urement of a single cytokine does not allow any conclusions on disease dependent effects. Rather, an overlapping set of cytokines as presented in this study may give more information. Most importantly, cytokine production is highly dependent on the health status. Previously reported higher levels of proinflammatory cytokines in aged persons as well as in AD might reflect an underlying but undiagnosed disease state (Beharka et al. 2001). On this background, in our study we excluded each person with the slightest sign of infection or other medical disease, because any comorbidity could influence the cytokine production. Moreover, since treatment with acetylcholinesterase inhibitors may modulate cytokine expression (Reale et al. 2004) patients only were included before starting antidementive therapy. The meas-urement of cytokine secretion was done using stimulated whole blood cell cultures. Whole blood cultures resemble more closely the in vivo situation since manipula-tion, prestimulation, and possible selection of PBMC are minimized, and the role of plasma factors is included.
We observed diminished levels of proinflammatory cytokines in CSF and serum and of the soluble receptors in the AD group compared with healthy, aged controls. In summary however, these in vivo concentrations have been shown to be very low.
1282 E. Richartz-Salzburger and N. Koehler
Critical parameters influencing cytokine levels in CSF are, e.g., the relatively large volume and the dynamics of the CSF system, the brain CSF barrier as well as the distance of the liquor system from the relevant brain regions (März et al. 1994). Similarly, some native cytokine concentrations in serum were near or under the detection limit. In contrast to our results, other investigators were able to found measurable cytokine levels. This discrepancy could be explained by undiagnosed comorbidity or intake of drugs leading to altered cytokine secretion. More impor-tant may be technical differences, particularly concerning origin, structure and sen-sitivity of the antibodies applied in the different ELISA kits.
Findings in stimulated blood cell cultures are much more expressive, since cytokine levels are markedly higher, and differences between groups are depicted more clearly. Moreover, the relative increase of cytokine levels upon stimula-tion reflects the functional responsiveness of the particular immune cells on inflammatory stimuli. In our study, the increase of all measured cytokines, i.e. IL-5, IL-6, IL-12, IL-13, TNF-α and IFN- in whole-blood cell cultures stimulated with mitogens, is significantly lower in AD patients than the increase of cytokine levels in the control group. The finding of an unidirectional decrease of all meas-ured cytokines points to a general dysfunction of the cellular immune response to stimulating agents. The main source of IL-6, IL-12, TNF-α and IFN- is the monocyte/macrophage system. Moreover, IFN-y, and to a lower degree TNF- , are also expressed by TH-1 cells. TH-1cells play a central role in the activation of the monocyte system. Additionally, they induce B-cells to produce opsoniz-ing antibodies. Opsonizing, again, promotes phagocytosis. Thus, a diminished production of these cytokines may be associated with an impaired phagocytic activity. As phagocytosis is essential for the removal of foreign bodies, debris and dysfunctional proteins, impairment can lead to accumulation also of amyloid proteins as is the case in a number of local and systemic amyloid diseases (Linke 1996). In contrast, IL-5 and IL-13 derive from TH-2 cells and act as antiinflam-matory immune mediators. Interestingly, their expression has been found to be significantly decreased as well. Taken together, we see a generally blunted secre-tory response of immune cells on activating stimuli in AD. This observation is in contrast to the protective effect of antiinflammatory drugs when taken for long term before the onset of AD, as seen in several epidemiological studies. However, a therapeutic effect of antiinflammatory substances is up to now not proved in prospective clinical studies. Moreover, the histopathological evidence of proin-flammatory molecules in the diseased brain is not necessarily in contrast to the assumption of an underlying general immune depression. A decline of phagocytic activity as one of the beneficial effects of the immune response may constitute an early event in the pathogenetic chain. However, the local overproduction of inflammatory markers have been attributed to a secondary reaction to the accu-mulating amyloid burden (Mc Geer and McGeer 2003) obviously overtaxing the phagocytic capacities of the AD brain. Finally, the mechanism of the antiinflam-matory drug effect in AD is not yet clarified. Possibly, they do not act via inhibi-tion of the prostaglandinsynthesis, but through reduction of the amyloid burden (Cirrito and Holtzmann 2003).
Decline of Immune Responsiveness: A Pathogenetic Factor in Alzheimer’s Disease? 1283
4.2 Consistent Findings Indicating an Immune Dysfunction in AD
Several studies point to an at least partial impairment of the immune system in AD. A decreased production of TNF-α in mild stages of AD was interpreted as a sign of defective immune functions (Huberman et al. 1994). Phytohemagglutinin (PHA)—stimulated proliferation and IL-2 production of nonadherent monocytes in AD patients has been shown to be significantly reduced (Fujiwara 1996). The lack of proliferative responsiveness to APP peptides in AD led to the assumption of a “T-cell anergy” in AD (Trieb et al. 1996). A generally decreased in vitro T-cell-acti-vation to a number of stimuli in AD has been reported, and an increase of acute reac-tants is interpreted as a compensatory reaction to in vivo functional alterations of leukocytes (Dickson et al. 1996). Other studies have shown imbalances of cellular immunity and immunoregulatory T-cells and a reduced T-cell response to various antigenic determinants suggesting a defect of the T-cell mediated immunity in AD (Giubilei et al. 2003; Streit 2001). Accordingly, a decrease of proliferation activity of AD lymphocytes has been reported, subsequently resulting in the impairment of immune functions in AD (Zhang et al. 2003). These functional defects have been attributed to oxidative damage of DNA in lymphocytes from AD patients (Mecocci et al. 1998) and an altered calcium response of peripheral T-lymphocytes in AD (Sulger et al. 1999). Most interestingly, an accelerated telomere shortening in lym-phocytes has been found as an underlying cause of the impaired lymphocyte func-tion in AD (Panossian et al. 2003; Zhang et al. 2003).
4.3 Putative Causal Role of Immune Dysfunction in AD
The question of a pathogenetic role of the immune dysfunction in AD is matter of ongoing discussion. One hypothesis suggests that a peripheral immune impairment is an epiphenomenon, secondary to the central immune activation seen in AD. Via the hypothalamic pituitary axis the cerebral inflammation may lead to an increased production of cortisol, resulting in a peripheral immunodepression (Woiciechowsky et al. 1999). Indeed, a mild hypercortisolemia has been shown in AD patients (Hart-mann et al. 1997).
On the other hand, a causal role of an underlying general impairment of the immune response in AD seems conceivable with respect to three major points of view:
4.3 . 1 Microglial Dysfunction in AD
The role of immunological and inflammatory processes in the pathogenesis of AD is widely understood in terms of the “bystander damage hypothesis” (Streit 2002).
1284 E. Richartz-Salzburger and N. Koehler
Accordingly, the neurodegeneration in AD is caused through bystander damage from autoaggressive microglial cells that produce neurotoxins in response to con-tinue A ß exposure (Akiyama et al. 2000; McGeer and McGeer 2001). However, the primary function of microglia is to support neuronal survival and regenerative proc-esses including phagocytosis (Rogers et al. 2002; Streit 2002). The role of microglia in the degradation and clearance of cell debris as well as of amyloid proteins is meanwhile well established (Popovic et al. 1998; Streit 2001). Microglia derives from the same stem cells as monocytes and have been shown to undergo simi-lar functional impairment in AD as assumed for the peripheral monocytes of AD patients (Streit 2001; Fiala et al. 2002). Histopathological studies on AD microglia showd altered morphology indicating a functional impairment (De Witt et al. 1998; Sasaki et al. 1997). The long-term presence of activated microglia around ß-amy-loid plaques has been referred their inability of phagocytosing and clearing senile plaque cores (Apelt et al. 2001). Microglial dysfunction may become manifest in a number of ways, including a decreased ability to produce neurotrophic factors, a decreased phagocytic capacity, as well as increased neurotoxicity (Streit 2002). These alterations may be of pathogenetic relevance in AD. It has been shown that deficient phagocytosis promotes inflammation and can lead to immune-mediated tissue degeneration (Wyss-Coray and Mucke 2002). Presumably, chronic struggle of microglia to remove Aß-containing plaque material promotes inflammatory proc-esses in AD (Lue and Walker 2002). These changes are assumed to be age-related, but are pronounced in AD.
Taken together, findings of a systemic attenuation of cellular immune response may be related to the cerebral pathology in AD in terms of insufficient phagocytosis of amyloid proteins and resulting neurotoxic effects.
4.3 .2 Decrease of Amyloid Burden Through Immunstimulation
The assumption of a causal significance of an immunological impairment in AD is even more intriguing in the light of the studies on immunization with ß -amyloid. Vaccination of transgenic mice with ß-amyloid leads to an enhanced removal of amyloid deposits in the brain (Schenk et al. 1999) by promoting microglial phago-cytosis. While the exact mechanisms are still point of discussion, also peripheral mechanisms have been considered (Lemere et al. 2003). Peripheral immune cells have been shown to invade the brain of adult mice as well as AD brain (Eglitis and Mezey 1997, Fiala 2002). Possibly, immunization leads to a peripheral immune response, which via penetration of T-cells and macrophages into the brain will enhance phagocytosis of local Abeta. Furthermore, immunstimulation with LPS results in reduction of ß-amyloid plaques in APP PS1 transgenic mice what has been shown for direct intrahippocampal injection (DiCarlo et al. 2001) as well as for systemic administration of LPS (Quinn et al. 2003).
In view of a putatively underlying immune deficit and impaired phagocytotic activity in AD, the effect of immunization or immunstimulation leading to a decrease of the cerebral amyloid burden seems consistent and conceivable.
Decline of Immune Responsiveness: A Pathogenetic Factor in Alzheimer’s Disease? 1285
4.3. 3 Role of Aging
Finally, there seems to be an obvious association between the immune altera-tions seen in AD and aging processes. Immune-aging phenomena constitute a major risk factor for AD (Blasko and Grubeck-Loebenstein 2003; Gasiorowski and Leszek 1997). The role of aging in AD development is conspicuous since epidemiological studies identified advanced age as the only consistent risk factor for AD. The age-dependent decrease of immune functions does not only involve the adaptive immunity (Blasko and Grubeck-Loebenstein 2003), but the innate immune system as well. T-cell derived cytokine production decreases with aging (Esumi et al. 1992; Gillis et al. 1981), and in vitro lymphocyte responsiveness to activating agents (e.g., lectins) has been shown to be reduced in elderly humans in several studies (DiCarlo et al. 2001). Macrophages, as well, underlie age-associ-ated functional alterations (Lloberas and Celada 2002).
Obviously, the immunological alterations in AD patients are more pronounced than the age-related changes in healthy persons. The T-cell observations in AD patients are characteristic of T-cells that reach a state of high replicative senescence after multiple rounds of antigen-induced cell-division (Effros 1998; Panossian et al. 2003).
Moreover, AD patients show, in comparison with healthy aged people, increased mitochondrial DNA mutations and genomic DNA damage which can lead to dys-function and decline of PBMC (De la Monte et al. 2000).
On this background, the observations of a blunted T-cell–response in AD patients finally could be understood as sequel of a premature immunosenescence, presum-ably being one important factor within the multifactorial etiopathogenesis of AD. This assumption is substantiated by the parallels between AD patients and patients with Down syndrome (DS). DS patients suffer from progerie and are of high risk to develop AD. Interestingly, DS patients show similar signs of advanced immu-nological senescence as seen in AD, such as telomere shortening (Park et al. 2000; Zhang et al. 2003) and altered intracellular calcium responses of T-cells, which might negatively influence the T-cell help required to generate an effective antibody response to A ß (Grossmann et al. 1993).
This study is limited due to the small amount of data and the heterogeneity of patients in terms of age, disease duration and severity. However, the present data support alternative views to the hypothesis of a mere inflammation-mediated patho-genesis, particularly since trials with antiinflammatory agents have not yet shown a clear benefit in preventing or delaying disease onset. Our hypothesis of a premature immunosenescence as a pathogenetically relevant factor in AD is in line with a “gerocentered” view rather than a just “amyloidocentered” approach in understand-ing the etiology of AD (Joseph et al. 2001). Conclusively, the development of thera-peutic strategies which stimulate the general immune responsiveness seems to be a promising challenge for future research.
1286 E. Richartz-Salzburger and N. Koehler
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