There is growing interest in the overlap among Alzheimer's disease, Parkinson's disease, and less common synucleinopathies and tauopathies that can share features of both diseases. Two current papers looking at different levels of investigation-one focusing on molecular interactions between tau and α-synuclein (α-syn) proteins, and the other on clinical manifestations of AD and PD-add new information to this topic.

In tomorrow’s Science, Virginia Lee and her colleagues at the University of Pennsylvania in Philadelphia report that both tau and α-syn synergistically promote fibril formation by the other protein, which the authors hypothesize to be the seeds of pathological inclusions in some neurodegenerative diseases. Tau and α-syn proteins share some features, including the propensity to form pathogenic amyloid aggregates, and both co-occur in a number of diseases (see ARF meeting report on this subject).

When they incubated the two proteins together, Lee and colleagues found that α-syn, which readily polymerizes on its own, was able to induce polymerization of tau, which usually requires cofactors. There was also a reciprocal effect whereby tau induced greater polymerization of α-syn, especially at lower concentrations of α-syn. Although most fibrils were homopolymers of tau or α-syn, some were heteropolymers with tau at one end and α-syn at the other, suggesting that two homopolymers had joined.

In-vivo experiments accompanying these in-vitro data were that about 50 percent of mice transgenic for A53T mutant human α-syn had tau inclusions along with α-syn inclusions. In mice transgenic for both wild-type human α-syn and P301L mutant tau, the researchers found that α-syn and tau inclusions co-occurred in a subset of oligodendrocytes.

These results "suggest that therapeutic agents that directly or indirectly inhibit the formation of one form of amyloid might be effective on several of these neurodegenerative disorders," conclude the authors.

Research into common mechanisms for these neurodegenerative diseases has been driven in part by pathological overlaps between AD, PD, and related diseases, and by clinical observations that early parkinsonian signs may be harbingers of impending Alzheimer's disease. In this month’s Archives of Neurology, Robert Wilson and colleagues from the Rush Alzheimer's Disease Center in Chicago, Illinois, report on data from more than 700 Catholic clergy in the ongoing Religious Orders Study of aging and AD. These men had undergone annual clinical exams that included tests of cognitive function, clinical classification of AD, and a modified version of the Unified Parkinson's Disease Rating Scale (UPDRS). Over an average follow-up period of 4.6 years, the researchers found a relationship between parkinsonian progression (indicated by higher scores on the UPDRS) and increased risk of AD. Men in the highest tertile of UPDRS progression had an eightfold increased risk of developing AD relative to those without progression (P = .02). Similarly, the rate of decline on cognitive testing was correlated with increasing UPDRS scores. A potentially interesting new finding was that not all parkinsonian signs were associated with the increase in risk of AD or rate of cognitive decline-progression of gait disorder and rigidity were associated, but not bradykinesia or tremor.

The underlying reasons for this intersection of parkinsonian symptoms and AD are uncertain, say the authors. One possibility is that AD pathology in the substantia nigra is to blame. The authors mention that neurofibrillary tangles in the substantia nigra in AD have been associated with PD-like symptoms (Liu et al., 1997). Other factors mentioned include possible pathologic consequences of Lewy bodies or cerebrovascular disease.—Hakon Heimer


  1. In a longitudinal cohort study of 824 older Catholic clergy members (mean age at baseline 75.4, SD 6.9 years) without clinical evidence of AD or PD at baseline, Wilson et al. found that 114 persons (13.8 percent) developed AD over the course of an average of 4.6 years of follow-up. The global UPDRS score increased in 79 percent of the participants, mainly due to worsening gait/posture and rigidity, and the relationship of progression to AD disease risk was examined in a proportional hazards model. Compared with the 21 percent of subjects without progression, the risk of developing AD more than doubled in the subgroup with the least progression (P = .08), more than tripled in the moderate progression subgroup (P = .02), and shot up by more than eightfold in the subgroup with the most rapid progression (P The data strongly suggest that progression of parkinsonian signs in old age is associated with decline in cognitive function and the development of AD. Gait disorders and rigidity may be seen in subjects with subcortical lacunes and (pre)frontal white matter lesions (3-5), and periventricular cerebral white matter lesions have also been shown to predict rate of cognitive decline (6). The reasons for the predominant signs of progression of both parkinsonian-like signs and cognitive decline seen in this cohort are unclear, since the authors did not perform CCT or MRI studies to exclude or to measure such subcortical and prefrontal lesions that may also be associated with AD or with atypical parkinsonian syndromes.

    However, even without further discussion of this open question, their data on the correlation between progression of extrapyramidal signs and the development of AD largely parallel our personal experience with a cohort of 200 autopsy-proven PD patients from a specialized Austrian brain bank (90 males, 104 females, mean age at onset of 68.6, SD 9.5 years, and an average disease duration of 8.4, SD 9.65 years) (2). Retrospective assessment of major initial clinical symptoms (tremor, akinesia, rigidity), moderate/severe dementia (MMSE Comparison of 32 patients (12 males, 20 females) with old-age onset of PD (mean age 82.4, SD 3.2 years) with 94 patients with middle-age onset (44-66, mean age 61.8, SD 9.8 years) showed that the duration of old-age-onset PD, ranging from 1-10 (mean 4.3, SD 2.2) years, was significantly shorter than that of middle-age onset (2-38, mean 10.5, SD 9.3) years (unpubl. data). This difference was similar to that found in the whole sample between patients with coexistent severe neuritic AD pathology (CERAD B or C, Braak stages 4.5-5) showing a mean survival of 4.46 (SD 3.55) years compared to 10.1 (SD 9.3) years in the patients without dementia and/or severe AD. Severe dementia (MMSE Most of the demented old-age-onset PD patients showed coexistent high-grade AD pathology (Braak stages 4-5, mean 4.7), and AD pathology was almost as severe (Braak stages 3-5, mean 4.5) in demented middle-age-onset patients. The finding that old age at onset is associated with more rapid disease process and increased incidence of dementia due to coexistent autopsy-proven AD pathology in this cohort is in keeping with the findings by Wilson et al. that progression of parkinsonian-like signs in old age is associated with decline in cognitive function and the development of AD. The strong association of dementia with frequently underlying AD pathology in both PD and non-PD patients may not only be a marker of an ongoing pathologic process inducing both dementia and parkinsonian-like signs that may reduce survival. It may also emphasize the importance of therapeutic approaches targeting progression of both dementia and parkinsonism—in particular, gait disorders and rigidity—in older persons, in order to improve their quality of life and life expectancy. However, as stated above, one should try to elucidate the causes of gait/posture disorders without classical PD signs and symptoms using CCT and MRI in order to exclude other treatable conditions, even in old-age subjects.


    . Parkinsonianlike signs and risk of incident Alzheimer disease in older persons. Arch Neurol. 2003 Apr;60(4):539-44. PubMed.

    . Impact of coexistent Alzheimer pathology on the natural history of Parkinson's disease. J Neural Transm. 2002 Mar;109(3):329-39. PubMed.

    . White matter lesions and disequilibrium in older people. II. Clinicopathologic correlation. Arch Neurol. 1995 Oct;52(10):975-81. PubMed.

    . Gait disorder and parkinsonian signs in patients with stroke related to small deep infarcts and white matter lesions. Mov Disord. 1998 Jan;13(1):89-95. PubMed.

    . Gait disturbance in Alzheimer's disease: a clinical study. Age Ageing. 1996 Jul;25(4):313-6. PubMed.

    . Periventricular cerebral white matter lesions predict rate of cognitive decline. Ann Neurol. 2002 Sep;52(3):335-41. PubMed.

  2. The Wilson et al. paper is relevant to the findings in our paper. While the authors do not establish the extent of co-morbid tau and α-synuclein in their patient cohort, it is likely that this is occurring, and it emphasizes once again the clinical relevance of the in-vitro data we report on cross-fibrillization of these two amyloidogenic proteins. We speculate about the basis for this, but obviously there is more to learn about mechanisms underlying this in human patients.

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News Citations

  1. Philipp Kahle and Bart De Strooper Report from Lake Titisee, Germany: Part II

Paper Citations

  1. . Pathological correlates of extrapyramidal signs in Alzheimer's disease. Ann Neurol. 1997 Mar;41(3):368-74. PubMed.

Further Reading


  1. . Prevalence and characteristics of dementia in Parkinson disease: an 8-year prospective study. Arch Neurol. 2003 Mar;60(3):387-92. PubMed.

Primary Papers

  1. . Parkinsonianlike signs and risk of incident Alzheimer disease in older persons. Arch Neurol. 2003 Apr;60(4):539-44. PubMed.
  2. . Initiation and synergistic fibrillization of tau and alpha-synuclein. Science. 2003 Apr 25;300(5619):636-40. PubMed.