From model system to clinical medicine: pathophysiologic links of common proteinopathies

Alzheimer disease (AD), the most common neurodegenerative disorder, is characterized by the accumulation of amyloid beta (Aβ) and tau into plaques and tangles, respectively. Other neurodegenerative disorders such as Parkinson disease (PD) and dementia with Lewy bodies (DLB) are broadly characterized as synucleinopathies because of the accumulation of alpha-synuclein (SNCA) into Lewy bodies. Although these disorders are not the same, there is overlap with respect to the pathogenic proteins Aβ, SNCA, and tau. A large subset of patients with AD (Lewy body variant, AD-LBV) exhibit Lewy body pathology in addition to plaques and tangles [1]. Lewy body pathology is also common in patients with early-onset familial AD [2,3]. Conversely, dementia in PD (PDD) may involve AD-related pathological changes. Increased Aβ plaque burden and low cerebrospinal fluid (CSF) Aβ levels have been demonstrated in PDD and are highly correlated with increased Lewy body pathology [4-7]. Evidence linking tau pathology to PDD is less evident, although one study has demonstrated increased phosphor-tau in post-mortem PDD brain [8]. Recent evidence suggests that this pathological overlap may predict the clinical course of the disease. Patients with AD-LBV exhibit a more aggressive disease course, a more severe memory impairment, and a more rapid rate of cognitive decline compared with AD patients without Lewy body pathology [9]. Reductions in CSF Aβ levels have been reported in PDD subjects and are associated with memory impairment [6], and there is a strong association between declines in CSF Aβ and longitudinal declines in cognition over time in patients with PDD [10]. Low CSF Aβ levels are considered a reflection of increased Aβ deposition in brain [11] and, along with high CSF tau levels, act as a biomarker to predict the presence of AD neuropathology [12] and a more rapid rate of cognitive decline during the course of the disease [13,14]. Thus, although there does not appear to be an associati