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Background Of the three transforming growth factor (TGF)-β isoforms known, TGFβ1 deficits have been widely reported in Alzheimer's disease (AD) and studied as a potential therapeutic target. In contrast, the status of TGFβ2, which has been shown to mediate amyloid-β (Aβ)-mediated neuronal death, are unclear both in AD and in Lewy body dementias (LBD) with differential neuritic plaque and neurofibrillary tangle burden. Objective To measure neocortical TGFβ2 levels and their correlations with neuropathological and clinical markers of disease severity in a well-characterized cohort of AD as well as two clinical subtypes of LBD, dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD), known to manifest relatively high and low Aβ plaque burden, respectively. Methods Postmortem samples from temporal cortex (BA21) were measured for TGFβ2 using a Luminex-based platform, and correlated with scores for neuritic plaques, neurofibrillary tangles, α-synuclein pathology, dementia severity (as measured by annual decline of Mini-Mental State Examination scores) as well as soluble and total fractions of brain Aβ42. Results TGFβ2 was significantly increased in AD and DLB, but not in PDD. TGFβ2 also correlated with scores for neurofibrillary tangles, Lewy bodies (within the LBD group), dementia severity, and soluble Aβ42 concentration, but not with neuritic plaque scores, total Aβ42, or monomeric α-synuclein immunoreactivity. Conclusions TGFβ2 is increased in the temporal cortex of AD and DLB, and its correlations with neuropathological and clinical markers of disease severity as well as with soluble Aβ42 load suggest a potential pathogenic role in mediating the neurotoxicity of non-fibrillar Aβ. Our study also indicates the potential utility of targeting TGFβ2 in pharmacotherapeutic approaches to AD and DLB.

Alpha-synuclein (α-syn) aggregations are the key pathological hallmark of dementia with Lewy bodies (DLB) and Parkinson’s disease dementia (PDD), but are also frequently present in Alzheimer’s disease (AD). Much remains unknown about the role of α-syn in the synapse and the wider role of synaptic dysfunction in these dementias. Changes in concentrations of key ‘SNAP (Soluble N-ethylmaleimide Sensitive Factor Attachment Protein) Receptor’ (SNARE) proteins as a consequence of alterations in the aggregation state of α-syn may contribute to synaptic dysfunction in patients with DLB, PDD, and AD and result in impaired cognition. We have studied a large cohort (n = 130) of autopsy confirmed DLB, PDD, AD, and control brains. Using semi-quantitative western blotting, we have demonstrated significant changes across the diagnostic groups of DLB, PDD, and AD in the SNARE and vesicle proteins syntaxin, Munc18, VAMP2, and monomeric α-syn in the prefrontal cortex, with a significant reduction of Munc18 in AD patients (p < 0.001). This correlated to the final MMSE score before death (p = 0.016). We also identified a significant negative correlation between the duration of dementia and the levels of the binding partners VAMP2 (p = 0.0004) and monomeric α-syn (p = 0.0002). Our findings may indicate that an upregulation of SNARE complex related proteins occurs in the early stages of disease as an attempt at compensating for failing synapses, prior to widespread deposition of pathological α-syn.

The prevalence of both Alzheimer's disease (AD) and vascular dementia (VaD) increase with advancing age, but epidemiologic data above age 85 are imprecise and inconsistent. A retrospective hospital-based study of the prevalence and pathology of VaD was performed in 1700 consecutive autopsy cases of demented elderly in Vienna, Austria (mean age 84.3 ± 5.4 SD; 90% over age 70). It assessed clinical and general autopsy data and neuropathology including immunohistochemistry. Neuropathologic diagnosis followed current consensus criteria. Four age groups (7th to 10th decade) were evaluated. "Pure" VaD (due to cerebrovascular disease without other pathologies; neuritic Braak stages 1.2-1.6) was observed in 12.3% of the total cohort, decreasing between age 60 and 90+ from 15.0 to 8.7%. Morphologic subtypes (subcortical arteriosclerotic encephalopathy, multi-infarct encephalopathy, and strategic infarct dementia) showed no age-related differences. By contrast, AD (without concomitant pathologies; 45.6% of total), mixed dementia (AD + cerebrovascular encephalopathy; 5.5%), and AD with minor cerebrovascular lesions (22.3%) increased with age. The relative prevalence of AD + Lewy pathology (9.3%) remained fairly stable, whereas other dementias (5.0%) decreased significantly over age 90. 85% of the patients with "pure" VaD had histories of diabetes, 75% of stroke(s), 95% morphologic signs of hypertension, 65% myocardial infarction (recent and old ones), 97% cerebral hypertonic-arteriosclerotic microangiopathy (associated with cerebral amyloid angiopathy in 23%) and 90% severe atherosclerosis of large cerebral arteries. Similar autopsy findings were seen in mixed dementia (MIX) and in AD + minor cerebrovascular lesions. Major vascular lesions differed between VaD and MIX, VaD showing more than 60% subcortical infarcts, MIX only 43% such lesions. This retrograde hospital-based study using strict morphologic diagnostic criteria confirmed the existence of "pure" VaD in old age, with a tendency to decline after age 90, while AD and AD + cerebrovascular pathologies showed considerable age-related increase, and "pure" AD slightly decreasing after age 90.

Olfactory dysfunction and tau pathology in the olfactory bulb increase with the severity of Alzheimer's disease. We report data of a postmortem study in the aged. 130 autopsy cases (81 female, 49 male, aged 61-102, mean 82.48 +/- 4.35 SD) years, underwent a standardized neuropathological assessment with immunohistochemical study of tau pathology in the olfactory bulb and nerve and of Alzheimer's disease using established criteria including Braak staging. All cases of definite Alzheimer's disease (Braak stages 5 and 6) (n = 40) showed large numbers of neuropil threads and neurofibrillary tangles, with amyloid deposits in 32.5% and neuritic plaques in one single case in the olfactory system. Braak stage 4 (n = 27) was associated with mild to moderate tau pathology in 85.2%, and amyloid plaques in 1.1%, Braak stage 3 (n = 28) with olfactory tau lesions in 37.0% and amyloid deposits in one single case, Braak stages 3 and 4 with olfactory tau lesions in 61.1%. Braak stage 2 (n = 15) showed olfactory tau pathology in 31.2%, whereas Braak stages 0 and 1 (n = 15) were all negative. The olfactory system tau score showed highly significant correlations with neuritic Braak stages in the brain, while both scores showed significant but low correlations with age. These data confirm previous studies demonstrating abundant tau pathology in the olfactory system in all definite Alzheimer's disease cases, in two-thirds of limbic Alzheimer's disease, and in almost one-third of non-demented elderly persons with Braak stage 2. There are strong correlations between tau pathology in the olfactory and limbic systems, both with similar increase in severity. Clinical dementia correlated with both Braak and olfactory system tau scores. Since the involvement of both systems is associated with a high risk of cognitive decline, future studies should validate the sensitivity of olfactory mucosa biopsies in the diagnosis of Alzheimer's disease.