Patients with Alzheimer's disease often have a mix of several different pathological processes in the brain. Besides beta-amyloid and tau pathologies, which are classic hallmarks of the disease, many patients also have a mix of different brain changes. This has been described in several autopsy based studies, for example in Schneider et al Ann Neurol 2009. It turns out that among elderly patients "pure" Alzheimer's is in fact a very rare thing. Most people have several brain problems at once rather than one isolated pathology. 

One of the most important co-pathologies in patients with Alzheimer's disease is Lewy body pathology. Lewy bodies are composed of the protein alpha-synuclein. These aggregates are key features of the synucleinopathies, which include Parkinson's disease and dementia with Lewy bodies. Dementia with Lewy bodies causes sleep and dream abnormalities, visual hallucinations  and executive dysfunction.

Click here for pictures of Lewy bodies.

Patients who have both typical Alzheimer's disease pathology and Lewy body pathology can have a mixed clinical presentation, with both memory problems and Lewy body-related problems. This continuum of pathological and clinical changes across neurodegenerative diseases has been recognized by researchers and clinicians for many years, but is only now attracting broader attention from the pharmaceutical industry. The reason for this interest is that the presence of mixed pathologies could have a critical impact on the success of therapies aimed at halting Alzheimer's disease.

So far there is no established biomarker that can reliably identify synuclein pathology in a patient with Alzheimer's disease. Such a biomarker would be very valuable, since it could be used to stratify patients with Lewy bodies to personalized treatments in clinical practice or in drug trials. Several researchers have tested cerebrospinal fluid levels of alpha-synuclein, the protein that is deposited in Lewy bodies, as a biomarker. Cerebrospinal fluid levels of this protein seem to be reduced in synucleinopathies, as shown in for example Mollenhauer et al 2011 and Hall et al 2012. 

Could cerebrospinal fluid alpha-synuclein be useful to identify Alzheimer's disease patients with Lewy body co-pathology? Very few studies have specifically tested this. One study with autopsy conformation was negative, but it included very few subjects. We selected another approach in an article that was published this summer in Journal of Alzheimer's disease (abstract available here). We tested if cerebrospinal fluid alpha-synuclein levels were related to the presence of Lewy body-like symptoms in Alzheimer's disease. 

We found that cerebrospinal fluid alpha-synuclein levels were significantly lower in Alzheimer's patients who reported hallucinations (see figure). Although this is only an indirect evidence, it may suggest that cerebrospinal fluid levels of alpha-synuclein are indeed related to Lewy bodies in patients with Alzheimer's disease. But much more work needs to be done to explore this biomarker. For example, it is possible that specific variants or oligomers of alpha-synuclein are more suitable as biomarkers than the total levels of the peptide.