Alzheimer’s Disease: Pathology Starts 10-20 Years Before Diagnosis

Prof. Dr. med. Piotr Lewczuk Head,Lab for Clinical Neurochemistry and Neurochemical Dementia Diagnostics, Universitätsklinikum Erlangen, Department of Psychiatry and Psychotherapy, 91054 Erlangen, Interview with:
Prof. Dr. med. Piotr Lewczuk
Head,Lab for Clinical Neurochemistry
and Neurochemical Dementia Diagnostics,
Universitätsklinikum Erlangen,
Department of Psychiatry and Psychotherapy,
91054 Erlangen, Germany What are the main findings of the study?

Prof. Dr. med. Piotr Lewczuk: In our study, we investigated the concentrations of four isoforms of amyloid beta peptides in the blood of healthy young volunteers without memory complains. The participants were stratified into three groups according to their apolipoprotein E (APOE) genotype, which is the mostly investigated and generally accepted genetic risk factor for sporadic Alzheimer’s Disease (AD). It is known that the alterations of the amyloid beta metabolism are the earliest changes in the course of AD, occurring many years (or even decades) before the onset of the clinical symptoms, but it is actually not known how early these alterations start. Correspondingly, we wanted to investigate if healthy persons with genetic risk factor show changes in their amyloid beta metabolism already 30-40 years before the age when AD is usually diagnosed. We did not find any differences between the groups with and without APOE-driven risk, which might be carefully interpreted as no signs of Alzheimer’s Disease pathology in persons at risk at such an early life stage. Taken together, we think that the Alzheimer’s Disease pathology starts some 10-20 years before the beginning of the clinical symptoms, but not earlier. Were any of the findings unexpected?

Prof. Dr. med. Piotr Lewczuk: Not really. As a matter of fact this study was, to my best knowledge, the first of this type, so it was difficult to make any predictions on its outcome. We were prepared to see and interpret any variants of the results. It was, however, interesting to see that the group of Dr. Andy Simmons, whose paper appeared currently in the Journal of Alzheimer’s Disease, came to the same conclusions using different methodological approach (they investigated the hippocampal volumes with neuroimaging methods). What should clinicians and patients take away from your report?

Prof. Dr. med. Piotr Lewczuk: The interpretation of our results in the scientific context is quite straightforward: no differences between the groups of persons with and without APOE risk. The interpretation for the individuals is, however, much more complex: as we state in the discussion of the paper, we cannot fully exclude that some cognitively normal persons bearing the genetic risk factor do show alterations of their amyloid beta metabolism, but that these alterations are statistically counter balanced by the normal results of other persons. For example, the persons with the lowest concentrations of amyloid beta 1-42 might indeed show the fist neurochemical Alzheimer’s Disease alterations, which are however “hidden” by the results of the subjects which have normal concentrations. Personally, I think this is the main problem of the translation of the research results into the messages for the practitioners and the patients: in science we investigate groups, but physicians and patients are not interested in the analyses of the groups, they always face individuals. What recommendations do you have for future research as a result of this study?

Prof. Dr. med. Piotr Lewczuk: We would like to perform a follow up study with the individuals with the extreme phenotypes (in this case, with the highest or the lowest concentrations of the amyloid beta in the blood) to see if they indeed are cognitively stable for up to the age when the usual amyloid beta alterations are observed as the first metabolic changes of Alzheimer’s Disease. Of course this rises major ethical and logistic problems, so it might be a project for many years and decades.


Plasma Concentrations of the Amyloid-β Peptides in Young Volunteers: The Influence of the APOE Genotype

Zimmermann R1, Huber E1, Schamber C1, Lelental N1, Mroczko B2, Brandner S3, Maler JM1, Oberstein T1, Szmitkowski M4, Rauh M5, Kornhuber J1, Lewczuk P1.
J Alzheimers Dis. 2014 Feb 20. [Epub ahead of print]