The identification of biomarkers that have diagnostic, prognostic, and/or therapeutic implications in AD is of critical importance. While previous research suggested that BDNF levels might hold promise as a diagnostic marker of early AD, the current findings do not support this hypothesis.
There are noteworthy differences between the current study and previous work. In the Yasutake et al[9
] study, the mean MMSE scores were 6.88 (sd = 6.78) and 6.75 (sd = 6.89) for the AD and VaD samples, respectively, whereas the mean MMSE score in the current sample was 20.5 (sd = 4.8) with the lowest score (10) being above the mean score of the Yasutake sample. Therefore, the Yasutake group consisted of late stage dementia patients, whereas current sample was comprised of early to moderate cases without any severe dementia cases available for analysis (i.e. CDR global score = 3). Additionally, the Laske et al[10
] study utilized MMSE scores to split the cases into “early” and “late” AD rather than by using the CDR, which is the most commonly utilized instrument for staging dementia severity. The assay procedures utilized in the current study (multiplex immunoassay) were also different from the studies mentioned above (enzyme-linked immuno sorbent assay, ELISA), which may have led to differential results. However, it is unlikely that any difference between methodologies would lead to a stage-dependent impact to obscure a difference only in early stage AD. Additionally, a recent study by Leyhe et al[19
] demonstrated that serum BDNF levels increased in patient's with Alzheimer's disease following 15-months treatment with donepezil, which may have impacted the current findings. However, the previous work does not offer any reason to hypothesize that the impact of drug utilization would be stage-dependent therefore it is unlikely that drug status altered BDNF levels only in those patients in the earliest stages of the disease (i.e. CDR = 0.5).
Taken together, the current study provides a more refined description of serum BDNF levels in early to moderate AD. There was a trend towards a possible decrease in BDNF levels in very early AD (CDR = 0.5); however, this difference did not reach statistical significance and completely disappeared once covariates were controlled for in the model. A recent study by Yu and colleagues[20
] found significantly lower serum BDNF concentrations in patients with amnestic mild cognitive impairment (aMCI), a condition often thought to be a transition stage between normal cognition and Alzheimer's disease, further supporting the possibility of alterations in this marker early on during disease development. From the Yasutake study, it appears there is decline in BDNF levels once the disease has progressed to a severe level. The possibility of a decrease in BDNF in very early AD followed by normalization (compared to controls) during mild-to-moderate AD and subsequent decline in BDNF during late stage AD should be evaluated in a larger population with sufficient sample sizes across CDR stages of dementia severity. It is also possible that subgroups of early AD (and MCI) patients experience alterations in BDNF, which might explain the contradictory findings and future studies should look for such an endophenotype. It is likely that the most accurate approach to identifying biomarkers for the identification of AD (blood-based or otherwise) will be through an integrated approach that combines multiple markers reflective of various neurobiological pathways[1