Our results are in accord with the existing literature reporting lower serum and plasma BDNF levels with increasing age 
, with significantly higher levels observed in women compared to men 
. We found that lower plasma BDNF was associated with steeper rates of age-related regional brain volume atrophy. Contrary to our expectations, however, we observed no associations between circulating plasma BDNF levels and either concurrent cognitive performance or the rate of change in cognitive performance with age.
Human genetic studies implicate BDNF gene involvement in cognitive function, specifically memory and executive function 
. Evidence also suggests that higher serum BDNF levels are associated with better cognitive performance in healthy older adults 
. We found no associations between plasma BDNF levels and either concurrent cognitive performance, mean cognitive performance across all available assessments, or the rate of change in cognition with age across domains in a large sample of healthy, older individuals. The lack of associations between plasma BDNF and cognitive performance in our sample stands in contrast to the only existent study exploring this relationship in a large Eastern Finnish sample (N
1389). In the Finnish sample, the risk for worse performance on tests tapping memory and general cognitive function increased with a drop in plasma BDNF, but the associations were only present for women and not men 
. Li and colleagues 
however, reported that lower CSF BDNF concentration was associated with poorer immediate and delayed recall measured at baseline and three years later. Given the general lack of studies on this topic, discrepancies between our findings and those of the two above-mentioned studies may reflect methodological differences in general and more specifically, differences in participant sampling. Cross-sectional studies of normal individuals may be contaminated with individuals in prodromal stages of impairment that goes unnoticed due to inherent lack of prospective information. It is possible that plasma BDNF may have little effect on cognitive performance within the normal range of function in non-demented, healthy older adults, whereby considerable decrease in BDNF may only be observable in the late stage of cognitive decline or dementia, as is the case with bipolar disorder for example 
We found that lower plasma BDNF is associated with steeper regional brain volume decline. In our sample, lower BDNF levels predicted steeper white matter atrophy and this relationship was present in women but not men. The mechanisms underlying the apparent sex differences in findings remain elusive, however, ovarian steroids have been implicated as a modulating factor on BDNF levels 
. Effects of estrogen on brain BDNF have been well documented in rodents 
, albeit mice used in these studies were young.
Our findings differ from the existing literature, which reports significant associations of gray matter and the hippocampus with either serum BDNF 
or Val66Met polymorphism 
. Basic research, however, suggests a role for BDNF in white matter neuroprotection, whereby BDNF application promotes secondary decrease of white matter lesion size even though it does not prevent lesions from appearing 
. Moreover, BDNF has been implicated as an important factor associated with white matter volume in patients with multiple sclerosis independent of BDNF Val66Met (rs6265) genotype 
Our study is not without limitations. There is currently no reliable method to detect both pro-BDNF and BDNF in human plasma or serum, as there is antibody cross-reactivity between pro-BDNF and BDNF due to their high sequence homology. Thus, at this point in time, it is difficult to determine whether changes in plasma or serum BDNF reflect pro-BDNF, BDNF or both. Novel assays need to be developed that can accurately and quantitatively distinguish between pro-BDNF and BDNF. Moreover, the present sample is not population-based; participants are highly educated and predominantly Caucasian. The relative homogeneity of the sample, however, may be seen as an advantage because the majority of our sample has good access to medical care and has remained relatively healthy over the follow-up interval. Moreover, average BDNF plasma values vary widely across studies, most likely owing to the fact that the concentration of BDNF in plasma is state-dependent 
. Methodological differences notwithstanding, the average BDNF plasma concentration in our study is similar to that of other non-clinical samples 
. These limitations, however, should not undermine the unique aspects of our study, namely a large number of elderly individuals who were prospectively followed for many years on an annual basis, extensively characterized, and studied with state-of-the art image processing methods. Moreover, we characterize age-related changes in many of the regional brain volumes that have not been previously investigated in relation to plasma BDNF.
Another issue in interpreting our results is the analysis of a number of cognitive domains and a number of brain volume measurements without adjustment for multiple comparisons. Given the relative dearth of studies investigating associations between plasma BDNF and cognitive and brain outcomes, our exploratory investigation in a well-characterized longitudinal sample should provide directions for future research. In addition, our long follow-up interval ensures great power for detecting even small changes with age, which would not be possible in a cross-sectional design.
To our knowledge, this study is the first longitudinal study exploring associations between plasma BDNF levels, brain volume and cognitive function in healthy older individuals. Overall, our results suggest a role for BDNF in structural brain integrity, but no direct associations with cognitive function or change in cognition with age. Together, our findings from the BLSA cohort contribute to furthering the understanding of the relationships between plasma BDNF concentration, brain volume integrity and cognitive function with age. Further research is needed in order to understand not only the role for BDNF in brain structure and function, but also the relationship between peripheral BDNF (both plasma and serum) and its genetic variants. Additional research is needed to demonstrate the mechanisms underlying the relationship between plasma BDNF and brain volume integrity, as well as the sex differences that might be moderating the relationship, especially considering that current knowledge is primarily based on animal studies and human genetic studies.