To the best of our knowledge, this is the first study to examine sex differences in those with MCI in terms of DTI measures of WM structural integrity. Our initial findings of significantly lower FA, and significantly higher DR, MD and DA in MCI participants relative to healthy older controls are broadly consistent with previous DTI studies 
. However, we also report a significant main effect of sex which has not been previously noted. This significant main effect of sex demonstrated that men have significantly raised DR and MD, and significantly lower FA, relative to women, both within healthy older and MCI participants. There was no sex by diagnosis interaction, indicating that increased WM microstructural damage in men relative to women at an equivalent cognitive status is constant within both healthy older and MCI participants. The main effect of sex was found to have a degree of laterality, with the right hemisphere being more affected than the left.
There have been extremely few studies investigating WM differences between men and women in older populations, but those that exist have reported a limited degree of sexual dimorphism 
. The differences between the current findings and those of Wu and colleagues, and Hsu and colleagues, may lie in the fact that these previous works report cross-sectional decline in WM microstructural parameters in men and women over the life span, whereas the current study focuses on sex differences within an age-matched elderly cohort. Sex differences in multiple indices of diffusion have not been systematically studied. Some DTI work in younger subjects showed no sex differences 
whereas others did show significant sex differences in young subjects though only when focusing on predefined brain regions, such as frontal lobe or corpus callosum 
. However, studies involving young subjects do not relate well to our older cohort.
Previous PET studies in AD dementia patients have noted that men have a pronounced hypermetabolism relative to women, particularly in the right hemisphere 
. These findings are relevant to the current results which indicate that the degree of WM damage is greater in the right hemisphere of male participants. Interestingly, an early PET study also noted that men tend to have greater metabolism in the right hemisphere than the left after the age of 60 
While the underlying reasons for this laterality are not known it is of interest that a model of aging, termed HAROLD (hemisphere asymmetry reductions in older adults) posits that there is an age-related loss of hemispheric asymmetry of task-related activation in the prefrontal cortex (PFC). While healthy young subjects show greater activation in left PFC compared with the right PFC during the execution of a variety of cognitive tasks, many studies indicate that this laterality is reduced in older subjects 
. This loss of laterality is frequently related to increased right PFC activation in older adults which has been suggested to serve as a possible compensatory mechanism in order to maintain cognitive performance in older age. The large number of functional activation studies showing increased right hemisphere functional activation in older age 
may serve as indirect evidence for chronically stressed right hemisphere structures being predilection sites for structural alterations in the early stages of neurodegeneration. A number of recent MCI and AD dementia classification studies have also noted a right-more-than-left pattern of WM damage 
. It is possible that while men are “chronologically” age-matched with women, the fact that women live longer than men on average 
could potentially result in men being “biologically” older than women of the same age which may account for a degree of extra WM damage in the right hemisphere of older men relative to women.
Another possible explanation for the overall greater structural damage in men may be that brain reserve is greater in older men compared with older women. Although men have more structural damage than women, they are at the same cognitive level as women, suggesting that women may manifest the symptoms of cognitive decline at a level of structural damage which would not cause the same amount of cognitive decline in men. This can be seen in the scheme proposed in where healthy older men have the equivalent microstructural WM status as women with MCI.
Model of sex-specific white matter degeneration.
Brain reserve refers to the fact that larger brains can sustain more structural damage before clinical deficits emerge because sufficient neural substrate for normal function is retained in larger brains following an insult 
. It has been proposed that when brain reserve is depleted beyond a critical threshold, then specific clinical or functional deficits may emerge 
. In the current study, this critical threshold appears to be higher in older men compared with older women. The fact that men have a greater absolute brain size, as well as a higher density of neurons compared with women may contribute to this proposed extra brain reserve in men 
In the current study, DA was found to increase in MCI, a finding which is at odds with animal studies and human callosotomy studies which have shown that axonal pathology results in a decrease in axial diffusion 
. Yet raised DA in MCI and AD dementia has consistently been found in recent DTI studies 
. The complexity of DA responses may reflect the fact that WM damage has been shown to lead to an initial decrease in DA followed by subsequent increases as axonal fragments are cleared by microglia and water molecules can diffuse longitudinally again 
. Also, where two crossing fibre tracts exist, it may be difficult to dissect out the axial diffusion of one of the two fibre tracts. Thus, increases in DA may reflect a degeneration of one of the two fibre populations in regions of crossing fibers 
WM and GM volumes were also found to have sex specific profiles. Male MCI participants showed significantly lower normalised GM volume than female MCI participants. Again, this suggests that for an equivalent diagnosis of MCI, men must sustain more GM atrophy than women in order to be diagnosed as MCI. Therefore, the threshold of structural damage which precipitates cognitive decline leading to a diagnosis of MCI appears to be lower in women. No sex-specific differences were found in normalised WM volume which suggests that while there are significant WM microstructural changes in male MCI participants, this has not reached the point of gross tissue loss. This result also highlights the fact that DTI has the ability to detect WM microstructural changes which may develop before global WM changes occur. This is particularly true in MCI, where the structural changes are subtle. In an earlier study we also noted diffusion changes in healthy older, MCIna and MCIa subjects, in the absence of significant changes in normalised WM volume 
. However, in the situation of AD dementia both WM volume and diffusion indices were significantly affected 
Absolute WM and GM volume were both greater in male controls relative to female controls, which is consistent with previous studies 
. No significant differences were found however, between absolute volumes of male and female MCI participants, or between absolute male MCI volumes and male controls, or between absolute female MCI volumes and female controls. These results concur with the hypothesis that the greater number of neurons in male brains may create a buffer against pathology translating into clinical symptoms of AD 
. This possibility of greater brain reserve in males may help to delay the onset of clinical symptoms of dementia in males 
. Thus healthy older men would have to reach a higher threshold of damage before expressing the earliest symptoms of neurodegeneration.
Although there have been conflicting results, the majority of studies also indicate that the incidence of AD dementia is greater in women than in men 
. At least one large meta-analysis confirmed that the risk of AD dementia is increased 1.6 fold in women 
. While caution is needed when relating the results of AD dementia studies to MCI, it is nevertheless reasonable to suggest that these studies are indicative of a greater vulnerability of women to neurodegeneration in older age. With 10–15% of MCI subjects converting to AD dementia, our finding that women may be more vulnerable than men to transition to MCI, may in turn lead to more women deteriorating to AD dementia than men.
Genetic and hormonal characteristics might contribute to the extra vulnerability of older women. Oestrogen has been shown to have a potent neuroprotective effect, and it is possible that there is a profile of increased protection from neurodegeneration while circulating oestrogen levels are normal, followed by increased risk of neurodegeneration in older women as oestrogen levels decline following menopause 
In addition to brain reserve, the role of cognitive reserve should also be noted. While brain reserve is a passive model that highlights the role of brain size or neuronal volume, cognitive reserve is an active model which suggests that the brain responds to brain damage by recruiting existing cognitive processes or by enlisting compensatory processes 
. In a situation where two people have the same brain reserve capacity, the person with more cognitive reserve may tolerate more neural damage before cognitive impairment is apparent. This model focuses on the processes that allow people to sustain brain damage and maintain function. Education and socioeconomic status such as income and occupational attainment have been shown to influence cognitive reserve 
. As the mean age of the current cohort is ~70, our participants were of school-going age during the 1940’s and were potentially in employment from the late 1950’s onwards. Significant differences in gender roles and opportunities may have disadvantaged women at this time. Although there were no significant differences between men and women in terms of years of education, both the quantity and quality of jobs available to women are likely to have been more limited for women. Also, aspects of occupational experiences have been found to impart additional cognitive reserve over and above that obtained from education 
. Thus, it is possible that within the current cohort, social and cultural factors may have negatively impacted the opportunities for women and led to lower occupational attainment, which in turn may negatively affect cognitive reserve. We should note that models of cognitive reserve and brain reserve are not mutually exclusive and may be interdependent 
Strikingly, Barnes and colleagues recently noted, using data from the Religious Orders Study, that the association between AD pathology and clinical AD was significantly stronger in women than in men 
. It was also noted that each unit of AD pathology increased the odds of clinical AD more than 20-fold in women compared with a three-fold increase in men. The authors suggested that AD pathology is more likely to be clinically expressed as dementia in women than in men. This relates to the findings in the current study, although caution is needed when applying the results of AD studies to the current MCI findings, particularly as we do not have follow-up data and thus do not know which MCI participants remained stable and which MCI participants progressed to AD dementia.
In terms of the rate of deterioration of WM microstructure with age (as measured by FA, DA, MD and DR), no age by sex interaction was found. The areas implicated in microstructural deterioration with age were dispersed through the brain, with a slightly more pronounced effect in frontal regions which is consistent with the concept of an anterior-posterior gradient of WM deterioration with age 
. The lack of any age by sex interaction for microstructural deterioration with age has been consistently noted by other studies 
Similarly, the rate of decline of GM with age was not found to be significantly influenced by sex which is also consistent with earlier work that has shown similar rates of GM volume decline in men and women which agrees 
. Previous studies investigating the effect of sex on the rate of WM volume decline with age in elderly populations are scarce and results have been equivocal 
but some evidence suggests that men show greater tendency for age-related differences in WM volume than women 
. The WM shrinkage with age identified in the current study is consistent with age-related changes reported in MRI relaxation times 
A limitation of the current study is the relatively small number of participants included. A study with a larger sample size of MCI participants is warranted to verify and further probe the impact of sex on mild cognitive impairment. This is being pursued as part of the European DTI Study in Dementia (EDSD) initiative. The small size of the current sample may weaken the ability to reliably identify interactions between sex and age, as well as, interactions between sex and diagnosis. It is now planned to assess these interactions in an independent sample with larger numbers of participants.
The cross-sectional nature of this study should be noted. We do not have follow-up data and thus do not know which participants subsequently developed AD or alternatively remained stable without deteriorating further. Therefore, the heterogeneity of the current cohort and the lack of diagnostic certainty in the cohort should be borne in mind. Future studies should also consider sex differences between those with MCI that remain stable and those that deteriorate to AD dementia. Technical limitation of the methodology should also be noted. Although TBSS strives to avoid the problems of voxel based morphology relating to partial voluming, some of these issues may still remain. Small WM tracts may be contaminated with GM if the tract width is smaller than the original voxel size, although applying a threshold of 0.2 or less to the WM skeleton in the TBSS preprocessing steps is thought to remove the potential occurrence of GM.
Overall our results show that in both control and MCI groups, men have greater WM damage than women with the same clinical diagnosis. This suggests that the threshold of WM damage that must be reached before entering the MCI spectrum is lower in women compared with men. The identification of older people with mild cognitive impairment that are at high risk of evolving to AD is vitally important for early treatment. The concept of MCI is now widely used to describe this high-risk group, and numerous research programmes have been undertaken with the aim of providing therapeutic intervention at the MCI stage which might reduce or prevent the possibility of progressing on to AD dementia. The current results indicate that sex differences need to be carefully considered when developing therapeutic strategies for the treatment of AD. While sex may have been overlooked in the past by simply including sex matched groups, the current study points to a need to take sex into account in all drug trials which seeks to target AD dementia and reduce its incidence in the population.