Three main findings emerged from our study. We found significantly higher t-tau/Aβ42 ratios and a higher prevalence of the rate of a “pathologic t-tau/Aβ42 endophenotype” in FH+ (versus FH−) CN and MCI groups. There was an additional effect of FH on these markers above and beyond that of ApoE4 in MCI subjects and the model estimated suggests that this additional effect is about half of the size of the ApoE4 effect. We found no FH effects on CSF pathologic markers in AD. We also found no FH effects on neuronal loss marker (hippocampal volume) both before and after adjusting for intracranial volume. We also found no FH effects on ICV. These data extend findings from prior studies of FH effects 
to the national ADNI sample and to MCI subjects. Our study also found that almost half of all normal controls with FH+ would have met research criteria for preclinical AD (based on CSF) 
at entry into ADNI but only about 20% of FH− subjects would have met such criteria. This result is also consistent with the view that a family history of AD does not reduce cognitive reserve, as there were no significant differences in cognitive test scores between FH+ and FH− groups. Rather, one can speculate that the risk of family history is probably mediated by earlier development of amyloid pathology or more rapid development of amyloid pathology with the same time of onset.
Of prior studies examining FH effects, three are particularly relevant to our analyses. In a study of 269 cognitively normal controls, Xiong et al 
reported that FH status was linked to a decrease in CSF Aβ42, a finding that we extend by reporting a similar and even more robust change in MCI. Honea et al 
examined the relationship between biomarkers and parental history of all dementia types in the ADNI sample, thus potentially including also FH of vascular dementia, DLB or FTD or other etiologies. In their study, the rate of FH+ subjects was different from ours and unlike our study, the effects of FH on t-tau/Aβ42 ratio and t-tau effects in MCI did not reach significance. They did report a significant FH effect on Aβ42 in MCI consistent with our finding, but in their study the FH effects in MCI were not significant after adjusting for ApoE4, whereas ours remained significant. They also found pathologic signatures of AD in a smaller percent of CN than we did. Thus, their looser definition appears to have resulted in an underestimation of the effect of FH of AD. Andrawis et al 
found MCI subjects with positive maternal history of dementia had smaller baseline hippocampal volumes and greater 12-month atrophy rates. The effect of positive maternal history of dementia on hippocampal atrophy in MCI and AD was significant after controlling for age, ApoE4 genotype, and paternal history of dementia. Taken together, these studies along with prior studies showing potential FH effects on brain networks and glucose metabolism highlight the need to further examine FH effects on multiple biomarkers simultaneously.
The mechanisms underlying the effects of FH status are not fully known but will likely vary depending on biomarker – ie genetic mechanisms underlying hippocampal volume changes are not likely to be identical to those underlying amyloid or tau processing. Prior autopsy, CSF and PET studies have linked ApoE4 to an amyloid phenotype and hippocampal changes 
, and studies have documented ApoE4 effects on greater neocortical amyloid-beta deposition and/or reduced clearance 
. However, E4 does not account for all of the variance and there is interest in determining the degree of unexplained heritability not accounted for by ApoE4 as well as the genes underlying such unexplained heritability. In our ADNI sample, the effect of adjusting for ApoE4 on pathologic markers was different in different diagnostic groups - the FH effect was considerably weakened in CN, remained significant in MCI subjects, and was not significant in AD. After adjusting for ApoE4, the remaining FH effect on CSF t-tau/Aβ42 was approximately half the size of the main ApoE4 effect. Thus, our data along with others 
confirms that there are as yet unidentified genetic factors embedded in FH status that influence pathology before the onset of dementia 
Our sensitivity/specificity analyses also suggest that the presence of FH+ controls in an AD control group may significantly reduce the specificity of CSF pathologic biomarkers for separating AD from controls. It may be worth examining whether including FH+ controls may have reduced the accuracy of calculations in other tests, such as amyloid PET or plasma Aβ42. Likewise our data also suggests that companies planning registration studies of diagnostic biomarkers to detect AD pathology in at-risk subjects may wish to exclude FH+ controls to enhance their power for achieving the desired 80% or greater specificity.
There are also some potential limitations of this study – by design ADNI’s sample size of controls and AD was relatively smaller than the MCI group, which may have limited power to detect small effects in controls. CSF data were only collected in a subset who agreed to volunteer, a selection bias that applies to most CSF biomarker studies. FH status was determined through interviews with subjects and informants, but may have been subject to a reporter bias and lack of informative pedigree (early death of relatives due to other causes, though this problem is less likely in the US due to longer life expectancies and greater awareness of dementia). Many respondents may not be well versed enough to know the difference between a dementia and AD. Because FH in most biomarker research and practice is usually collected only by simple history, our findings are relevant. We also did not distinguish between maternal and paternal inheritance and hence our data cannot be compared with findings that maternal family history may have greater risk for metabolic changes or hippocampal atrophy 
. Furthermore, given that there is a mitochondrial hypothesis providing an underlying biological mechanism for promoting disease on the maternal side we believe future studies should examine maternal versus paternal family history. However a recent longitudinal study of 108 middle-aged normal controls (of younger age than ADNI cohort) found that FH status predicted greater atrophy only within a posterior sub-region of the hippocampus but not in other gray matter regions, and that there was no effect of maternal versus paternal history 
. Differences in sampling, FH ascertainment, and biomarker methods could account for some of the discrepant findings. While the means differ significantly, the overlap in CSF data boxplots between FH+ and FH− MCI groups suggests that these findings may not be as robust a biomarker as one where the boxplots do not overlap at all - unfortunately no such biomarker exists.
What do these phenotypic differences related to a positive FH in MCI mean for the subject? Other studies have linked CSF pathologic phenotypes with faster rates of future decline in CN and MCI subjects 
. By extrapolation, this would imply that the subset of FH+ MCI and CN subjects with abnormal biomarker phenotypes would decline faster than FH− subjects. Longitudinal data from ADNI and standardization of hippocampal sub-region analyses as well as CSF soluble amyloid oligomer assays 
may permit more definitive testing of the prognostic significance of FH differences on risk for decline.
In summary, our study, derived from a large national biomarker cohort, documents that a positive family history of AD is associated with an abnormal beta-amyloid and tau endophenotype prior to the onset of clinical AD in mildly symptomatic subjects, and that there are genetic influences embedded within FH beyond that due to ApoE4 that are most obvious in the MCI cohort. Since CSF biomarkers correlate highly with cerebral neuritic beta-amyloid and neurofibrillary tangle changes 
, we also speculate that FH status is associated with earlier onset of preclinical pathologic AD. These findings have implications for the design of future research studies, heritability of AD and personalizing testing and care of at risk subjects.