Overall, we found that a family history of dementia is associated with AD-typical biomarker changes. More specifically, we found that a maternal family history of AD is associated with increased global PiB uptake, specifically in the parietal, precuneus, and sensorimotor cortices, as well as decreased CSF Aβ levels and increased tau/Aβ ratio. When analyzing diagnostic group separately, this family history relationship with CSF measures was only significant in individuals with MCI, a heterogeneous pathological state. These data complement and extend reports of increases in Aβ burden on PiB-PET scans in FHm subjects in these same parietal and association cortex regions, and another report of increases in an AD-like CSF biomarker signature in individuals with a maternal family history of AD [20
Our findings suggest that a maternal family history of dementia may be associated with increased fibrillar Aβ deposition in the brain in posterior parietal and association cortex regions, a hallmark of AD pathophysiology. Increased brain Aβ levels in individuals with MCI have been associated with accelerated gray matter atrophy within temporal and parietal brain regions, and increased risk for progression to AD [21
]. Interestingly, increased Aβ deposition on PiB PET scans has recently been shown in healthy individuals with a maternal family history of LOAD in the interior and posterior cingulate cortex, precuneus, and parietal regions among others [8
]. Thus, impairment of the posterior cingulate and precuneus may be a marker to distinguish early stage AD from healthy aging [22
]. For instance, otherwise healthy individuals at genetic risk for AD have abnormal default mode activity in the precuneus and parietal cortex [23
]. Longitudinal studies in nondemented individuals with FHm have also shown a progressive decline in posterior cortical glucose uptake [7
], and increased regional gray matter atrophy in posterior parietal cortices [24
]. Furthermore, reduced precuneus choline acetyltrans-ferase enzyme activity postmortem has been associated with increased [(3)H]PiB binding, increased soluble Aβ42
, lower MMSE score, genetic risk, and more advanced AD pathophysiology [25
]. We found a significant effect of FH on CSF biomarkers in MCI, as opposed to ND individuals, similar to another ADNI report of differences in hippocampal atrophy rates between FH groups [26
]. This could be because of the stringency of clinical criteria for ND in the ADNI sample, a difference of parental history grouping, or differences in the CSF assay or processing. Overall, our results support these prior findings and demonstrate that individuals with a maternal family history of dementia have significantly increased fibrillar Aβ deposition in the precuneus, parietal cortex, and sensorimotor cortices. To our knowledge, this is the first report of parental history of dementia affecting PiB uptake in AD-vulnerable regions in MCI subjects.
CSF measures of Aβ1-42
and tau have shown prognostic value in discriminating MCI patients that will develop AD [27
]. We found that a maternal family history of AD is associated with decreased Aβ levels and increased tau/Aβ42
ratio in CSF, adding to a growing literature showing increased AD-associated biomarkers in individuals with a family history of AD. A recent report from the Washington University Adult-Children Study found that among cognitively normal middle- to older-aged individuals, age-related changes in brain Aβ42
amounts were influenced by FH of AD [20
]. In addition, Mosconi et al. recently reported reduced Aβ40/42
ratio levels in CSF of nondemented FHm individuals [9
]. Concurrently, we report that FHm individuals with MCI had the only significant reductions in CSF Aβ42
. Studies have shown that reduced Aβ42
levels in CSF are predictive of AD and reflect increased brain Aβ load [27
]. Population-based CSF studies have found that reduced Aβ levels were related to AD risk in elderly individuals more than CSF total tau or phosphorylated tau [30
]. Thus, ours and other studies show that individuals with a maternal family history of AD may have greater AD pathophysiology.
While the genetic basis for the transmission of imaging and CSF phenotypes of AD pathophysiology are unknown, studies of maternal inheritance, mitochondrial DNA (mtDNA) mutations, and cytochrome oxidase deficits in AD provide converging evidence for the role of mitochondria in risk for LOAD [5
]. Mitochondria supply energy from aerobic metabolism and play an important regulatory role in apoptosis, and produce and detoxify free radicals. Mitochondrial DNA is exclusively maternally inherited in humans, and may differ between persons with and without AD [34
]. Studies of cytoplasmic hybrids (cybrids) demonstrate that AD mtDNA has decreased cytochrome oxidase activity and increased oxidative stress, among other abnormalities [35
]. Moreover, a recent study connected mitochondrial malfunction with a family history of AD by demonstrating that otherwise healthy FHm individuals have reduced cytochrome oxidase activity in platelet mitochondria compared to those with a paternal or no family history of AD, suggesting that mtDNA may influence AD risk [37
]. Thus, converging evidence of platelet mitochondrial malfunction [37
], AD-like brain imaging phenotypes [5
], and CSF biomarkers of AD pathophysiology contribute to our hypothesis that increased risk for LOAD in FHm individuals may be due to mutations in mtDNA.
This study has several important limitations. In ADNI, parental history of dementia is provided by subject self-report, which, while practical to obtain, does not provide a neuropathologic diagnosis. Similar to a recent ADNI study on family history and structural imaging markers [26
], we chose to use a parental history of dementia as opposed to a parental history of AD, as in many instances the suspected etiology of parental dementia was never recorded. The rationale for using “family history of dementia” was based on the number of available subjects with a positive parental history with PiB PET data. This likely led to the inclusion of some subjects with parental non-AD dementia, such as vascular dementia, Parkinson's disease dementia, or dementia with Lewy bodies. Both limitations may have influenced our analyses by reducing our power to detect the presence or true extent of family history effect in AD. We did not observe a consistent relationship of FH with CSF measures in the AD group although we suspect the restricted variance in these measures reduce the power to detect a significant relationship. Moreover, there was an imbalance of individuals with a paternal versus a maternal family history in both PiB and CSF analysis, possibly limiting our power to find more significant relationships of FHp with AD biomarkers. We also had limitations in our small sample size of individuals with PiB data, with samples too small to perform analyses within clinical groups. Thus there was an imbalance within this sample of proportions of FHm versus FHp individuals in the ND and AD groups (all AD FH+ individuals were FHm, and the ND group had only 1 FHp individual). To address this, we corrected for clinical status as a covariate while examining PiB measures across all diagnostic groups. However, despite these statistical corrections, analysis of a combined diagnostic sample may have limited our ability to interpret our findings in terms of the role of PiB in risk for AD, since increased PiB in FHm may be due to a higher proportion of AD patients in the FHm group. Additionally, our findings were confined to associations between AD biomarkers and FH at baseline, and follow-up time in the ADNI study is warranted to investigate the causal relationship between FH and change in biomarkers, as well as progression to AD.
In conclusion, our results support and extend previous studies of FH and AD biomarkers, which demonstrate a relationship between FH, and particularly FHm status, and AD pathophysiology in the earliest stages of AD. These results are consistent with the view that in the earliest stages of AD, changesinthe brain associated with the disease process are influenced by a maternally inherited genetic factor.