Beyond age, the next biggest risk factor for late-onset Alzheimer’s disease is having the disorder in one’s pedigree, especially on Mom’s side. Neuroimaging studies have supported this observation, revealing more preclinical AD-like brain changes in healthy seniors with a maternal history of AD, compared to those with a paternal or negative history. In this month’s Neurology, first author Robyn Honea and colleagues at the University of Kansas School of Medicine, Kansas City, extend this line of evidence with two-year longitudinal data showing faster regional brain atrophy in adult children of mothers with AD. The finding was enough to catch the attention of The New York Times.

When monitored using positron emission tomography (PET), cognitively intact elderly with a maternal history of AD show ominous brain features—among them, decreased glucose metabolism (ARF related news story and Mosconi et al., 2007; Mosconi et al., 2009) and greater amyloid load (ARF related news story on Mosconi et al., 2010). On magnetic resonance imaging (MRI), these folks also have reduced gray matter volume, according to a recent study by Honea and colleagues (Honea et al., 2010; see also Berti et al., 2011). The current paper is a longitudinal extension of that cross-sectional MRI study, with brain atrophy rates determined two years after baseline.

In the cross-sectional study, Honea and colleagues analyzed structural MRI data on 67 cognitively intact seniors enrolled in the University of Kansas’ Brain Aging Project. Compared to participants with a paternal history, or no family history, of Alzheimer’s disease, the group with AD mothers showed lower gray matter volume in AD-vulnerable brain regions. Now, with two-year follow-up MRI data on 53 subjects (32 with no family history, 10 with paternal history, and 11 with maternal history of AD), the present study suggests that people with AD mothers also have accelerated brain atrophy in disease-affected regions. The researchers found strongest evidence of decay in the precuneus and parahippocampal gyrus, areas that overlap with those showing high fibrillar Aβ burden (Mosconi et al., 2010).

The new findings are important for a number of reasons, noted Lisa Mosconi, New York University School of Medicine, New York, in an e-mail to ARF. Brain atrophy rates have been linked to future decline from normal cognition to AD (see ARF related news story), and MRI is widely available for clinical practice as well as clinical trials, she wrote. “Together with previous studies, these new findings strengthen the hypothesis of a genetic component to the biomarker abnormalities in this group of at-risk individuals [i.e., seniors with a maternal history of AD],” wrote Mosconi (see full comment below).

The authors speculate that the “genetic component” may lie within mitochondrial DNA, considering its exclusively maternal transmission and growing evidence for the role of mitochondrial dysfunction in AD (see Reddy and Beal, 2008). Indeed, mitochondrial DNA “may very well be associated with the imaging findings,” Mosconi noted. She added that larger, longer studies will need to follow people with AD mothers “until some of them actually develop AD, in order to determine the prediction accuracy and absolute risk of MRI-determined atrophy and other biomarkers for AD.” Honea expressed similar views in the New York Times article on the current study, noting that more research is needed to achieve the goal of using diagnostic brain scans to identify high-risk individuals before they deteriorate.—Esther Landhuis

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  1. The study by Honea and colleagues adds very nicely to an increasing body of literature showing that having a maternal history of Alzheimer's disease (AD) is a major risk factor for developing AD among normal individuals. In a series of brain imaging papers starting back in 2007, we showed that adult children of AD-affected mothers have progressively reduced brain glucose metabolism and increased amyloid-β pathology consistent with AD, as compared to demographically matched individuals with AD fathers and those with no parents affected. The study by Honea et al. shows that normal elderly with AD mothers also show higher rates of atrophy (reflecting neuronal loss) on MRI over a two-year window.

    These findings are very important because 1) increased brain atrophy rates are known to be strongly associated with future decline from normal cognition to AD; 2) they provide evidence from structural, besides functional and pathological, deficits in individuals with AD mothers; 3) MRI is widely available for clinical practice as well as clinical trials, and is non-invasive and affordable; and 4) together with previous studies, these new findings strengthen the hypothesis of a genetic component to the biomarker abnormalities in this group of at-risk individuals.

    The genetics of late-onset AD are still elusive, but it seems clear that late-onset AD is a complex and possibly multifactorial disease where many different risk factors play a role. It is becoming clear that genes involved with maternal transmission lead the offspring to develop an AD-biological phenotype around middle age. Among other possibilities, mitochondrial DNA is entirely maternally inherited in humans and may very well be associated with the imaging findings.

    Additionally, these findings are consistent with epidemiological studies showing that maternal transmission of AD is more frequent than paternal transmission, and is associated with greater risk and poorer cognitive performance in the offspring. We published a review chapter that summarizes these data (Mosconi et al., 2010).

    More studies with larger samples and longer follow-ups are needed to follow individuals with AD mothers (and fathers) until some of them actually develop AD in order to determine the prediction accuracy and absolute risk of MRI-determined atrophy and other biomarkers for AD.

    References:

    . Maternal transmission of Alzheimer's disease: prodromal metabolic phenotype and the search for genes. Hum Genomics. 2010 Feb;4(3):170-93. PubMed.

    View all comments by Lisa Mosconi

References

News Citations

  1. Functional Imaging Gives Early Glimpse of AD
  2. Do Mothers’ Mitochondria Magnify Dementia Risk?
  3. ADNI: One-year Data Narrow Field of MRI, FDG-PET Approaches

Paper Citations

  1. . Maternal family history of Alzheimer's disease predisposes to reduced brain glucose metabolism. Proc Natl Acad Sci U S A. 2007 Nov 27;104(48):19067-72. PubMed.
  2. . Declining brain glucose metabolism in normal individuals with a maternal history of Alzheimer disease. Neurology. 2009 Feb 10;72(6):513-20. PubMed.
  3. . Increased fibrillar amyloid-{beta} burden in normal individuals with a family history of late-onset Alzheimer's. Proc Natl Acad Sci U S A. 2010 Mar 30;107(13):5949-54. PubMed.
  4. . Reduced gray matter volume in normal adults with a maternal family history of Alzheimer disease. Neurology. 2010 Jan 12;74(2):113-20. PubMed.
  5. . Structural brain changes in normal individuals with a maternal history of Alzheimer's. Neurobiol Aging. 2011 Dec;32(12):2325.e17-26. PubMed.
  6. . Amyloid beta, mitochondrial dysfunction and synaptic damage: implications for cognitive decline in aging and Alzheimer's disease. Trends Mol Med. 2008 Feb;14(2):45-53. PubMed.

External Citations

  1. The New York Times

Further Reading

Papers

  1. . Increased fibrillar amyloid-{beta} burden in normal individuals with a family history of late-onset Alzheimer's. Proc Natl Acad Sci U S A. 2010 Mar 30;107(13):5949-54. PubMed.
  2. . Reduced gray matter volume in normal adults with a maternal family history of Alzheimer disease. Neurology. 2010 Jan 12;74(2):113-20. PubMed.
  3. . Structural brain changes in normal individuals with a maternal history of Alzheimer's. Neurobiol Aging. 2011 Dec;32(12):2325.e17-26. PubMed.
  4. . Maternal family history of Alzheimer's disease predisposes to reduced brain glucose metabolism. Proc Natl Acad Sci U S A. 2007 Nov 27;104(48):19067-72. PubMed.
  5. . Declining brain glucose metabolism in normal individuals with a maternal history of Alzheimer disease. Neurology. 2009 Feb 10;72(6):513-20. PubMed.
  6. . The influence of parental history of Alzheimer's disease and apolipoprotein E epsilon4 on the BOLD signal during recognition memory. Brain. 2009 Feb;132(Pt 2):383-91. PubMed.
  7. . Maternal transmission of Alzheimer's disease: prodromal metabolic phenotype and the search for genes. Hum Genomics. 2010 Feb;4(3):170-93. PubMed.

Primary Papers

  1. . Progressive regional atrophy in normal adults with a maternal history of Alzheimer disease. Neurology. 2011 Mar 1;76(9):822-9. PubMed.