New research shows that cognitively normal people whose parents were both diagnosed with late-onset (after age 60) Alzheimer's disease (LOAD) have greater β-amyloid (Aβ) burden, hypometabolism, and gray matter volume (GMV) loss compared with those with no family history of AD or those with just 1 parent with LOAD.
The new analysis provides biological evidence for the "parent-dose" effect on LOAD. Brain abnormalities also seemed to be greater in those with a maternal history of AD than in those with a paternal history.
"The results showed that there's a kind of gradient effect," lead author, Lisa Mosconi, PhD, assistant professor, psychiatry, New York University School of Medicine, told Medscape Medical News.
"If no parent is affected, you're doing just fine. If your father is affected, you're starting to show some amyloid," she said."If your mother is affected, the amyloid gets worse and you're starting to show hypometabolism. And if both of your parents are affected, your brain shows changes similar to what we find in clinical Alzheimer's disease patients; it's not as bad, but the pattern is the same."
The study was published online February 12 in Neurology.
The analysis included 52 clinically and cognitively normal individuals aged 32 to 72 years who were enrolled in longitudinal studies at New York University School of Medicine. The participants had at least 12 years of education, a Clinical Dementia Rating score of 0, a Global Deterioration Scale score of 2 or less, a Mini-Mental State Examination score of at least 28, and a Modified Hachinski Ischemia Scale score of less than 4.
Researchers divided the participants into 4 equal groups: controls with no family history of AD (FH-), those with a mother with AD (FHm), those with a father with AD (FHp), and those for whom both parents had AD (FHmp).
The biomarkers of interest were MRI-based measures of regional brain volume and positron emission tomography (PET)–based measures of retention of Aβ (PiB), a toxic protein thought to play a role in AD, and of glucose metabolism (FDG).
The MRI analysis showed that those with both a mother and father with AD had reduced GMV in the temporal cortex and striatum compared with both controls and the FHm group, and in the parietal and frontal regions compared with the FHp and FHm groups (P < .001).
Both the FHm and FHp groups had reduced GMV in the precuneus compared with the FH- group, and the FHm group showed additional GMV reductions in the parietal cortex compared with the FHp group (P < .001)
The PiB-PET analysis showed that the FHmp group had increased PiB retention in frontal and parietal regions and the striatum compared with the FH- and FHp groups (P < .001).
On FDG-PET, both the FHmp and FHm groups showed reduced FDG uptake in the posterior cingulate, precuneus, and temporal regions compared with controls and in frontal regions compared with the FHp group (P < 0.001).
An important aspect of the study was that it revealed differences between groups based on parental history of AD. Those with a family history of AD in both parents consistently had the greatest brain effects, and those with 1 affected parent showed more effects than the group with no affected parent.
Results of an analysis of 36 cognitively normal persons 60 years old or younger, including 9 in each group who were matched by age, sex, and education, were mostly similar to those of the main analysis. This, said the authors, "showed that the younger FHmp still had higher Aβ burden than the other groups."
These results were independent of APOE genotype; only 30% of the participants were ε4 carriers. The small sample size prevented analysis of interactions between FH and APOE genotypes.
"These subjects don't have genetic mutations, but something is pushing their brain to develop AD pathology when they are fairly young," said Dr. Mosconi. "But we don't know if that means they're at increased risk for dementia."
The study also uncovered significant effects related to the sex of the affected parent. Participants whose mother was affected had a higher level of AD pathology than those with an affected father. This is consistent with other findings that maternal transmission is associated with higher risk than paternal transmission, independent of increased female longevity.
Researchers are not clear on why there's such a strong maternal effect, commented Dr. Mosconi. It's likely not due to environmental factors, but it could be a result of a chromosome X abnormality or defective mitochondrial DNA, which is 100% maternally transmitted, she said. "If the mitochondria don't work, you won't be able to use sugar to produce energy, and that affects the brain."
According to Dr. Mosconi, the new results are useful in terms of prevention in children of parents with LOAD who are asymptomatic but have AD pathology — at least when AD treatments become available. "People should be treated when they're still young and healthy so the treatment has the greatest chance of success," said Dr. Mosconi.
As treatments do become available, they will likely be expensive and may carry significant adverse effects. It therefore will be important to determine which asymptomatic patients with AD pathology will develop dementia and might benefit from the therapy and which ones will live a healthy life without dementia anyway, she said.
Dr. Mosconi stressed that lifestyle approaches — for example, getting enough exercise, eating properly, and managing stress — can also lower AD risk. There's mounting evidence, for example, of the protective effect of getting enough sleep, she said, adding that the turnover of the amyloid protein that is so dangerous in AD is regulated in part by sleep.
According to Dr. Mosconi, less than 5% of the population have both parents affected by LOAD, some 30% have a mother with AD, and 10% have a father with AD. Because having 2 parents with LOAD is so unusual, it was difficult to recruit participants for the study.
However, after 2 years, participants in the study are starting to come back for follow-up testing. About 25 have now completed the second round of examinations, said Dr. Mosconi.
Approached for a comment, Richard B. Lipton, MD, professor and vice chair of neurology, director, Division of Cognitive Aging and Dementia, Albert Einstein College of Medicine, New York, New York, and member of the American Academy of Neurology, said the study results add to evidence that even in its late-onset form, AD begins in asymptomatic individuals long before cognitive impairment.
"The design of this study — comparing healthy adults in late middle life, based on the detailed family histories of LOAD, including the number and gender of their effected parents — is an insightful and obviously rewarding solution to an important problem," said Dr. Lipton.
The study, added Dr. Lipton, "is an important step towards developing strategies for screening individuals at high family risk for the early brain changes of AD as a prelude to developing preventive interventions."
Dr. Lipton noted that the "family history dose effect" discussed in the study supports the role of genetic factors in late-onset AD.
While some of the best evidence of AD-related biomarker changes comes from studies of early-onset AD, a rare autosomal dominant disorder that usually begins in the 40s and 50s, results of these studies may not pertain to the more common LOAD, which is more difficult to study in an asymptomatic stage, he added.
The suggestion that a maternal family history of AD has greater effects than a paternal family history needs to be pursued, stressed Dr. Lipton.
And while the finding that a family history is associated with biomarkers of AD is interesting, studies are also needed to identify those at high risk for the onset of AD dementia, said Dr. Lipton. "To see if the carriers of these markers are at high risk, we would follow people over time to see if the presence of the markers predicts the development of AD. It's possible that relatives of AD patients have AD markers but that the markers do not predict disease."
The study was supported by grants from the National Institute on Aging and the Alzheimer's Association. Dr. Mosconi has a patent on a technology that was licensed to Abiant Inc by New York University, and as such, has a financial interest in this licence agreement and holds stock and stock options on the company. She has received compensation for consulting services from Abiant Inc.
Neurology. Published online February 12, 2014. Abstract
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Cite this: Alzheimer's Pathology Seen in Children of Patients With AD - Medscape - Feb 14, 2014.