Genetic epidemiological study of maternal and paternal transmission of alzheimer's disease

Ehrenkrantz, David; Silverman, Jeremy M.; Smith, Christopher J.; Birstein, Sandra; Marin, Deborah B.; Mohs, Richard C.; Davis, Kenneth L.

doi:10.1002/(sici)1096-8628(19990820)88:4<378::aid-ajmg15>3.0.co;2-8

Cited by 31 publications

(23 citation statements)

References 27 publications

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“…Epidemiological studies have provided evidence for both maternal and paternal transmission of AD (23,24), but none of these studies used biological measures to characterize the phenotypes. There is, however, evidence for parent-of-origin effects in lateonset AD families.…”

Section: Discussionmentioning

confidence: 99%

Maternal family history of Alzheimer's disease predisposes to reduced brain glucose metabolism

Mosconi

Bryś

Switalski

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

217

235

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Having a parent affected with late-onset Alzheimer's disease (AD) is a risk factor for developing AD among cognitively normal subjects. We examined whether cognitively normal subjects with a parental family history of AD show cerebral metabolic rate of glucose (CMRglc) reductions consistent with AD as compared with those without a family history and whether there are parent gender effects. Fortynine 50-to 80-year-old normal subjects were examined who received clinical, neuropsychological, and 2-[ 18 F]fluoro-2-deoxy-D-glucosepositron emission tomography examinations, including 16 subjects with a maternal (FHm) and eight with a paternal (FHp) family history of AD and 25 with no family history (FH ؊ ). FH groups were comparable for demographic and neuropsychological measures. As compared with both FH ؊ and FHp groups, FHm subjects showed CMRglc reductions in the same regions as clinically affected AD patients, involving the posterior cingulate cortex/precuneus, parietotemporal and frontal cortices, and medial temporal lobes (P < 0.05, corrected for multiple comparisons). These effects remained significant after accounting for possible risk factors for AD, including age, gender, education, apolipoprotein E genotype, and subjective memory complaints. No CMRglc differences were found between FHp and FH ؊ subjects. This study shows a relationship between reduced CMRglc in AD-vulnerable brain regions and a maternal family history of AD in cognitively normal individuals.A fter advanced age, the most significant risk factor for late-onset Alzheimer's disease (AD) is a family history of AD (1). Normal individuals with a first-degree relative affected by AD, especially a parent, are at a 4-to 10-fold higher risk for developing AD as compared with individuals with a negative family history (2-4). Apart from the rare early-onset form of familial AD related to autosomal dominant genetic mutations, genes with a clear Mendelian pattern of transmission for lateonset familial AD have not been identified. To date, the 4 allele of the apolipoprotein E (ApoE) gene is the only established genetic risk factor for late-onset AD and is found in Ϸ40% of late-onset AD cases with a positive family history (1). The ApoE-4 genotype has, however, no clear familial pattern of transmission and appears to act as a risk modifier by lowering the age at onset of clinical symptoms, rather than as a genetic determinant (see ref. 5 for review), indicating that other factors contribute to the etiology and phenotypic expression of disease. The biological mechanisms through which family history of AD confers increased susceptibility to late-onset AD are not known.A consistent feature of AD is the marked reduction of the cerebral metabolic rate of glucose (CMRglc) as measured by using positron emission tomography (PET) imaging with 2-[ 18 F]fluoro-2-deoxy-D-glucose (FDG) as the tracer (FDG-PET). FDG-PET studies demonstrate a specific pattern of CMRglc impairment in AD, involving the parietotemporal, posterior cingulate, and to a lesser extent frontal cort...

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Section: Discussionmentioning

confidence: 99%

Maternal family history of Alzheimer's disease predisposes to reduced brain glucose metabolism

Mosconi

Bryś

Switalski

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

217

235

View full text Add to dashboard Cite

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“…In vitro binding studies demonstrated that A (1-42), A (1-40) and A (1-20) each display dosedependent saturable binding to ABAD. In contrast, the Cterminal portion of A (25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35) does not bind to ABAD, indicating that ABAD-A interaction was not due to nonspecific interaction with aggregated or fibrillar material. This observation also suggested the possibility that A might anchor, via its N-terminus, in ABAD thereby leaving the C-terminus free and allowing it to multimerize with additional A .…”

Section: Direct Interaction Of a With Mito-chondriamentioning

confidence: 95%

“…Although genetic factors have been found to be important in the pathogenesis, the common lateonset form of AD does not appear to follow Mendelian genetics and shows only modest familial clustering. In this context, maternal inheritance had been suggested in limited cases [26,27]. However, AD is a complex disorder with multiple genetic and environmental factors affecting its development.…”

Section: Ad-associated Mitochondrial Dna Vari-antsmentioning

confidence: 99%

Mitochondrial Dysfunction and Alzheimers Disease

Chen¹,

Stern²,

Yan³

2006

CAR

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Mitochondrial dysfunction has been implicated in causing metabolic abnormalities in Alzheimer's disease (AD). The searches for mitochondrial DNA variants associated with AD susceptibility have generated conflicting results. The age-related accumulation of somatic mitochondrial DNA deletion has been suggested to play a pathogenic role in the development of AD. Recent studies have demonstrated that amyloid-beta peptide (Abeta) progressively accumulates in mitochndrial matrix, as demonstrated in both transgenic mice over-expressing mutant amyloid precursor protein (APP) and autopsy brain from AD patients. Abeta-mediated mitochondrial stress was evidenced by impaired oxygen consumption and decreased respiratory chain complexes III and IV activities in brains from AD patients and AD-type transgenic mouse model. Furthermore, our studies indicated that interaction of intramitochondrial Abeta with a mitochondrial enzyme, amyloid binding alcohol dehydrogenase (ABAD), inhibits its enzyme activity, enhances generation of reactive oxygen species (ROS), impairs energy metabolism, and exaggerates Abeta-induced spatial learning/memory deficits and neuropathological changes in transgenic AD-type mouse model. Interception of ABAD-Abeta interaction may be a potential therapeutic strategy for Alzheimer's disease.

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“…67 First-degree relatives of patients with AD are at 4-to 10-fold increased risk of developing AD as compared with individuals with no family history. [68][69][70] Although there is mixed evidence for parent-of-origin effects in late-onset AD families, 71,72 several epidemiologic data indicate that having an AD-affected mother confers greater risk than having an AD-affected father. 71 The authors' recent FDG-PET study on normal individuals with parental family history of AD showed that subjects with a maternal family history of AD exhibited CMRglc reductions as compared with subjects with a paternal history and those without a family history of AD.…”

Section: Maternal Family History Of Admentioning

confidence: 99%