Abstract
After advanced age, having a parent affected with Alzheimer's disease (AD) is the most significant risk factor for developing AD among cognitively normal (NL) individuals. Although rare genetic mutations have been identified among the early-onset forms of familial AD (EOFAD), the genetics of the more common forms of late-onset AD (LOAD) remain elusive. While some LOAD cases appear to be sporadic in nature, genetically mediated risk is evident from the familial aggregation of many LOAD cases. The patterns of transmission and biological mechanisms through which a family history of LOAD confers risk to the offspring are not known. Brain imaging studies using 2-[18F]fluoro-2-deoxy-D-glucose positron emission tomography (18F-FDG PET) have shown that NL individuals with a maternal history of LOAD, but not with a paternal family history, express a phenotype characterised by a pattern of progressive reductions of brain glucose metabolism, similar to that in AD patients. As maternally inherited AD may be associated with as many as 20 per cent of the total LOAD population, understanding the causes and mechanisms of expression of this form of AD is of great relevance. This paper reviews known genetic mutations implicated in EOFAD and their effects on brain chemistry, structure and function; epidemiology and clinical research findings in LOAD, including in vivo imaging findings showing selective patterns of hypometabolism in maternally inherited AD; possible genetic mechanisms involved in maternal transmission of AD, including chromosome X mutations, mitochondrial DNA and imprinting; and genetic mechanisms involved in other neurological disorders with known or suspected maternal inheritance. The review concludes with a discussion of the potential role of brain imaging for identifying endophenotypes in NL individuals at risk for AD, and for directing investigation of potential susceptibility genes for AD.
Highlights
Alzheimer’s disease (AD) is the most common form of dementia in late life, affecting approximately 10 per cent of individuals of 65 years of age, with the prevalence doubling every five years up to the age of 80, above which the prevalence is 40 per cent.[1]
Symptomatic mutation carriers showed significant tracer retention in the cortical regions, uptake was not as high as in sporadic AD subjects.[32]. These findings suggest that amyloid deposition in presenilin 1 (PSEN1) mutation carriers may begin in the striatum before the onset of symptoms, and later spread to neocortical regions.[32,33]
A genomewide screening of AD families reported a linkage between late onset AD (LOAD) and a region close to the centromere of chromosome 10q only in families with an AD affected mother.[91]. While these findings suggest imprinting,[91] there is no clear evidence for the existence of imprinted genes in AD families on chromosome 10 or on other chromosomes
Summary
APP to Ab42 Rapid progression amyloid deposition on PIB PET in Associated with seizures, pre-symptomatic and myoclonus and language symptomatic mutation deficits carriers. ApoE 14 carriers vs Hippocampal atrophy variants: 12, LOAD, non-carriers show lower on MRI and reduced. 10 –20% of age at onset, reduced Ab CMRglc on FDG-PET controls clearance, poorer in pre-symptomatic and cognitive performance in symptomatic ApoE 14 late life carriers vs non-carriers. LOAD 45% of Poorer episodic memory Increased hippocampal in CC carriers vs TT and activation on fMRI, and TC carriers reduced CMRglc on FDG-PET in CC carriers vs CT and TT. TC – GCA – TGAGGTGTCTT haplotype: Less protection from neuronal tangle formation and cell death Increased risk of AD
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