How heritable is Alzheimer’s disease late in life? Findings from Swedish twins
Pedersen NL, Gatz M, Berg S and Johansson B;
Commented by , 20 Apr 2004
Aim of the study
Characterize the relative importance of genetic and environmental factors for incident Alzheimer’s disease (AD) late in life and test for differences in the importance of genetic effects at different ages.
Method
Prospective cohort of 662 pairs of Swedish twins 52 to 98 years of age, initially without symptoms of dementia. Follow-up over 5 years using cognitive testing or telephone screening at 2 to 3-year intervals, followed by dementia workups including physical and neurological evaluations, neuropsychological assessments, laboratory tests and neuroimaging.
Consensus opinion towards diagnosis of AD following DSM-III-R and NINCDS-ADRDA criteria was obtained from a physician, a psychologist and a nurse.
Results
5.8% of the persons in the cohort were diagnosed with AD over the 5 year follow-up, the average age of onset being 83.9 years. Among the 26 monozygotic pairs in which at least one twin developed AD, 5 were concordant (probantwise concordance 32.2%). The concordance rate for dizigotic pairs was 8.7% (2 of 44 pairs). Structural model fitting indicated that 48% of the variation in liability to AD could be genetic.
Estimates did not differ significantly between twins younger than age 80 and those older than 80 at baseline. The presence of apolipoprotein E4 allele was significantly associated with AD but not different between age groups (odds ratio 3.58, CI 1.32-9.67 for younger age than 80, and 2.72, CI 1.44-5.15 for over 80).
Discussion
Despite the rapid advances in molecular genetics of AD, there is still a paucity of genes clearly established as linked to late onset AD. The apolipoprotein E4 mutations on chromosome 19 is the best known, but there are clearly others still to be found. Studies are under way in Canada and elsewhere to collect DNA from large (1000 or more) numbers of persons with probable AD and from age, gender and education-matched controls.
Another approach is illustrated by this article: the use of twins in a well designed cohort study over five years, looking for new (incident) cases to emerge. The authors interpret their findings as suggesting that environmental factors are as important as genetic factors in accounting for late-onset AD.
This is encouraging news considering the numerous possibilities in reduction of risk factors, including control of systolic hypertension during middle-life, use of NSAIDS, statins, red wine, possibly vitamins E and C, amenable to all persons, and amyloid-modifying drugs under development for persons at higher genetic risk.