Genetic linkage studies suggest that Alzheimer's disease is not a single homogeneous disorder

Abstract

Alzheimer's disease, a fatal neurodegenerative disorder of unknown aetiology, is usually considered to be a single disorder because of the general uniformity of the disease phenotype. Two recent genetic linkage studies revealed co-segregation of familial Alzheimer disease with the D21S1/S11 and D21S16 loci on chromosome 21. But two other studies, one of predominantly multiplex kindreds with a late age-of-onset, the other of a cadre of kindreds with a unique Volga German ethnic origin, found absence of linkage at least to D21S1/S11. So far it has not been possible to discern whether these conflicting reports reflect aetiological heterogeneity, differences in methods of pedigree selection, effects of confounding variables in the analysis (for example, diagnostic errors, assortative matings), or true non-replication. To resolve this issue, we have now examined the inheritance of five polymorphic DNA markers from the proximal long arm of chromosome 21 in a large unselected series of pedigrees with familial Alzheimer's disease. Our data suggest that Alzheimer's disease is not a single entity, but rather results from genetic defects on chromosome 21 and from other genetic or nongenetic factors.

Heritability of schizophrenia and major affective disorder as a function of age, in the presence of strong cohort effects

“…In other multifactorial disorders with a variable age at onset (AAO), such as breast cancer and Alzheimer's disease, earlier AAO has been a useful clinical factor to separate out more genetically homogenous entities [13,16]. AAO in both schizophrenia and major affective disorders (e. g., bipolar disorder) varies considerably, spanning several decades.…”

Linking vascular disorders and Alzheimer's disease: Potential involvement of BACE1

“…Whereas VaD results from ischemic or hemorrhagic cerebrovascular disease, as well as from hypoperfusive ischemic cerebral injury resulting from circulatory and cardiovascular disorders (Roman et al, 1993;Roman, 2002), the etiology of AD remains elusive. While the mutations that cause the rare, familial AD (FAD) have been identified (St. George-Hyslop et al, 1990;Goate et al, 1991;Schellenberg et al, 1992;Levy-Lahad et al, 1995), the causative factors in the remaining ~95% of so-called sporadic AD cases are unknown.…”

Resemblance of psychotic symptoms and syndromes in affected sibling pairs from the Irish Study of High-Density Schizophrenia Families: evidence for possible etiologic heterogeneity

“…If it is possible, on clinical grounds, to divide the sample before linkage into etiologically distinct subgroups, a great gain in power is possible. This a priori heterogeneity test has, for example, been successfully applied in linkage studies of Alzheimer's disease (20) and breast cancer (21) on the basis of early-versus late-onset of illness.…”