Aggregation and deposition of amyloid-β (Aβ) in the brain is thought to be the central event in the pathogenesis of Alzheimer disease (AD). Altered cerebrospinal fluid (CSF) levels of Aβ1-40 and Aβ1-42 and the Aβ42/40 ratio are used as biomarkers to support the clinical diagnosis in AD. Several studies have reported on decreased CSF levels of Aβ1-42, and various studies suggest that Aβ levels might be increased in plasma, including in familial AD forms.

Despite many studies, many factors, such as genetic polymorphisms, which might be associated with disease or even alter the disease phenotype, are not well understood. These studies are complicated by distinct clinical phenotypes of AD, and even more by the fact that frequently, the diagnosis is done on clinical grounds. Therefore, in complex diseases with heterogeneous phenotypes, new approaches are urgently needed. One way to overcome the problem of clinical heterogeneity is to use intermediate traits, or endophenotypes, which are less heterogeneous than clinical diagnoses and might be more directly affected by genetic...  Read more

Aggregation and deposition of amyloid-β (Aβ) in the brain is thought to be the central event in the pathogenesis of Alzheimer disease (AD). Altered cerebrospinal fluid (CSF) levels of Aβ1-40 and Aβ1-42 and the Aβ42/40 ratio are used as biomarkers to support the clinical diagnosis in AD. Several studies have reported on decreased CSF levels of Aβ1-42, and various studies suggest that Aβ levels might be increased in plasma, including in familial AD forms.

Despite many studies, many factors, such as genetic polymorphisms, which might be associated with disease or even alter the disease phenotype, are not well understood. These studies are complicated by distinct clinical phenotypes of AD, and even more by the fact that frequently, the diagnosis is done on clinical grounds. Therefore, in complex diseases with heterogeneous phenotypes, new approaches are urgently needed. One way to overcome the problem of clinical heterogeneity is to use intermediate traits, or endophenotypes, which are less heterogeneous than clinical diagnoses and might be more directly affected by genetic variations. In this study, Kauwe et al. analyzed if extreme Aβ levels might be used as an endophenotype for AD.

The study comprised 191 volunteers participating in a study of aging and dementia. Sixty-four percent of them have a positive family history of AD (one or more first-degree relatives). One hundred forty-three were not demented, 33 percent had a very mild dementia (Clinical Dementia Rating 0.5), and 15 had mild dementia (CDR 1.0). They were studied for Aβ levels in CSF and blood, ApoE genotype, and various clinical characteristics. The levels of Aβ1-40 and Aβ1-42 differed by 10-fold between maximum and minimum in subjects studied. Aβ1-42 levels in CSF significantly decreased with age and increased with CDR scale. Aβ1-40 correlated with sex, but not with age, dementia severity, or ApoE status.

In contrast to common studies on biomarkers, the authors followed a completely new approach. They hypothesized that extreme Aβ1-40 or Aβ1-42 levels might indicate some specific disease phenotypes and therefore can be used as endophenotypes to characterize AD. To study this, individuals with extreme CSF values of Aβ1-40, Aβ1-42, and Aβ42/40 ratio (top and bottom 5 percent values) were identified for DNA sequencing. Eight genetic variants of PSEN1 were identified in the sample. In one individual, a missense mutation in exon 4, A79V, was identified. This is a known mutation in familial Alzheimer disease that has been previously reported in four families. The carrier is nondemented and has the fifth highest adjusted Aβ1-42 value and the third highest Aβ42/40 ratio in the sample studied. To investigate the consequences of this mutation on Aβ levels, the A79V mutation was introduced into the wild-type PSEN-1 sequence and then transfected into PSEN1/2 knockout mouse embryonic fibroblasts. The Aβ levels and the Aβ42/40 ratio in conditioned media from these cells were significantly higher than the wild-type PSEN-1 sequence, thus suggesting a direct effect of the mutation on Aβ levels.

The results of the study, which follows a completely novel approach to biomarkers, suggests that CSF or potentially blood levels of certain proteins might be a useful endophenotype for genetic studies in AD and might lead to the identification of atypical disease phenotypes or genetic variations. However, the study opens new questions which are related to the diagnosis of AD, which is most always done on clinical grounds. Since the “typical” CSF pattern seen in AD is a decrease of Aβ1-42, patients with abnormally high levels in CSF, which might also display an atypical clinical presentation, might be missed. As a consequence, a careful follow-up of all suspected cases is needed to solve the question of atypical presentations in AD and potentially to detect novel mutations that might cause AD.

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