The pivotal molecule in the AD brain is the amyloid peptide. In familial autosomal dominant AD, the disease may be caused by increased cleavage of the amyloid precursor protein to release amyloid peptide. In such cases mutations of presenilins (components of the gamma secretase complex) or the amyloid precursor protein augment cleavage; this is reflected in elevated amyloid peptide levels in plasma 3
. In Down syndrome, a likely cause of amyloid accumulation in brain is the extra copy of APP gene which resides on chromosome 21; whether this is reflected in changes in plasma peptide levels remains controversial.
We took advantage of a well characterized group of individuals with Down syndrome at least 50 years of age who enrolled in a clinical trial 9
to study the relationship among amyloid peptide levels and demographic, clinical and genetic data. We used highly sensitive and specific assays for Aβ40 and Aβ42 8
. In this population, we found associations between peptide levels and sex, APOE genotype, level of mental retardation, cognitive function, and the presence of dementia. The relationship of Aβ42 peptide level to MR level in our study is quite intriguing, suggesting the possibility that amyloid peptides may be involved in the static encephalopathy of DS.
Of particular note, some studies now suggest that it is the ratio of Aβ42 to Aβ40 that causes AD in families carrying presenilin mutations 14, 15
. Presenilin mutations that cause familial autosomal dominant AD are not invariably associated with increased amyloid peptide generation resulting from augmented γ-secretase activity; some mutations modulate γ-secretase activity to increase Aβ42 or decrease Aβ40 without increasing overall levels 15
. Thus, while not all disease-associated mutations increase Aβ production, all do increase the ratio of Aβ42 to Aβ40 14, 15
. Further, age of onset in familial AD is correlated to both increased Aβ42 and decreased Aβ40, suggesting that the former is toxic while the latter may be protective 14
. It is thus of interest that we found an association between the Aβ42 to Aβ40 ratio and presence of dementia, though levels of the peptides themselves were not related to dementia. We found no relationship between the peptide ratio and BPT score; BPT score was not related to dementia diagnosis, perhaps due to a confounding relationship between BPT score and level of mental retardation.
In sporadic AD, interpretation of plasma Aβ levels has not been straight-forward. Higher plasma levels of Aβ40 16
or Aβ42 17
have been reported to show an association with risk of dementia, and with mild cognitive impairment 18-20
. Most studies indicate normal levels of Aβ42 in sporadic AD 2, 18, 21-24
, though some investigators find the levels to be high 17
or low 25
in comparison to non-demented controls. Plasma Aβ42 may decline during early AD 17
. One interpretation is that in the presymptomatic and early clinical phases of AD, Aβ42 adheres to plaques, reducing concentrations in the cerebrospinal fluid and plasma.
The literature on plasma Aβ levels in Down syndrome also has not been entirely consistent. Aβ42 levels may be elevated in adults with Down syndrome [4, 6]. One prior study reported no relationship between APOE genotype and plasma peptide levels 5
; however, another study found Aβ42 to be related to APOE genotype 6
. One study has suggested that Aβ42 levels increase with age in Down syndrome 7
; the restricted age range of our study participants (all at least 50 years old) could have obscured such a relationship. Recently reported data from a large Down syndrome cohort suggested a relationship between higher levels of plasma Aβ42 and both risk of dementia and current dementia26
. In this New York State community-based study of 204 aging individuals with Down syndrome, the risk of incident AD among non-demented participants was twice as high in those with Aβ42 levels in the highest two tertiles compared with the lowest tertile; further, those with AD at baseline had Aβ42 levels about 13% higher than those who remained dementia-free throughout the multi-year study. Prospective longitudinal studies such as this may be particularly useful in elucidating the role of Aβ peptides in AD pathophysiology. In contrast, our results reflect a cross-sectional evaluation of peptide levels and prevalent dementia.
Differences in assay procedures may have contributed to the variable findings among studies. Published reports have used ELISA assays utilizing antibodies of varying specificity. Multiple secretases cleave APP in the Aβ region, leading to the generation of a number of fragments that may bind to anti-Aβ antibodies. Thus, accurate measurement of full-length Aβ40 and Aβ42 is essential. To quantify these peptides, a sandwich ELISA using specific antibodies against both the N and C terminus end are required. While C terminus end specific antibodies are commonly available, N terminus end specific antibodies are not. We previously developed an N terminus antibody for our Abeta ELISAs 8
, our assays specifically detect full-length Aβ40 and Aβ42. Differences in subject characteristics (our trial participants were medically stable, and from several countries) and collection procedures (time of day, fasting status at time of venipuncture, and specimen handling) may also have contributed to different findings in this study compared to the New York State community-based study 26
. For example, our initial collection of blood in glass tubes may have led to reduced Aβ measurements due to adsorption, though analysis of the Aβ42/40 ratio reduces the impact of this issue.
Our findings in Down syndrome support the idea suggested by the presenilin mutation studies that the ratio of Aβ42 to Aβ40 is more salient than absolute level of either peptide as a marker of clinical dementia in genetically susceptible individuals. In the therapeutic trial in which these subjects are enrolled, plasma specimens are again obtained after three years of participation. We will thus have the opportunity to study the relationship among baseline plasma peptide levels, change in levels and incident dementia.