B. Tycko

Association between the APOE genotype and psychopathologic symptoms in Alzheimer's disease.

Background Psychiatric symptoms occur frequently in the course of AD, are a frequent contributor to institutionalization, predict cognitive decline and death, and often require treatment with psychotropic medications. Previous studies investigating the association between APOE genotype and psychiatric symptomatology in AD have reported contradictory results. Objective To determine whether APOE genotype predicts incident psychiatric symptomatology in patients with AD. Methods Eighty-seven patients with AD at early stages and no psychiatric history were followed semiannually for up to 9.3 years (mean 5.5 years) for development of delusions, illusions, hallucinations, behavioral symptoms, and depression. Cox proportional hazards models were used to examine the relative risk for incident psychiatric symptomatology (outcome) in relation to APOE genotype (predictor). Results The presence of one &egr;4 allele carried a 2.5-fold risk, whereas the presence of two &egr;4 alleles carried a 5.6-fold risk for development of delusions. The associations remained significant even when age, ethnicity, sex, education, duration of disease, and cognitive and functional performance were controlled for. The presence of two &egr;4 alleles was associated with reduced risk for developing hallucinations in the adjusted analysis only. No significant associations were detected between APOE genotype and the incidence of illusions, behavioral symptoms, or depression. Conclusion The presence of one or more &egr;4 alleles is a significant predictor for the incidence of delusions in the course of AD.

Earlier onset of Alzheimer's disease in men with Down syndrome

Background: Virtually all individuals with Down syndrome (DS) have neuropathologic changes characteristic of Alzheimers disease (AD) beginning at 40 years of age. Few studies have examined factors that influence age at onset of AD in DS. We investigated whether sex differences in age at onset and risk of AD among adults with DS are similar to those observed in the general population and whether the effect of sex on risk of AD is modified by apolipoprotein E(APOE) genotype. Methods: A community-based sample of 111 adults with cytogenetically confirmed DS(34 to 71 years of age) was ascertained through the New York State Developmental Disabilities system. A semistructured interview with caregivers and review of medical records was used to ascertain the presence or absence of AD. APOE genotyping was carried out without knowledge of the subjects medical history or clinical diagnosis. Results and conclusions: Both male gender and the presence of an APOE ϵ4 allele were associated with an earlier onset of AD. Compared with women, men with DS were three times as likely to develop AD. Compared with those with the APOE 3/3 genotype, adults with DS with the 3/4 or 4/4 genotypes were four times as likely to develop AD. No individual with an APOE ϵ2 allele developed AD. No evidence of interaction of sex and APOE genotype was found in risk of AD. The higher risk of AD in men may be related to differences in hormonal function between men and women with DS that are distinct from those in the general population.

The Imprinted Phlda2 Gene Regulates Extraembryonic Energy Stores

ABSTRACT An important difference between placental mammals and marsupials is the maturity of the fetus at birth. Placental mammals achieved this maturity by developing a complex and invasive placenta to support and prolong internal development. The exact genomic modifications that facilitated the evolution of this complex structure are unknown, but the emergence of genomic imprinting within mammalian lineages suggests a role for gene dosage. Here we show that a maximally altered placental structure is achieved by a single extra dose of the imprinted Phlda2 gene characterized by a dramatically reduced junctional zone and a decrease in stored glycogen. In addition, glycogen cells do not migrate into the maternal decidua in a timely fashion, but instead, Tpbpa-positive cells progressively mislocalize into the labyrinth. These defects are linked to a progressive restriction of embryonic growth from embryonic day 16.5. This work has identified a critical role for the imprinted Phlda2 gene in regulating glycogen storage in the eutherian placenta and implies that imprinting has provided a mechanism to boost nutrient supply to the fetus late in gestation, when the fetus is placing the highest demands on maternal resources, to enhance growth.

Fine mapping of 10q and 18q for familial Alzheimer's disease in Caribbean Hispanics

Familial Alzheimers disease (AD [MIM 104300]) has been a focus of intense investigation, primarily in Caucasian families from Europe and North America families. Although the late-onset form of familial AD, beginning after age 65 years, has been linked to regions on chromosomes 10q and 12p, the specific genetic variants have not yet been consistently identified. Using a unique cohort of families of Caribbean Hispanics ancestry, we screened the genome using 340 markers on 490 family members from 96 families with predominantly late-onset AD. We observed the strongest support for linkage on 18q (LOD=3.14). However, 17 additional markers (chromosomes 1–6, 8, 10, 12, and 14) exceeded a two-point LOD score of 1.0 under the affecteds-only autosomal dominant model or affected sibpair model. As we previously reported the fine-mapping effort on 12p showing modest evidence of linkage, we focused our fine-mapping efforts on two other candidate regions in the current report, namely 10q and 18q. We added 31 family members and eight additional Caribbean Hispanic families to fine map 10q and 18q. With additional microsatellite markers, the evidence for linkage for 18q strengthened near 112 cM, where the two-point LOD score for D18S541 was 3.37 and the highest NPL score in that region was 3.65 (P=0.000177). This narrow region contains a small number of genes expressed in the brain. However, at 10q (134–138 cM), the NPL score decreased from 3.15 (P=0.000486) to 2.1 (P=0.0218), but two broad peaks remained overlapping with previously reported peaks. Our results provide modest support for linkage on 10q and 12p in this cohort of Caribbean Hispanic families with familial Alzheimers disease, and strong evidence for a new locus on 18q.

The product of the imprinted gene IPL marks human villous cytotrophoblast and is lost in complete hydatidiform mole.

The IPL/TSSC3 gene is expressed nearly exclusively from the maternal allele, and its protein product acts to limit placental growth in mice. This protein specifically marks Type II trophoblast in the labyrinthine layer of the mouse placenta. To investigate mouse-human homologies, we carried out immunohistochemistry with antibodies against human IPL. There was strong expression of IPL in villous cytotrophoblast of the human placenta, contrasting with complete lack of expression in syncytiotrophoblast. Staining for IPL was weak in cells of the villous mesenchyme and extravillous trophoblast, including the cytotrophoblast columns in the basal plate and the intervillous trophoblast islands. The IPL and p57(KIP2)/CDKN1C genes are closely linked and coordinately imprinted, and immunostaining showed that their protein products are co-expressed in villous cytotrophoblast. However, other cell types, including extravillous cytotrophoblast and cells in various non-placental tissues, expressed p57(KIP2), but not IPL. IPL protein was absent in both of two cases of androgenetic complete hydatidiform mole examined by immunostaining, and IPL mRNA was absent in an additional three cases of this neoplasm examined by northern blotting. In the mouse, Ipl-expressing cells disappear at mid- to late-gestation when placental growth ceases, but persistent IPL mRNA and protein expression was observed throughout human gestation, correlating with the continuous growth of the human placenta. These findings highlight dosage regulation of human IPL by imprinting and, more generally, suggest homology between Type II labyrinthine trophoblast in the mouse and villous cytotrophoblast in humans, both of which are proliferative stem cell-like compartments.

Genetic influences on memory performance in familial Alzheimer disease

Objective: To investigate the heritability of memory and other cognitive measures in families with multiple individuals with Alzheimer disease (AD) to determine if neuropsychological measures can be used to better understand genetic contributions to AD. Methods: The genetic contributions to the variation in declarative memory, attention, abstract reasoning, language, and visuospatial function using a variance component method were estimated. For memory scores, the proportion of genetic contribution was estimated, controlling for APOE. Results: The unadjusted heritability estimates for the declarative memory tasks ranged from 0.47 for delayed recall to 0.25 for delayed recognition, where a heritability estimate of 1 indicates that genetic factors explain all of the phenotypic variance and a heritability score of 0 indicates that genetic factors explain none. When adjusted for sex, age, education, and general intelligence, the heritability estimates increased to 0.60 for delayed recall and 0.41 for delayed recognition. None of the other cognitive tests showed heritability estimates as high as that observed for memory. When the influence of APOE was taken into account, the heritability estimates changed modestly for delayed recall and consistent long-term retrieval, whereas the estimates for other memory scores did not change, suggesting that APOE contributes little to these memory scores. Conclusions: Declarative memory in familial AD is under strong genetic influence, only part of which is attributable to APOE. Memory performance should prove to be a useful phenotypic component in the investigation of the genetic basis of AD.

Influence of APOE genotype on familial aggregation of AD in an urban population.

Objective: To examine the influence of the proband’s APOE genotype on AD among first-degree relatives in a community-based study of African Americans, whites, and Caribbean Hispanics. Methods: History of AD and demographic information were obtained on 1,073 siblings and parents of 312 patients with AD and 2,722 siblings and parents of 802 nondemented controls. APOE genotyping was performed on all 1,114 patients and controls. Results: A higher proportion of patients with AD (35%) than controls (27%) had one or more APOE-ε4 alleles (p = 0.03). When compared with relatives of controls without an APOE-ε4 allele, the risk for AD was increased in first-degree relatives of both patients (rate ratio [RR] = 1.9, 95% confidence interval [CI] = 1.2 to 3.1) and controls (RR = 1.8, 95% CI = 1.2 to 2.6) with one or more APOE-εe alleles, regardless of ethnic group. There was a similar trend of increased risk in relatives of patients without an APOE-ε4 allele, but this was limited to Hispanics and African Americans. Conclusions: The presence of an APOE-ε4 allele increases risk for AD among first-degree relatives, regardless of the probands’ disease status, among all ethnic groups. Relatives of patients without an APOE-ε4 allele were also at increased risk for AD among Hispanics and African Americans, suggesting that other genes or risk factors may influence risk.