Seppo Helisalmi

APOE and Alzheimer disease: a major gene with semi-dominant inheritance

Apolipoprotein E (APOE) dependent lifetime risks (LTRs) for Alzheimer Disease (AD) are currently not accurately known and odds ratios alone are insufficient to assess these risks. We calculated AD LTR in 7351 cases and 10 132 controls from Caucasian ancestry using Rochester (USA) incidence data. At the age of 85 the LTR of AD without reference to APOE genotype was 11% in males and 14% in females. At the same age, this risk ranged from 51% for APOE44 male carriers to 60% for APOE44 female carriers, and from 23% for APOE34 male carriers to 30% for APOE34 female carriers, consistent with semi-dominant inheritance of a moderately penetrant gene. Using PAQUID (France) incidence data, estimates were globally similar except that at age 85 the LTRs reached 68 and 35% for APOE 44 and APOE 34 female carriers, respectively. These risks are more similar to those of major genes in Mendelian diseases, such as BRCA1 in breast cancer, than those of low-risk common alleles identified by recent GWAS in complex diseases. In addition, stratification of our data by age groups clearly demonstrates that APOE4 is a risk factor not only for late-onset but for early-onset AD as well. Together, these results urge a reappraisal of the impact of APOE in Alzheimer disease.

A severe loss of choline acetyltransferase in the frontal cortex of Alzheimer patients carrying apolipoprotein ε4 allele

We measured the activities of choline acetyltransferase (ChAT) in the post mortem frontal cortex in 32 Alzheimers disease (AD) patients with different apolipoprotein E (apoE) genotypes. The ChAT values were significantly lower for the AD patients with 2 e4 alleles than for those with 0 e4 (ANOVA, P < 0.05). The ChAT activities of AD patients carrying 2 or 1 e4 alleles and those without the e4 allele also differed significantly: 16.3 ± 15.2 versus 30.5 ± 20.6 pmol/mg protein per min, ANOVA, P < 0.05. However, the AD patients carrying the e4 allele were significantly younger than those with 0 e4 allele. The study indicates that AD patients carrying the e4 allele have a more severe cholinergic deficit than the AD patients without the e4 allele.

Volumes of hippocampus, amygdala and frontal lobe in Alzheimer patients with different apolipoprotein E genotypes

An increased frequency of apolipoprotein E E4 allele has been reported in patients with late onset Alzheimers disease. Apolipoprotein E participates in the transport of cholesterol and other lipids and interferes with the growth and regeneration of both peripheral and central nervous system tissues during development and after injury. Apolipoprotein E is also implicated in synaptogenesis. Apolipoprotein E isoforms differ in binding to amyloid-beta-protein and tau protein in vitro. Here, we wanted to study the effect of apolipoprotein E genotype on the magnitude of damage in the hippocampus, where a marked synapse loss exists in Alzheimers disease. We measured by magnetic resonance imaging the volumes of the hippocampus, amygdala, and frontal lobes in the three Alzheimer subgroups: patients with 2, 1 or 0 E4 alleles. We also investigated the profile of deficits on tests assessing memory, language, visuospatial, executive, and praxic functions of these Alzheimer subgroups. All Alzheimer patients were at early stage of the disease. We found that Alzheimer patients with E4/4 genotype (N = 5) had smaller volumes of the hippocampus and the amygdala than those with E3/4 (N = 9) and those with E3/3 or E2/3 (N = 12). The difference was significant for the right hippocampus (-54% of control) and the right amygdala (-37% of control). The volumes of the frontal lobes were similar across the Alzheimer subgroups. The patients with E4/4 also showed lowest scores on delayed memory tests and differed from E3/3, 3/2 patients in the list learning test (< 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Clinical and neuropsychological characteristics in familial and sporadic Alzheimer's disease: Relation to apolipoprotein E polymorphism

Alzheimers disease (AD) is a heterogeneous entity presenting as sporadic and familial disease.In familial AD, there is evidence for genetic linkage to a yet undefined gene on chromosome 14 in early-onset pedigrees and on chromosome 19 in late-onset pedigrees. In a few early-onset kindreds, there were mutations in the amyloid precursor gene on chromosome 21. There is an increased frequency of apolipoprotein E (ApoE) epsilon 4 allele in patients with late-onset AD. We studied the clinical presentation and profile of cognitive deficits in 58 AD patients at the early stage of the disease. We divided the AD patients into subgroups of sporadic late-onset (SLO) (more than equals to 65 years), familial late-onset (FLO) (more than equals to 65 years), sporadic early-onset (SEO) (less than 65 years), and familial early-onset (FEO) (less than 65 years) patients and into three subgroups according to their ApoE genotype zero epsilon 4, one epsilon 4, and two epsilon 4 alleles. The AD subgroups did not differ in the global clinical severity of dementia or the duration of the disease. SLO, FLO, SEO, and FEO subgroups did not differ in clinical characteristics such as occurrence of rigidity, hypokinesia, tremor, myoclonus, hallucinations, delusions, or epileptic seizures nor in the profile of deficits on tests assessing memory, language, visuospatial, executive, and praxic functions. The epsilon 4 allele frequency was 0.43 for all AD patients and did not differ across subgroups divided according to the familial aggregation and age of onset. Patients with two epsilon 4 alleles had earlier age at onset of dementia than those with no epsilon 4 allele (63 plus minus 9 versus 68 plus minus 9 years), but otherwise the clinical symptoms and signs were not related to the ApoE genotype. However, the AD patients with two epsilon 4 alleles had lowest scores on memory tests and differed significantly from those with one or zero epsilon 4 allele in the delayed list learning (p less than 0.05) and from those with zero epsilon 4 allele in the immediate and delayed story recall. In contrast, verbal functions were better preserved in two epsilon 4 patients than in those with other ApoE genotypes. This study failed to confirm the earlier reports of severe aphasia, agnosia, and apraxia in familial AD patients, but the clinical phenotype was similar irrespective to the familial aggregation. However, AD patients with two epsilon 4 alleles are characterized by more severe memory loss and earlier age of onset than those without the epsilon 4 allele. NEUROLOGY 1996;46: 413-419

Metabolome in progression to Alzheimer's disease

Mild cognitive impairment (MCI) is considered as a transition phase between normal aging and Alzheimers disease (AD). MCI confers an increased risk of developing AD, although the state is heterogeneous with several possible outcomes, including even improvement back to normal cognition. We sought to determine the serum metabolomic profiles associated with progression to and diagnosis of AD in a prospective study. At the baseline assessment, the subjects enrolled in the study were classified into three diagnostic groups: healthy controls (n=46), MCI (n=143) and AD (n=47). Among the MCI subjects, 52 progressed to AD in the follow-up. Comprehensive metabolomics approach was applied to analyze baseline serum samples and to associate the metabolite profiles with the diagnosis at baseline and in the follow-up. At baseline, AD patients were characterized by diminished ether phospholipids, phosphatidylcholines, sphingomyelins and sterols. A molecular signature comprising three metabolites was identified, which was predictive of progression to AD in the follow-up. The major contributor to the predictive model was 2,4-dihydroxybutanoic acid, which was upregulated in AD progressors (P=0.0048), indicating potential involvement of hypoxia in the early AD pathogenesis. This was supported by the pathway analysis of metabolomics data, which identified upregulation of pentose phosphate pathway in patients who later progressed to AD. Together, our findings primarily implicate hypoxia, oxidative stress, as well as membrane lipid remodeling in progression to AD. Establishment of pathogenic relevance of predictive biomarkers such as ours may not only facilitate early diagnosis, but may also help identify new therapeutic avenues.

CSF biomarkers for Alzheimer disease correlate with cortical brain biopsy findings

Objective: To assess the relationship between Alzheimer disease (AD)–related pathologic changes in frontal cortical brain biopsy and AD biomarkers in ventricular vs lumbar CSF, and to evaluate the relationships of AD biomarkers in CSF and cortical biopsy with the final clinical diagnosis of AD. Methods: In 182 patients with presumed normal pressure hydrocephalus (152 with known APOE carrier status), Aβ plaques and tau in the cortical brain biopsies were correlated with the ventricular and lumbar CSF Aβ42, total tau, and p-tau levels measured by ELISA. In a median follow-up of 2.0 years, 51 patients developed AD dementia. Results: The patients with Aβ plaques in the cortical biopsy had lower (p = 0.009) CSF Aβ42 levels than those with no Aβ plaques. The patients with tau in the cortical biopsy had lower (p = 0.014) Aβ42 but higher (p = 0.015) p-tau 181 in CSF as compared to those with no tau in the cortical biopsy. The patients with amyloid + tau + biopsies had the lowest Aβ42 and highest tau and p-tau 181 levels in CSF. The Aβ42 levels were lower and the tau and p-tau 181 higher in the ventricular vs corresponding lumbar CSF samples. In multivariate analysis, the presence of cortical Aβ was independently predicted by the APOE ϵ4 carrier status and age but not by CSF Aβ42 or tau levels. Conclusions: Amyloid plaques and hyperphosphorylated tau in cortical brain biopsies are reflected by low CSF Aβ42 and high CSF tau and p-tau levels, respectively.

The level of cerebrospinal fluid tau correlates with neurofibrillary tangles in Alzheimer's disease

WE measured tau concentrations in cerebrospinal fluid (CSF) samples taken during the lifetime of 43 patients with Alzheimers disease (AD) and correlated these values with neurofibrillary tangle (NFT) scores as well as glial fibrillary acidic protein (GFAP) expression as a marker of astrocytosis in the brain post-mortem. The CSF tau values showed a positive correlation with neocortical NFT scores (r = 0.44, p < 0.005), while GFAP immmunoreactivity did not correlate with CSF tau. This study reveals a high variation in CSF tau values in patients with neuropathologically confirmed AD (range 194–1539 pg/ml) and indicates that high CSF tau values in the late phase of Alzheimers disease predict severe neurodegeneration as evidenced by increased NFT scores.

Loss-of-function variants in ABCA7 confer risk of Alzheimer's disease.

We conducted a search for rare, functional variants altering susceptibility to Alzheimers disease that exploited knowledge of common variants associated with the same disease. We found that loss-of-function variants in ABCA7 confer risk of Alzheimers disease in Icelanders (odds ratio (OR) = 2.12, P = 2.2 × 10−13) and discovered that the association replicated in study groups from Europe and the United States (combined OR = 2.03, P = 6.8 × 10−15).

Decreased hippocampal volume asymmetry on MRIs in nondemented elderly subjects carrying the apolipoprotein E 4 allele

1. Levin MJ, Gardner P, Waldvogel F. “Tropical” pyomyositis, an unusual infection due to Staphylococcus aureus. N Engl J Med 1971;284:196198. 2. Back SA, O’Neill T, Fishbein G, Gwinup G. A case of group B streptococcal pyomyositis. Rev Infect Dis 1990;12784-787. 3. Mustafa MM, Scarvey L, Rollins N, Siege1 JD. Primary suppurative myositis associated with HaemophiEus influenzae type B septicemia. Pediatr Infect Dis J 1988;7:815-817. 4. Solbrig MV, Sher JH, Kula RW. Rhabdomyolysis in leptospirosis (Weil’s disease). J Infect Dis 1987;156:692-693. 5. Adamski GB, Garin EH, Ballinger WE, Shulman ST. Generalized nonsuppurative myositis with staphylococcal septicemia. J Pediatr 1980;96694-697. 6. Lannigan R, Austin TW, Vestrup J. Myositis and rhabdomyolysis due to Staphylococcus aureus septicemia. J Infect Dis 1984;150:784. 7. Felice K, DeGirolami U, Chad DA. Pyomyositis presenting as rapidly progressive generalized weakness. Neurology 1991;41:944-945.

SPECT and MRI analysis in Alzheimer's disease: relation to apolipoprotein E epsilon 4 allele.

OBJECTIVES--The epsilon 4 allele of apolipoprotein E (ApoE) is a risk factor for late onset Alzheimers disease. ApoE is present in senile plaques, neurofibrillary tangles, and cerebrovascular amyloid, and it is implicated in synaptogenesis. The effect of ApoE polymorphism on the volumes of hippocampus, amygdala, and frontal lobe was studied. The hypothesis was that the patients with Alzheimers disease carrying the epsilon 4 allele have more pronounced atrophy. The relation of ApoE and cerebral blood flow on cortical areas was also assessed. METHODS--Fifty eight patients with Alzheimers disease at the early stage of the disease and 34 control subjects were studied. Patients with Alzheimers disease were divided into subgroups according to the number of the epsilon 4 alleles. Volumes were measured by MRI and regional cerebral blood flow ratios referred to the cerebellum were examined by 99mTc-HMPAO SPECT. ApoE genotypes were determined by digestion of ApoE polymerase chain reaction products with the restriction enzyme Hha1. RESULTS--patients with Alzheimers disease had smaller volumes of hippocampi and amygdala compared with control subjects, and the patients with Alzheimers disease homozygous for the epsilon 4 allele had the most prominent volume loss in the medial temporal lobe structures. The frontal lobe volumes did not differ significantly. All patients with Alzheimers disease had bilateral temporoparietal hypoperfusion and the subgroups with one or no epsilon 4 alleles also had frontal hypoperfusion compared with control subjects. The occipital perfusion ratios tended to decrease with increasing number of epsilon 4 alleles. CONCLUSIONS--Patients with Alzheimers disease homozygous for the epsilon 4 allele seem to have severe damage in the medial temporal lobe structures early in the disease process and differ from the patients with Alzheimers disease with one or no epsilon 4 alleles.