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Background: Dietary fish or fish oil rich in n-3 fatty acids (n-3 FAs), eg, docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), ameliorate inflammatory reactions by various mechanisms. Whereas most studies have explored the effects of predominantly EPA-based n-3 FAs preparations, few have addressed the effects of n-3 FAs preparations with DHA as the main FA. Objective: The objective was to determine the effects of 6 mo of dietary supplementation with an n-3 FAs preparation rich in DHA on release of cytokines and growth factors from peripheral blood mononuclear cells (PBMCs). Design: In a randomized, double-blind, placebo-controlled trial, 174 Alzheimer disease (AD) patients received daily either 1.7 g DHA and 0.6 g EPA (n-3 FAs group) or placebo for 6 mo. In the present study blood samples were obtained from the 23 first randomized patients, and PBMCs were isolated before and after 6 mo of treatment. Results: Plasma concentrations of DHA and EPA were significantly increased at 6 mo in the n-3 FAs group. This group also showed significant decreases of interleukin (IL)-6, IL-1 [beta], and granulocyte colony-stimulating factor secretion after stimulation of PBMCs with lipopolysaccharide. Changes in the DHA and EPA concentrations were negatively associated with changes in IL-1 [beta] and IL-6 release for all subjects. Reductions of IL-1 [beta] and IL-6 were also significantly correlated with each other. In contrast, this n-3 FA treatment for 6 mo did not decrease tumor necrosis factor-[alpha], IL-8, IL-10, and granulocyte-macrophage colony-stimulating factor secretion. Conclusion: AD patients treated with DHA-rich n-3 FAs supplementation increased their plasma concentrations of DHA (and EPA), which were associated with reduced release of IL-1 [beta], IL-6, and granulocyte colony-stimulating factor from PBMCs. This trial was registered at clinicaltrials.gov as NCT00211159.

Preclinical and clinical studies gave evidence that lithium could be useful in the treatment of Alzheimers disease (AD). One possible mechanism of action might be the induction of neurotrophins. Recently, we found a significant increase of brain-derived neurotrophic factor (BDNF) serum levels in AD patients treated with lithium and a significant decrease of ADAS Cog sum scores in comparison to placebo-treated patients. In another previous study we have shown that glial cell line-derived neurotrophic factor (GDNF) levels in CSF of patients with early AD are increased most probably due to an upregulated expression in CNS as an adaptive process of the impaired brain to enhance neurotrophic support at least in early stages of disease. Here we assessed the influence of a lithium treatment on GDNF serum and cerebrospinal fluid (CSF) concentrations in a subset of a greater sample recruited for a randomized, single-blinded, placebocontrolled, parallel-group multicenter 10-week study, investigating the efficacy of lithium treatment in AD patients. We found a significant negative correlation of lithium concentration in serum with GDNF concentration in CSF at the end of treatment (r -0.585, p 0.036) and with the difference of GDNF concentration in CSF before and after treatment (r - 0.755, p 0.003). However, we could not show a difference in GDNF concentrations between the patients after the treatment with lithium or placebo (serum, mean ± standard deviation: 434.3 ± 117.9 pg/ml versus 543.8 ± 250.0 pg/ml, p 0.178; CSF, 62.3 ± 37.4 pg/ml versus 72.8 ± 43.9 pg/ml, p 0.511). The findings of the present investigation indicated that beneficial effects of the lithium treatment might reduce the necessity of enhanced GDNF expression in the CNS in early AD.

Omega-3 fatty acids, e.g., dokosahexaenoic acid (DHA) and eikosapentaenoic acid (EPA), ameliorate inflammatory reactions by various mechanisms, but the role of prostaglandins remains unclear. Our aim was to determine if dietary supplementation with a DHA-rich fish oil influenced the release of PGF2αfrom peripheral blood mononuclear cells (PBMC). In the OmegAD study, 174 Alzheimer disease patients received either 1.7 g DHA plus 0.6 g EPA or a placebo daily for six months. PBMCs from the 21 (9 on fish oil and 12 on placebo) first-randomized patients were stimulated with either lipopolysaccharide (LPS) or phytohemagglutinin (PHA) before and after 6 months. Our results showed that plasma concentrations of DHA and EPA increased significantly at 6 months in the omega-3 group. PGF2αrelease from LPS- (but not from PHA-) stimulated PBMC was significantly diminished in this group; no change was noted in the placebo group. PGF2αchanges correlated inversely with changes in plasma DHA and EPA. Decreased IL-6 and IL-1βlevels correlated with decreased PGF2αlevels. The stimulus-specific PGF2αrelease from PBMC after 6 months of oral supplementation with the DHA-rich fish oil might be one event related to reduced inflammatory reactions associated with omega-3 fatty acid intake.

BACKGROUND A majority of mutations within the β-amyloid region of the amyloid precursor protein (APP) gene cause inherited forms of intracerebral hemorrhage. Most of these mutations may also cause cognitive impairment, but the Arctic APP mutation is the only known intra–β-amyloid mutation to date causing the more typical clinical picture of Alzheimer disease. OBJECTIVE To describe features of 1 Swedish and 1 American family with the previously reported Arctic APP mutation. DESIGN, SETTING, AND PARTICIPANTS Affected and nonaffected carriers of the Arctic APP mutation from the Swedish and American families were investigated clinically. In addition, 1 brain from each family was investigated neuropathologically. RESULTS The clinical picture, with age at disease onset in the sixth to seventh decade of life and dysfunction in multiple cognitive areas, is indicative of Alzheimer disease and similar to the phenotype for other Alzheimer disease APP mutations. Several affected mutation carriers displayed general brain atrophy and reduced blood flow of the parietal lobe as demonstrated by magnetic resonance imaging and single-photon emission computed tomography. One Swedish case and 1 American case with the Arctic APP mutation came to autopsy, and both showed no signs of hemorrhage but revealed severe congophilic angiopathy, region-specific neurofibrillary tangle pathological findings, and abundant amyloid plaques. Intriguingly, most plaques from both of these cases had a characteristic ringlike character. CONCLUSIONS Overall, our findings corroborate that the Arctic APP mutation causes a clinical and neuropathological picture compatible with Alzheimer disease.Arch Neurol. 2008;65(4):499-505--

BACKGROUND β Amyloid (Aβ) protein accumulates in the brains of individuals with Alzheimer disease (AD) and is detectable in cerebrospinal fluid and plasma. OBJECTIVE To examine plasma levels of Aβ peptides Aβ40 and Aβ42 as predictors of incident AD and other types of dementia. DESIGN Prospective, population-based cohort study. SETTING The Uppsala Longitudinal Study of Adult Men. PARTICIPANTS Plasma Aβ40 and Aβ42 levels were analyzed as predictors of incident AD in 1045 men at age 70 years and 680 men at age 77 years using Cox proportional hazards analyses. Alzheimer disease and other types of dementia were diagnosed by standardized screening, clinical evaluation, and medical record review. MAIN OUTCOME MEASURES Hazard ratios of AD (primary outcome) and vascular dementia or other dementia (secondary outcomes) according to baseline levels of plasma Aβ40 and Aβ42. RESULTS From the age of 77 years at baseline, 46 individuals developed AD at follow-up (median, 5.3 years). A low plasma Aβ40 level at age 77 years was associated with higher incidence of AD. The multivariate-adjusted hazard ratio was 4.87 (95% confidence interval, 1.63-14.6) for the lowest Aβ40 tertile compared with the highest tertile. On follow-up from age 70 years at baseline (median, 11.2 years), 82 individuals developed AD. Plasma Aβ40 and Aβ42 levels measured at age 70 years were not significantly associated with incident AD. CONCLUSIONS Low plasma Aβ40 levels predicted incident AD in elderly men independently of potential confounders. Plasma Aβ42 levels were not significantly associated with AD incidence. The clinical value of Aβ measurement in plasma remains to be established in future studies.Arch Neurol. 2008;65(2):256-263--

BACKGROUND Epidemiologic and animal studies have suggested that dietary fish or fish oil rich in ω-3 fatty acids, for example, docosahexaenoic acid and eicosapentaenoic acid, may prevent Alzheimer disease (AD). OBJECTIVE To determine effects of dietary ω-3 fatty acid supplementation on cognitive functions in patients with mild to moderate AD. DESIGN Randomized, double-blind, placebo-controlled clinical trial. PARTICIPANTS Two hundred four patients with AD (age range [mean ± SD], 74 ± 9 years) whose conditions were stable while receiving acetylcholine esterase inhibitor treatment and who had a Mini-Mental State Examination (MMSE) score of 15 points or more were randomized to daily intake of 1.7 g of docosahexaenoic acid and 0.6 g of eicosapentaenoic acid (ω-3 fatty acid–treated group) or placebo for 6 months, after which all received ω-3 fatty acid supplementation for 6 months more. MAIN OUTCOME MEASURES The primary outcome was cognition measured with the MMSE and the cognitive portion of the Alzheimer Disease Assessment Scale. The secondary outcome was global function as assessed with the Clinical Dementia Rating Scale; safety and tolerability of ω-3 fatty acid supplementation; and blood pressure determinations. RESULTS One hundred seventy-four patients fulfilled the trial. At baseline, mean values for the Clinical Dementia Rating Scale, MMSE, and cognitive portion of the Alzheimer Disease Assessment Scale in the 2 randomized groups were similar. At 6 months, the decline in cognitive functions as assessed by the latter 2 scales did not differ between the groups. However, in a subgroup (n = 32) with very mild cognitive dysfunction (MMSE >27 points), a significant (P<.05) reduction in MMSE decline rate was observed in the ω-3 fatty acid–treated group compared with the placebo group. A similar arrest in decline rate was observed between 6 and 12 months in this placebo subgroup when receiving ω-3 fatty acid supplementation. The ω-3 fatty acid treatment was safe and well tolerated. CONCLUSIONS Administration of ω-3 fatty acid in patients with mild to moderate AD did not delay the rate of cognitive decline according to the MMSE or the cognitive portion of the Alzheimer Disease Assessment Scale. However, positive effects were observed in a small group of patients with very mild AD (MMSE >27 points). TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00211159Arch Neurol. 2006;63:1402-1408--

Frontotemporal dementia and Parkinsonism linked to chromosome 17 (FTDP-17) is an autosomal dominant condition clinically characterized by behavioral, cognitive and motor disturbances. It was recently discovered that the majority of the FTDP-17 families carry missense or 5' splice mutations in the exons coding for the microtubule-binding domains of the tau protein. However, in at least five FTDP-17 families, no such mutations could be identified. In the present study, we aimed at further investigate abnormalities in the tau gene in a Swedish FTDP-17 family, where no mutations in the tau gene previously have been identified. Initially, we searched for larger deletions by Southern blot hybridization. Furthermore, possible abnormal splicing events was investigated by RT-PCR from brain tissue of affected individuals. In addition, we investigated the presence of mutations in other genes in the FTDP-17 candidate region on chromosome 17q21; Gamma-tubulin, Glial Fibrillary Acid Protein (GFAP), Human dual specificity phosphatase tyrosine/serine (VHR), Rap-interacting protein 8 (RPIP8), P35, and the recently identified FTDCG1. In conclusion, no pathological changes in the tau gene were observed, neither was any mutations segregating with the disease detected in the investigated candidate genes. Further investigation of extended intron sequences or promoter regions of the tau gene and additional candidate genes on chromosome 17q21, therefore seems to be necessary in order to identify the additional causes of FTDP-17. © 2003 Wiley-Liss, Inc.

Concentration of mercury (Hg) in whole blood in an elderly urban population with a mean age of 87 years was studied in relation to cognitive function, arterial blood pressure (arterial BP), age, gender, body mass index (BMI) and smoking habits. This population-based study consisted of 106 subjects both males and females. Clinical assessment of the subjects included medical and social history, physical and neurologic examination and assessment of cognitive functions with Mini-Mental State Examination (MMSE). Information on use of all potentially anti-hypertensive drugs was collected. Whole blood from 106 subjects were collected and analysed for mercury by Cold Vapour Atomic Absorption Spectrometry (Milton Ray ASS-CV) with Seronorm Trace Element as matrix matched quality control. Males and females did not differ in blood-mercury (B-Hg) concentrations or in any of the other studied variables. B-Hg concentrations did not differ between smokers and non-smokers. Females were treated more often than males with antihypertensive drugs. There was no relation found between B-Hg concentration and cognitive function, arterial BP, age, gender or BMI. In conclusion, no relations were found between B-Hg concentrations and the studied variables.

Deregulation of amyloid precursor protein (APP) processing with increased production of amyloid β-peptide (Aβ) is considered to be a key pathogenic event in Alzheimer’s disease (AD). It has been suggested that stimulation of the muscarinic M1 receptor subtype affects APP processing and leads to a change in Aβ concentration. To test the hypothesis that treatment with a cholinesterase inhibitor could change the levels of Aβ in plasma, we measured Aβ42 and Aβ40 plasma levels in AD subjects before tacrine treatment and at weeks 2 and 6 of treatment. Treatment with tacrine had no statistically significant effect on plasma Aβ42 and Aβ40 either at 2 weeks or at 6 weeks of administration compared to baseline levels. Plasma Aβ42 and Aβ40 levels showed large subject-to-subject variation but small variation within the same patient over the 3-sample interval. After 2 weeks of treatment with tacrine, there was a strong negative correlation between tacrine concentration and levels of Aβ42 (r = –0.64; p = 0.01) and Aβ40 (r = –0.55; p = 0.04). However, after 6 weeks there was no correlation between plasma concentrations of tacrine and Aβ42 (r = 0.33; p = 0.34) or Aβ40 (r = –0.22; p = 0.54) levels in plasma. After 2 weeks of treatment with an acetylcholinesterase inhibitor, we found a correlation between higher drug concentrations and lower β-amyloid levels. This might indicate an effect on APP metabolism with an increased α-cleavage. But after 6 weeks of drug treatment, there was no obvious drug effect on β-amyloid concentrations. This finding may indicate that compensatory mechanisms have started at 6 weeks and that no long-term effect on key pathological features in AD is to be expected by an inhibition of acetylcholinesterase.

Cerebrospinal fluid (CSF) tau is a promising biochemical ante-mortem marker for Alzheimer’s disease (AD). Levels are increased in AD compared to other dementias, neurological diseases and healthy controls. An age-related decrease in both soluble tau and tau bound to paired helical filaments has been shown in brains from non-demented subjects. To study tau levels in normal ageing, we investigated CSF in 29 healthy individuals aged 45–80 years. A statistically significant increase in CSF tau with increasing age was found which might be caused by neuronal loss during normal ageing and redistribution of soluble tau from the brain into CSF. We could not demonstrate any influence by the APOE genotype, though larger populations have to be investigated to confirm this result. In conclusion, we found an age-dependent increase in CSF tau in healthy individuals. We emphasise the importance of establishing an age-dependent interval of CSF tau in non-demented subjects.

Concentration of cadmium in blood in an elderly population with a mean age of 87 years was studied in relation to age, blood pressure, BMI, cognitive function, gender and smoking. This population-based study consisted of 804 subjects both men and women. Clinical examination included medical and social history, physical and neurologic examination, and assessment of cognitive functions with Mini-Mental State Examination (MMSE). Information on prescription and non-prescription drug use was collected. Anti-hypertensive drugs included all medicines potentially used for treating high blood pressure. Blood pressure was measured. Whole blood from 763 subjects was analysed for cadmium by atomic absorption spectrophotometry (GFAAS) with Zeeman background correction and with a graphite furnace using the L'vov platform technique including quality control. Differences in cadmium concentrations were related to non- smokers (3.9 nmol/l), previous smokers (4.4 nmol/l) and current smokers (7.5 nmol/l). There were no relations between cadmium and age, blood pressure or cognitive functions. In conclusion, increased cadmium levels were found in smokers. A possible contribution from previous occupational exposure needs to be further evaluated.

All mutations known to cause familial Alzheimer's disease (AD) act by increasing the levels of soluble β-amyloid peptide (Aβ), especially the longer form, Aβ42. However, in vivo elevation of soluble Aβ in sporadic AD has so far not been shown. In the present study, we used enzyme-linked immunosorbent assays specific for Aβ42 and Aβ40 to investigate cerebrospinal fluid from sporadic AD at different stages of disease severity, to clarify the roles of Aβ42 and Aβ40 during disease progression. We also evaluated three other groups—one group of patients with mild cognitive impairment who were at risk of developing dementia, a cognitively intact, nondemented reference group diagnosed with depression, and a perfectly healthy control group. We found that Aβ42 is strongly elevated in early and mid stages of AD, and thereafter it declines with disease progression. On the contrary, Aβ40 levels were decreased in early and mid stages of AD. The group of cognitively impaired patients and the depression reference group had significantly higher levels of Aβ42 than the healthy control group, implying that Aβ42 is increased not only in AD, but in other central nervous system conditions as well. Our data also point out the importance of having thoroughly examined control material. The initial increase and subsequent decrease of Aβ42 adds a new biochemical tool to follow the progression of AD and might be important in the monitoring of therapeutics. Ann Neurol 1999;45:504–511

Objective:To study the progression of Alzheimer’s disease (AD) at a very early stage and to evaluate clinical markers of presymptomatic AD. Setting:Longitudinal study at a university hospital. Subjects:A Swedish family harboring a double mutation at codons 670/671 of the APP gene on chromosome 21 was followed longitudinally for 3 years. Both mutation carriers and noncarriers participated. Outcome Measurements:Results from clinical investigations, electroencephalography, neuropsychological and neuroradiological examinations including magnetic resonance imaging, single-photon emission computed tomography and positron emission tomography were assessed and compared on two or more occasions. Main Outcome:During follow-up, 1 initially asymptomatic mutation carrier who was near the expected age of onset for this family, developed cognitive symptoms, and at the end of the follow-up fulfilled the diagnostic criteria for AD. One mutation carrier with cognitive symptoms at the first examination showed clinical deterioration and was diagnosed with AD. One demented mutation carrier died and was shown to have typical AD neuropathology at autopsy. The two remaining asymptomatic mutation carriers, as well as all the noncarriers were asymptomatic. These mutation carriers who were near the expected age of onset of AD but without clinical signs of the disease, did not show changes in either electrophysiological parameters or volumes of the temporal lobes. However, in these 2 individuals the blood flow in the temporal lobe showed intermediate values between the symptomatic mutation carriers and healthy noncarriers. Two neuropsychological tests showed a deterioration that paralleled clinical symptoms in 1 of the mutation carriers who was close to the expected age of onset and who at the end of the follow-up had clinical signs of AD. In the same subject, brain glucose metabolism was pathologically reduced in the temporal lobes before other clinical symptoms were obvious. Conclusion:In this familial form of AD a reduced temporal lobe glucose metabolism was indicative of AD before the expected clinical onset. Reduced glucose metabolism even preceded the development of subjective or objective cognitive dysfunction and might therefore serve as a clinical marker for AD before the onset of clinical symptoms. Reduced cerebral blood flow in the temporal lobes and cognitive deterioration paralleled the clinical decline in the early stage of the disease.

Apolipoprotein E (APOE) and α1-antichymotrypsin (ACT) genotype and allele frequency distribution were investigated in 113 familial Alzheimer’s disease (AD) cases. A significantly higher σ4 frequency was observed in patients with an age of onset between 55–64 and 65–74 years compared to individuals with later or earlier onset. No difference in ACT Aallele frequency was seen in any onset group, nor was any influence of ACT genotypes on the age of onset observed. However, the mean age of onset was lowered by the presence of the ACT/AA and ACT/TT genotypes among APOE σ3/3 bearers. Possible APOE effects on age of onset were evaluated in 78 affected sib pairs. An earlier age of onset was observed in siblings with an σ4 allele compared to siblings without an σ4 allele. This supports the notion that the σ4 allele promotes an earlier age of onset. However, in siblings with the same APOE genotype, a wide range of onset was seen, indicating that unknown genetic or environmental factors affect the expression of AD.

OBJECTIVE: To explore the relationship between possible biological markers of Alzheimer disease that are related to amyloid metabolism and mental functions. PARTICIPANTS: Twelve individuals from a Swedish family with Alzheimer disease and a double mutation at codons 670/671 of the amyloid precursor protein gene participated in the study. DESIGN: Cerebrospinal fluid levels of α-secretase cleaved soluble amyloid precursor protein (α-sAPP), total sAPP, and amyloid β-peptide were correlated with data on multiple cognitive functions that covered the whole range of human performance. SETTING: The Alzheimer's Disease Research Centre, Department of Clinical Neuroscience, Section of Geriatric Medicine, Karolinska Institute, Huddinge University Hospital, Huddinge, Sweden. RESULTS: There were highly significant linear correlations between low levels of α-sAPP and poor performance on neuropsychological tests that assessed intelligence, verbal and visuospatial functions, memory, and attention. Within the group of nonmutation carriers, significant correlations were also obtained between the levels of α-sAPP and cognitive functions. A less striking association was seen between the levels of total sAPP and cognition. No association was found between the levels of amyloid β-peptide and cognition. CONCLUSIONS: The strong relationship between α-sAPP levels and cognition in both patients with Alzheimer disease and normal-aging persons may imply that α-sAPP is involved in basic protective brain processes. Alternatively, less amyloid β-peptide amounts are produced, leading to diminished plaque formation, when α-sAPP is generated.

OBJECTIVE: To describe symptoms, signs, neuroimaging results, and neuropathologic findings in patients from a family with chromosome 17q21—linked autosomal dominant frontotemporal dementia. DESIGN: Multiple case report with genetic investigations. SUBJECTS: The disease was observed in a Swedish family and documented in 3 generations. Four siblings are described in this article. RESULTS: A rapidly progressive dementia with genetic linkage to chromosome 17q21 was observed. The mean age of onset was 51 years and the average duration of disease to death was 3 years. Two patients started with speech disturbances leading to a progressive, nonfluent aphasia, 1 patient had onset symptoms of leg apraxia and akinesia and muscular rigidity, and in 1 patient reckless driving was the first symptom. Loss of spontaneous speech developed later in all patients and emotional bluntness in 3 of the patients. Cerebral perfusion was decreased in the frontal areas in all patients. In the person with apraxia as the onset symptom, the cerebral blood flow was also diminished in the left hemisphere, where a slight atrophy was detected on magnetic resonance imaging scans. At the postmortem examination, slight gliosis of the parietal lobes was observed in this patient. In all patients there was a frontocentral degeneration of the cortex with discrete microvacuolation and gliosis. CONCLUSION: Clinical features of frontotemporal dementia, parkinsonism, an early age of onset, a rapid disease progression, and variable onset symptoms were seen in these patients. Two other clinically distinct diseases, dementia with pallido-ponto-nigral degeneration and a disinhibition-dementia-parkinsonism-amyotrophy complex, have recently been mapped to chromsome 17q21. In the family described in this article, genetic linkage was detected to the same region, suggesting the possibility that these diseases may originate from pathogenic mutations in the same gene.

BACKGROUND: Recent findings of a reduced cerebral metabolic rate of glucose (CMRGlu) in at-risk relatives of patients with Alzheimer disease (AD) who carry the apolipoprotein E (APOE) ϵ4 allele suggest a causative role for the E4 isoform in cognitive changes that lead to AD. It is not known whether ϵ4 allele—associated deficits exist in patients with clinical AD. OBJECTIVE: To determine whether distinct patterns of cerebral hypometabolism exist in patients who carry the ϵ4 allele. PATIENTS AND METHODS: Information on the CMRGlu and APOE genotype was available for 46 patients at a memory disorders clinic: 31 patients were diagnosed as having probable AD, 3 demented patients did not meet criteria for AD, and 12 patients had mild memory complaints. Positron emission tomography with the use of 18F-fludeoxyglucose was used to calculate the CMRGlu in the frontal and temporoparietal regions of the cortex. Estimates were standardized to the sensorimotor area of the cortex. Linear regression models were constructed to relate the APOE genotype to the CMRGlu, adjusting for cognitive status (ie, the Mini-Mental State Examination score). RESULTS: Distinct patterns of the CMRGlu did not emerge for patients with different APOE genotypes. Bilateral deficits in the CMRGlu were found in the patients with AD. Left-right asymmetry was found in 8 of 12 patients with mild memory complaints: 7 of 8 had CMRGlu ratios less than 0.85 in the left side of the temporoparietal region of the cortex. CONCLUSIONS: The APOE ϵ4 allele does not appear to be associated with specific deficits in brain metabolism in patients with AD despite evidence that the ϵ4 allele is associated with preclinical alterations. This finding is consistent with previous epidemiologic results that have demonstrated a higher risk for AD in carriers of the ϵ4 allele, but no change in the rate of progression of AD.

OBJECTIVE: To describe clinical and genealogic features in a Swedish family with Alzheimer's disease with a double mutation of the amyloid precursor protein gene at codon 670/671 and to study the effects of anticipation and imprinting. DESIGN: Interviews with relatives, clinical investigations of the diseased, pedigree analysis, studies of medical records, and comparison with other families affected by Alzheimer's disease with amyloid precursor protein mutations. SETTING: The Alzheimer's Disease Research Centre, Department of Clinical Neuroscience, Section of Geriatric Medicine, Karolinska Institute, Huddinge (Sweden) University Hospital. PATIENTS AND OTHER PARTICIPANTS: Individuals with the amyloid precursor protein codon 670/671 mutation and their relatives (N=66). RESULTS: The trait was traced through eight generations, and an autosomal dominant inheritance with very high penetrance was observed. Onset occurred between 44 and 61 years of age (mean, 53 years). The mean duration of disease was 8.5 years (range, 3 to 13 years). The earliest clinical manifestations were deficits in memory function and abstract reasoning. Myoclonic jerks and seizures were common symptoms late in the disease. Anticipation and imprinting effects were not found in this family. CONCLUSIONS: The disease in this family has a single origin—a double mutation in the amyloid precursor protein gene at codon 670/671 transmitted as an autosomal dominant trait. The wide range in age at onset and the clinical symptoms in this pedigree give a characteristic phenotype similar to that seen in some of the other pedigrees with amyloid precursor protein mutations.

OBJECTIVE: To quantify the influence of apolipoprotein E (APOE) polymorphism on cognition and survival in a population sample aged 75 years or older. DESIGN: The Kungsholmen Project established a cohort of 1810 residents in a district in Stockholm, Sweden, aged 75 years or older in 1987. Information on cognition at cohort inception is available for all subjects. Subjects were followed up for mortality to January 1,1995. SUBJECTS: Included in this study are 1077 subjects (of 1124 genotyped for APOE) with the common ϵ2/3, ϵ3/3, and ϵ3/4 APOE genotypes. RESULTS: The odds of cognitive impairment for the ϵ3/4 vs ϵ3/3 genotype declined with age: 4.8 for age 75 through 79 years; 1.7 for age 80 through 84 years; and 1.0 (ie, no association) for age 85 years or older. Despite this association, APOE polymorphism did not significantly predict survival in subjects younger than 85 years, nor did it predict survival in subjects 85 years or older who were cognitively impaired. Instead, survival varied fourfold with respect to APOE polymorphism in those 85 years or older who had good cognition: Mortality in subjects with the ϵ2/3 genotype was half that in those who carried the ϵ3/3 genotype (hazard ratio, 0.5; 95% confidence interval, 0.2 to 0.9), and mortality in subjects with the ϵ3/4 genotype was twice that in those who carried the ϵ3/3 genotype (hazard ratio, 2.0; 95% confidence interval, 1.1 to 3.5). This fourfold variation resulted in 2-year differences in survival. CONCLUSIONS: The minor sequence variation in the apolipoprotein E isoforms resulted in a fourfold difference in the risk of death among the oldest old (age ≥85 years) with good cognition. The observed variation in mortality was unlikely to have been caused by cognitive impairment, as APOE polymorphism was not a risk factor for cognitive impairment in this age group.

Objective:To determine whether there is a relationship between serum cobalamin levels, normal aging, and Alzheimer's Disease (AD).

The neuropathologic hallmarks of Alzheimer's disease (AD) are extracellular plaques and intracellular neurofibrillary tangles. A constituent of senile plaques in AD is β-amyloid, a hydrophobic peptide of 39–43 amino acids1and a fragment of the amyloid precursor protein (APP). APP can be metabolized by at least two pathways, one of which involves generation of soluble APP by an unidentified enzyme named α-secretase. This cleavage generates α-secretase-cleaved, soluble APP (α–sAPP), which in this investigation was measured by a new assay in cerebrospinal fluid (CSF) from members of a Swedish AD family with a pathogenic mutation at APP670/671(ref. 2). Family members who carry the mutation and are diagnosed with AD had low levels of α–sAPP (160 ± 48 ng ml−1), with no overlap compared with non-carriers (257 ± 48 ng ml−1). Carriers of the presymptomatic mutation showed intermediate α–sAPP levels. Today there exists no antemortem marker in AD with sufficient sensitivity and specificity, but measurement of α–sAPP represents a new and promising diagnostic marker.

WE explored the relationship between cerebrospinal fluid (CSF) tau levels as indirect markers of tau-related pathology in Alzheimer's disease (AD) and EEG slowing, a typical neurophysiological finding in the disease. A positive correlation between CSF tau levels and ratio of alpha/delta global field power was found in 14 AD patients (r = 0.65, p= 0.01). This relationship was better approximated by polynomial fit of 2nd degree (p= 0.002). A subgroup of AD patients (n= 7) with higher tau levels and shorter duration of illness showed a strong relationship between CSF tau levels and alpha/theta (r = 0.83, p= 0.02), and alpha/delta (r = 0.87, p = 0.01) ratios of the global field power. There were no significant correlations between EEG slowing and CSF tau levels in 12 patients with mild cognitive dysfunction or in 14 healthy control subjects. That a strong inverse linear correlation exists in AD patients with higher levels of tau and shorter duration of illness may imply that with longer illness duration CSF tau levels decrease due to neuronal death.

• The relationship between quantitative measurements of brain white-matter hyperintensity (WMH), assessed by magnetic resonance imaging and neuropsychological functions, was explored in demented patients and healthy aged individuals with and without WMH in 12 brain regions. The prevalence of WMH was significantly higher in vascular dementia compared with Alzheimer's disease, especially in posterior periventricular regions. Results showed no difference in any neuropsychological measurement between healthy aged adults with and without WMH. The demented patients with WMH were more impaired in tests of visuoconstruction, attention, finger-motor speed, and latency of tactile identification of objects compared with patients without WMH. These impairments were related mainly to posterior periventricular WMH. There was no relationship between WMH and global cognitive functioning in the demented patients. The degree of WMH was related to age and blood pressure. The data suggest that specific regional WMH may result in specific neuropsychological impairments.

Five men were investigated after having pulmonary aluminosis due to exposure to aluminium pyrotechnic flake powder during the late 1940s. Two of the men had died 6 years and 20 years after exposure respectively, due to their lung disease. One man had died from heart failure 34 years after the end of exposure. Today, more than 40 years after exposure, two men were available for investigation. They had no respiratory symptoms and their vital lung capacities had not deteriorated during these years. One of the two survivors had developed a dementia with motor disturbances, which is not consistent with Alzheimer's dementia. This man had a very high concentration of aluminium in his cerebrospinal fluid. The other survivor had a normal concentration and was not demented.

Familial frontotemporal dementia (FTD) is a complex disorder with lack of distinctive histopathological markers found in other types of dementia. Most of the linkage reports from FTD families map the disease loci to chromosome 17q21-22. However, FTD is genetically heterogeneous, as linkage also has been reported to chromosome 3. In the present study, we investigated the genetics of a Swedish family with an early-onset type of rapidly progressive FTD, associated with muscular rigidity and akinetic movements. Neuropathological features such as severe frontal lobe degeneration, spongy changes, and gliosis were present in affected family members. We here report probable linkage to chromosome 17q12-21 with a maximum two-point lod score of 2.76 at θ = 0 for marker D17S806, and a peak multipoint lod score of 2.86 for the same marker. Linkage to chromosome 3 was excluded, as two-point lod scores of −2.79, and −2.27 at θ = 0.01 for markers D3S1603 and D3S1552, respectively, were obtained. Sequencing of the translated exons of a strong candidate gene in the linked region of chromosome 17, the tau gene, failed to identify any mutations segregating with the disease. Am. J. Med. Genet. 74:380–385, 1997. © 1997 Wiley-Liss, Inc.

The apolipoprotein E (ApoE) ε4 gene-dose effect1-3 involves the increased risk of late-onset Alzheimer disease (AD) in relation to the number of inherited copies of the ε4 allele; eg, persons who carry the ApoE ε3/3 genotype have lower risk than those with ε3/4 and those who carry ε3/4 have lower risk than those with ε4/4. This pattern of risk was identified for late-onset AD, defined as the onset of AD symptoms at or after age 60 years, and appears to apply to both familial and sporadic late-onset AD. The ε4 gene-dose effect does not directly translate into large differences in mean age at onset in groups of patients with AD, although it has sometimes been interpreted in this fashion.4 Specifically, Dal Forno et al4 use the similar mean ages at onset in a series of persons already affected with AD, those carrying 0,1, or 2 copies of