The role of lysosomes and autophagosomes in frontotemporal lobar degeneration.

INTRODUCTION: Cell biological and genetic evidence implicate failures in degrading aggregating proteins, such as tau and TDP-43, through the autophagy or lysosomal pathways in the pathogenesis of frontotemporal lobar degeneration (FTLD). METHODS: We investigated changes in the degradative pathways in 60 patients with different pathological or genetic forms of FTLD employing immunohistochemistry for marker proteins such as lysosomal-associated membrane proteins 1 (LAMP-1) and 2 (LAMP-2), cathepsin D (CTSD) and microtubule-associated protein 1 light chain 3 alpha (LC3A). Immunostained sections were qualitatively and semi-quantitatively assessed for the appearance, distribution and intensity of staining in neurones of the dentate gyrus (DG) and CA4 region of the hippocampus, and the temporal cortex (Tcx). RESULTS: Lower levels of neuronal LAMP-1 immunostaining were present in the DG and Tcx in FTLD-tau compared to FTLD-TDP. There was less LAMP-1 immunostaining in FTLD-tau with MAPT mutations, and FTLD-tau with Pick bodies, compared to FTLD-TDP types A and B, and less LAMP-1 immunostaining in FTLD-TDP type C than in FTLD-TDP types A and B. There was greater LAMP-1 immunostaining in GRN mutation which may reflect the underlying type A histology rather than mutation. There were no differences in neuronal LAMP-2, CTSD, EEA-1 or LC3A immunostaining between any of the five FTLD histological or four genetic groups, nor between FTLD-TDP and FTLD-tau. CONCLUSIONS: The underlying pathological mechanism in FTLD-tau may lie with a relative deficiency of lysosomes, or defective vesicular transport, whereas the failure to clear TDP-43 aggregates may lie with lysosomal dysfunction rather than a lack of available lysosomes or degradative enzymes.

Early changes in extracellular matrix in Alzheimer's disease.

AIMS: Although changes in extracellular matrix (ECM) scaffold have been reported previously in Alzheimer's disease (AD) compared to normal ageing, it is not known how alterations in the numerous components of the perivascular ECM might occur at different stages of AD. This study therefore investigates potential changes in basement membrane-associated ECM molecules in relation to increasing Braak stages. METHODS: Thirty patients were divided into three groups (control subject, subclinical AD and AD patients). ECM levels of collagen IV, perlecan and fibronectin as well as human platelet endothelial cell adhesion molecule (hPECAM) were quantified by immunohistochemistry. Von Willebrand factor staining was measured to assess vessel density. Expression levels were correlated with the presence of amyloid plaques. RESULTS: Collagen IV, perlecan and fibronectin expression was increased in subclinical AD and AD patients when compared to controls, in frontal and temporal cortex, whilst no further increase was detected between subclinical AD and AD. These changes were not associated with an increase in vessel density, which was instead decreased in the temporal cortex of AD patients. In contrast, hPECAM levels remained unchanged. Finally, we found similar pattern in levels of amyloid deposition between the different Braak stages and showed that changes in ECM components correlated with amyloid deposition. CONCLUSION: Present data support the hypothesis that significant ECM changes occur during the early stages of AD. ECM changes affecting brain microvascular functions could therefore drive disease progression and provide potential new early investigational biomarkers in AD.

Neurodegeneration in frontotemporal lobar degeneration and motor neurone disease associated with expansions in C9orf72 is linked to TDP-43 pathology and not associated with aggregated forms of dipeptide repeat proteins.

AIMS: A hexanucleotide expansion in C9orf72 is the major genetic cause of inherited behavioural variant Frontotemporal dementia (bvFTD) and motor neurone disease (MND), although the pathological mechanism(s) underlying disease remains uncertain. METHODS: Using antibodies to poly-GA, poly-GP, poly-GR, poly-AP and poly-PR proteins, we examined sections of cerebral cortex, hippocampus, thalamus, cerebellum and spinal cord, from 20 patients with bvFTD and/or MND bearing an expansion in C9orf72 for aggregated deposits of dipeptide repeat proteins (DPR). RESULTS: Antibodies to poly-GA, poly-GP and poly-GR detected numerous rounded cytoplasmic inclusions (NCI) within granule cells of hippocampal dentate gyrus and those of the cerebellum, as well as 'star-burst' shaped NCI in pyramidal neurones of CA3/4 region of hippocampus. NCI were uncommon in Purkinje cells, and only very rarely seen in anterior horn cells. Poly-PA antibody detected occasional NCI within CA3/4 neurones alone, whereas poly-PR antibody did not identify any NCI but immunostained the nucleus of anterior horn cells, CA3/4 neurones and Purkinje cells, in patients with or without expansion in C9orf72, as well as in normal controls. Poly-GA antibody generally detected more DPR than poly-GP, which in turn was greater than poly-GR. All patients with bvFTD + MND or MND showed plentiful p62/TDP-43 positive inclusions in remaining anterior horn cells. CONCLUSION: Degeneration and loss of anterior horn cells associated with expansions in C9orf72 occurs in the absence of DPR, and implies that changes involving loss of nuclear staining for and a cytoplasmic aggregation of TDP-43 are more likely to be the cause of this.

Patterns of cerebral amyloid angiopathy define histopathological phenotypes in Alzheimer's disease.

AIMS: Pathological heterogeneity of Aß deposition in senile plaques (SP) and cerebral amyloid angiopathy (CAA) in Alzheimer's disease (AD) has been long noted. The aim of this study was to classify cases of AD according to their pattern of Aß deposition, and to seek factors which might predict, or predispose towards, this heterogeneity. METHODS: The form, distribution and severity of Aß deposition (as SP and/or CAA) was assessed semiquantitatively in immunostained sections of frontal, temporal and occipital cortex from 134 pathologically confirmed cases of AD. RESULTS: Four patterns of Aß deposition were defined. Type 1 describes cases predominantly with SP, with or without CAA within leptomeningeal vessels alone. Type 2 describes cases where, along with many SP, CAA is present in both leptomeningeal and deeper penetrating arteries. Type 3 describes cases where capillary CAA is present along with SP and arterial CAA. Type 4 describes a predominantly vascular phenotype, where Aß deposition is much more prevalent in and around blood vessels, than as SP. As would be anticipated from the group definitions, there were significant differences in the distribution and degree of CAA across the phenotype groups, although Aß deposition as SP did not vary. There were no significant differences between phenotype groups with regard to age of onset, age at death, disease duration and brain weight, or disease presentation. Women were over-represented in the type 1 phenotype and men in type 2. Genetically, type 3 (capillary subtype) cases were strongly associated with possession of the APOE ε4 allele. CONCLUSIONS: This study offers an alternative method of pathologically classifying cases of AD. Further studies may derive additional genetic, environmental or clinical factors which associate with, or may be responsible for, these varying pathological presentations of AD.

Nuclear carrier and RNA-binding proteins in frontotemporal lobar degeneration associated with fused in sarcoma (FUS) pathological changes.

AIMS: We aimed to investigate the role of the nuclear carrier and binding proteins, transportin 1 (TRN1) and transportin 2 (TRN2), TATA-binding protein-associated factor 15 (TAF15) and Ewing's sarcoma protein (EWS) in inclusion body formation in cases of frontotemporal lobar degeneration (FTLD) associated with fused in sarcoma protein (FTLD-FUS). METHODS: Eight cases of FTLD-FUS (five cases of atypical FTLD-U, two of neuronal intermediate filament inclusion body disease and one of basophilic inclusion body disease) were immunostained for FUS, TRN1, TRN2, TAF15 and EWS. Ten cases of FTLD associated with TDP-43 inclusions served as reference cases. RESULTS: The inclusion bodies in FTLD-FUS contained TRN1 and TAF15 and, to a lesser extent, EWS, but not TRN2. The patterns of immunostaining for TRN1 and TAF15 were very similar to that of FUS. None of these proteins was associated with tau or TDP-43 aggregations in FTLD. CONCLUSIONS: Data suggest that FUS, TRN1 and TAF15 may participate in a functional pathway in an interdependent way, and imply that the function of TDP-43 may not necessarily be in parallel with, or complementary to, that of FUS, despite each protein sharing many similar structural elements.

Magnetic resonance imaging of fixed post mortem brains reliably reflects subcortical vascular pathology of frontal, parietal and occipital white matter.

AIMS: Subcortical vascular pathology of the white and deep grey matter (WM and DGM) is associated with cognitive impairment. Routine neuropathological assessment of subcortical vascular pathology is based on semiquantitative scoring of characteristic lesions in a limited number of histological slides from selected WM and DGM areas. Clinically, WM and DGM lesions are visualized as hyper-intensities on magnetic resonance imaging (MRI). The aim of this study was to evaluate the feasibility of MRI on fixed post mortem brain hemispheres to complement routine neuropathological assessment of subcortical vascular pathology. METHODS: We assessed subcortical vascular pathology in 40 post mortem brain hemispheres from demented (n = 26) and nondemented (n = 14) individuals (mean age 83.2 ± 14.8 years; 62.5% female) using (i) routine histological assessment; (ii) extensive histological assessment of the entire hemisphere at 7-mm intervals; and (iii) full T2-weighted MRI performed on fixed post mortem brain hemispheres. RESULTS: In both WM and DGM routine histological scores for subcortical vascular pathology were significantly lower (P < 0.01) than the corresponding scores obtained by extensive histological assessment. In contrast, no significant differences were seen between scores obtained by MRI and extensive histological assessment in frontal, parietal and occipital lobes while MRI scores were significantly lower in the temporal WM and DGM (P < 0.01). CONCLUSIONS: The results of our study indicate that routine histological assessment underrates subcortical vascular pathology and we conclude that MRI could be used in addition to complement neuropathological post mortem assessment of subcortical vascular pathology of the WM.

Post mortem cerebrospinal fluid α-synuclein levels are raised in multiple system atrophy and distinguish this from the other α-synucleinopathies, Parkinson's disease and Dementia with Lewy bodies.

Differentiating clinically between Parkinson's disease (PD) and the atypical parkinsonian syndromes of Progressive supranuclear palsy (PSP), corticobasal syndrome (CBS) and multiple system atrophy (MSA) is challenging but crucial for patient management and recruitment into clinical trials. Because PD (and the related disorder Dementia with Lewy bodies (DLB)) and MSA are characterised by the deposition of aggregated forms of α-synuclein protein (α-syn) in the brain, whereas CBS and PSP are tauopathies, we have developed immunoassays to detect levels of total and oligomeric forms of α-syn, and phosphorylated and phosphorylated oligomeric forms of α-syn, within body fluids, in an attempt to find a biomarker that will differentiate between these disorders. Levels of these 4 different forms of α-syn were measured in post mortem samples of ventricular cerebrospinal fluid (CSF) obtained from 76 patients with PD, DLB, PSP or MSA, and in 20 healthy controls. Mean CSF levels of total and oligomeric α-syn, and phosphorylated α-syn, did not vary significantly between the diagnostic groups, whereas mean CSF levels of phosphorylated oligomeric α-syn did differ significantly (p<0.001) amongst the different diagnostic groups. Although all 4 measures of α-syn were higher in patients with MSA compared to all other diagnostic groups, these were only significantly raised (p<0.001) in MSA compared to all other diagnostic groups, for phosphorylated oligomeric forms of α-syn. This suggests that this particular assay may have utility in differentiating MSA from control subject and patients with other α-synucleinopathies. However, it does not appear to be of help in distinguishing patients with PD and DLB from those with PSP or from control subjects. Western blots show that the principal form of α-syn within CSF is phosphorylated, and the finding that the phosphorylated oligomeric α-syn immunoassay appears to be the most informative of the 4 assays would be consistent with this observation.

Synaptic changes in frontotemporal lobar degeneration: correlation with MAPT haplotype and APOE genotype.

AIMS: This immunohistochemical study quantified synaptic changes (synaptophysin and SNAP-25) in the frontal lobe of subjects with frontotemporal lobar degeneration (FTLD) and Alzheimer's disease (AD), and related these to APOE genotype and MAPT haplotype. METHODS: Frontal neocortex (BA9) of post mortem brains from subjects with FTLD (n = 20), AD (n = 10) and age-matched controls (n = 9) were studied immunohistochemically for synaptophysin and SNAP-25. RESULTS: We report that patients with FTLD have a significant increase in synaptophysin and depletion in SNAP-25 proteins compared to both control subjects and individuals with AD (P < 0.001). The FTLD up-regulation of synaptophysin is disease specific (P < 0.0001), and is not influenced by age (P = 0.787) or cortical atrophy (P = 0.248). The SNAP-25 depletion is influenced by a number of factors, including family history and histological characteristics of FTLD, APOE genotype, MAPT haplotype and gender. Thus, more profound loss of SNAP-25 occurred in tau-negative FTLD, and was associated with female gender and lack of family history of FTLD. Presence of APOEε4 allele and MAPT H2 haplotype in FTLD had a significant influence on the expression of synaptic proteins, specifically invoking a decrease in SNAP-25. CONCLUSIONS: Our results suggest that synaptic expression in FTLD is influenced by a number of genetic factors which need to be taken into account in future neuropathological and biochemical studies dealing with altered neuronal mechanisms of the disease. The selective loss of SNAP-25 in FTLD may be closely related to the core clinical non-cognitive features of the disease.

Imbalance of a serotonergic system in frontotemporal dementia: implication for pharmacotherapy.

RATIONALE: Information is sparse on neurotransmitter deficiencies in frontotemporal dementia (FTD), in particular with reference to distinct histological subgroups and Alzheimer's disease (AD). OBJECTIVES: To evaluate in FTD with the major histologies, and compare with AD and controls, neurotransmission indices, as these may help in developing treatment. MATERIALS AND METHODS: Post-mortem grey matter from Brodmann Area 21, 9 and 7 of 51 brains was assayed for ten neurochemical parameters indexing neurotransmission. Repeated measures analyses of variance were carried out for each parameter comparing groups (FTD vs AD vs control) at each anatomical site. RESULTS: In FTD only the indices of alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid, serotonin (5-HT)(1A) and 5-HT(2A) receptors were significantly reduced from control values. Of the ten parameters only 5-HT(1A) receptors showed significant group x site interaction. This reflected disproportionate reduction in frontal and temporal compared to parietal cortex. In FTD three other receptors (muscarinic, M(1), N-methyl-D: -aspartate, NMDA, and kainate), choline acetyltransferase (ChAT) activity, 5-HT and 5-hydroxyindoleacetic acid content and 5-HT reuptake site values were not significantly reduced from control values. Only 5-HT, 5-HT reuptake site and ChAT values were significantly higher in FTD than AD. NMDA receptor and ChAT values were significantly reduced from control only in AD. CONCLUSIONS: Neurochemical results in FTD indicate degeneration and loss of pyramidal neurones in frontotemporal neocortex, yet 5-HT afferents and 5-HT concentration, which are inhibitory on pyramidal neurones, were relatively preserved. This could lead to an excess of extraneural 5-HT causing underactivity of surviving pyramidal neurones. Pharmacotherapy with a 5-HT(1A) receptor antagonist may be indicated.

Accuracy of single-photon emission computed tomography in differentiating frontotemporal dementia from Alzheimer's disease.

BACKGROUND: Alzheimer's disease (AD) and frontotemporal dementia (FTD) are the commonest causes of presenile dementia. In the absence of a biological marker, diagnosis is reliant on clinical evaluation. Confirmation is often sought from neuroimaging, including single-photon emission computed tomography (SPECT). Most previous SPECT studies lack pathological validation. AIM: To examine the accuracy of SPECT in differentiating FTD from AD in patients with subsequent pathological confirmation. METHODS: Technetium-99-labelled hexamethyl propylene amine oxime SPECT images obtained at initial evaluation in 25 pathologically confirmed cases of FTD were examined. These images were visually rated by an experienced blinded nuclear medicine consultant and compared with those of 31 patients with AD, also with pathological validation. RESULTS: A reduction in frontal cerebral blood flow (CBF) was more common in FTD and was of diagnostic value (sensitivity 0.8, specificity 0.65 and likelihood ratio (LR) 2.25; 95% CI 1.35 to 3.77). A pattern of bilateral frontal CBF reduction without the presence of associated bilateral parietal CBF change is diagnostically more accurate (sensitivity 0.80, specificity 0.81 and +LR 4.13, 95% CI 1.96 to 8.71). Diagnostic categorisation (FTD or AD) on the basis of SPECT alone was less accurate than clinical diagnosis (based on neurology and detailed neuropsychological evaluation). One patient with FTD was initially clinically misdiagnosed as AD, owing to the lack of availability of full neuropsychological assessment. However, SPECT correctly diagnosed this patient, providing a diagnostic gain of 4%. CONCLUSION: Technetium-99-labelled hexamethyl propylene amine oxime SPECT CBF patterns provide valuable information in the diagnosis of FTD and AD. These data can be better used as an adjunct to clinical diagnosis if pathology is to be correctly predicted in life.

Progranulin gene mutations associated with frontotemporal dementia and progressive non-fluent aphasia.

Frontotemporal lobar degeneration (FTLD) refers to a focal, non-Alzheimer form of cerebral degeneration that encompasses the distinct clinical syndromes of frontotemporal dementia (FTD), progressive non-fluent aphasia (PNFA) and semantic dementia. Some patients show tau-based pathological changes and in familial cases mutations have been identified in the microtubule-associated protein tau gene (MAPT) on chromosome 17q21. However, many cases are tau-negative, showing instead ubiquitin-immunoreactive (UBQ-ir) neuronal cytoplasmic inclusions and neurites, and in some familial cases UBQ-ir neuronal intranuclear inclusions of a lentiform appearance. Very recently, mutations have been identified in familial cases in the progranulin (PGRN) gene, also on chromosome 17q21. Clinical, pathological and molecular diversity within FTLD highlights the importance of careful examination of clinical-pathological-genetic relationships. This paper reports, for the first time, a clinico-pathological investigation of two FTLD families with PGRN mutations, and compares the clinical characteristics with those of patients studied in the department with MAPT mutations. The clinical profile associated with PGRN mutations constituted, in some patients, a prototypical picture of FTD and in others one of PNFA, both profiles occurring within the same family. Patients with PGRN mutations exhibited phonological deficits, whereas in patients with MAPT mutations language abnormalities, when present in addition to the prominent behavioural disorder, take the form of semantic disturbance. The findings provide compelling evidence for the link between FTD and PNFA, while raising the possibility of identifiable clinical differences between FTLD patients with MAPT and PGRN mutations.

Association between interleukin-1A polymorphism and cerebral amyloid angiopathy-related hemorrhage.

BACKGROUND AND PURPOSE: It has been suggested that the interleukin-1A (IL-1A) allele 2 is a risk factor for Alzheimer's disease (AD). Because cerebral amyloid angiopathy-related hemorrhage (CAAH) often coexists with AD, we examined the IL-1A polymorphism in CAAH. METHODS: In a case-control study, patients with pathologically verified CAAH, AD patients without intracerebral hemorrhage, and neuropathologically normal control subjects were studied. DNA was extracted from brain tissue, and IL-1A was genotyped. Logistic regression was used to examine the IL-1A polymorphism in CAAH patients with and without AD compared with AD and non-AD control subjects. RESULTS: There were 42 patients with CAAH, 232 AD patients, and 167 non-AD control subjects. In age-adjusted analyses, there was no association between possession of IL-1A allele 2 and risk of CAAH compared with AD control subjects (odds ratio [OR], 0.94; 95% confidence interval [CI], 0.45 to 1.97; P=0.87) or non-AD control subjects (OR, 0.94; 95% CI, 0.47 to 1.87; P=0.86). Stratifying for the presence of apolipoprotein E epsilon2 or epsilon4 demonstrated the known increased risk of CAAH from these lipoprotein E alleles. Subgroup analyses demonstrated a nonsignificant excess of the IL-1A 2,2 genotype in patients with CAAH and AD compared with those CAAH patients who did not have histological evidence indicating AD (OR, 2.17; 95% CI, 0.15 to 122.3; P=0.64). Comparisons between CAAH patients with AD and AD control subjects and between CAAH patients without AD and non-AD control subjects did not demonstrate an association between CAAH and possession of either the IL-1A allele 2 or the 2,2 genotype. CONCLUSIONS: The IL-1A allele 2 or 2,2 genotype does not appear to be a major risk factor for CAAH.

Are interleukin-1 gene polymorphisms risk factors or disease modifiers in AD?

Polymorphisms in the interleukin-1 genes, IL-1A and IL-1B, have been associated with AD, but not in all studies. The authors genotyped the IL-1A(-889) and IL-1B(-511) polymorphisms in large independent cohorts of 503 control individuals and 395 patients with AD, and a further 100 with brain Abeta load. No evidence was found of risk for AD with these variants, nor of an effect on age at onset. However, an impact of IL-1B(-511) on Abeta(40) load (p < 0.05) was detected.

Negative association between amyloid plaques and cerebral amyloid angiopathy in Alzheimer's disease.

Cerebral amyloid angiopathy (CAA) is an important, though still relatively neglected, aspect of the pathology of Alzheimer's disease (AD), and both the source of amyloid beta protein (Abeta) in CAA, and its relationship to senile plaque (SP) Abeta, remain unclear. We have investigated the relationship between Abeta deposition in SP and CAA in four regions of brain from 69 patients with AD in order to gain insight into the pathogenetic mechanism(s) underlying these pathologies. CAA was present to some degree in all 69 patients, with the occipital cortex being affected more often and more severely than frontal, temporal and parietal cortices. By definition, SPs were present in all brain areas in all 69 patients, with greater uniformity of distribution than CAA, though the occipital cortex was less severely affected than the other brain regions. There was no significant (positive) correlation between CAA rating and that of SP for any one cortical region, but on combining data from all four regions there was a significant inverse correlation (P=0.037) between CAA and SP ratings. Such data suggest that the cellular sources and mechanisms leading to Abeta deposition as SP or CAA are likely to differ and may proceed independently of each other.

Pathological relationships between microglial cell activity and tau and amyloid beta protein in patients with Alzheimer's disease.

The extent of microglial cell activation (microglial cell load) was estimated by image analysis of ferritin-immunostained sections of frontal cortex from 72 patients with pathologically confirmed Alzheimer's disease (AD), and correlated with the amount of pathological tau and amyloid beta protein (Abeta), as both Abeta(40) and Abeta(42) load, in adjacent sections of the same cases. Microglial cell load did not correlate with either Abeta(40) or Abeta(42) load but was significantly correlated with pathological tau load. Microglial cell load was unrelated to age at onset of disease or duration of illness. It is possible that because the presence of microglial cells predates that of pathological tau proteins within the cerebral cortex in AD, neurofibrillary damage to nerve cells may stem from the release of proinflammatory and other potentially neurotoxic molecules from microglial cells.

A polymorphism within intron 11 of the tau gene is not increased in frequency in patients with sporadic Alzheimer's disease, nor does it influence the extent of tau pathology in the brain.

There are numerous polymorphisms within the tau gene but these are in complete linkage disequilibrium and exist as two common extended haplotypes H1 and H2. We have investigated the frequency of these haplotypes in 83 cases of sporadic Alzheimer's disease (AD) using the +34 polymorphism in intron 11 of the tau gene as a marker of H1 and H2 haplotypes. The total amount of hyperphosphorylated tau protein (tau load), present as neurofibrillary tangles, neuropil threads or plaque neurites, was quantified in the frontal cortex of these patients and related to tau haplotype. We found no increase in H1H1 haplotype in this autopsy population of cases with AD compared to published control data. Stratification of cases for apolipoprotein E (APO E) genotype showed a slight, but not statistically significant, overrepresentation of epsilon 4 allele amongst bearers of H2 haplotype. There were no overall differences in tau load between haplotype groups though cases within each haplotype group bearing APO E epsilon 4 allele had a significantly higher tau load than those without epsilon 4 allele. Neither age at onset or duration of illness differed according to tau haplotype. We conclude that the frequency of tau gene H1 haplotype is not elevated in AD and possession of this has no impact upon the amount of tau pathology in AD.

A polymorphism in the angiotensin 1-converting enzyme gene is associated with damage to cerebral cortical white matter in Alzheimer's disease.

The impact of the insertion (I)/deletion (D) (I/D) polymorphism in the angiotensin 1-converting enzyme (ACE) gene on the extent of white matter myelin loss (ML) was investigated in four regions of the cerebral cortex in an autopsy-confirmed series of 93 patients with Alzheimer's disease (AD). The possible influence of APO E epsilon4 allele acting in concert with ACE D allele was assessed. The extent of ML did not differ between D/D, I/D and I/I genotype groups when data from all four brain regions were combined. However, separate analysis showed that the frontal and temporal cortex tended to be affected more severely by ML in patients with D/D genotype compared to those with I/D and I/I genotypes. Stratification according to APO E epsilon4 allele revealed a greater overall ML in patients bearing at least one copy of ACE D allele and one APO E epsilon4 allele, especially in individuals homozygous for both. The APO E epsilon4 allele may therefore act synergistically in patients with AD (and other subjects) bearing ACE D/D genotype to increase the risk of ML, perhaps through transient ischaemic episodes consequent upon poor cardiac output associated with coronary atherosclerosis in patients with the APO E epsilon4 allele.

The angiotensin 1-converting enzyme insertion (I)/deletion (D) polymorphism does not influence the extent of amyloid or tau pathology in patients with sporadic Alzheimer's disease.

An insertion (I)/deletion (D) polymorphism in the angiotensin 1-converting enzyme (ACE) gene has, in some studies, been associated with increased risk for Alzheimer's disease (AD), and functionally the enzyme has been implicated in the degradation of amyloid beta protein (Abeta). We have investigated the frequency of the I/D polymorphism in a clinic-based and autopsy-confirmed series of cases of AD, and investigated what impact the I/D polymorphism in ACE gene might have on the extent of Abeta and tau pathology in the frontal cortex in the autopsy-confirmed series. We found no differences in I/D allele or genotype frequencies between the clinic-based and autopsy-confirmed AD cases, or between the pooled clinic-based and autopsy-confirmed AD cases and a series of normal control subjects. Moreover, Abeta (Abeta(40) and Abeta(42)) load, tau load or extent of amyloid angiopathy did not differ between D/D, I/D and I/I genotype groups, though Abeta(42) load tended to be higher in bearers of I/I genotype (compared to D/D genotype). Neither age at onset nor duration of illness differed according to genotype. We conclude therefore that the frequency of ACE I-allele is not increased in AD and, in autopsy-confirmed AD cases, possession of the ACE I allele has no impact upon the pathology of AD, at least in terms of the amount of Abeta or tau deposited in the brain.