Neuritic pathology and dementia in Alzheimer's disease

Previous studies of Alzheimer's disease (AD) have correlated the severity of dementia with either the number of senile plaques or neurofibrillary tangles. We used antibodies raised against amyloid beta/A4 protein of senile plaque cores and tau protein as well as thioflavine S and the Campbell-Switzer modification of the Hicks silver method to examine the hippocampal formation and five neocortical regions from 22 nondemented elderly control subjects and 34 demented patients with cerebral senile plaques and neurofibrillary tangles, without complicating disease processes. Ten control subjects (46%) had no beta/A4 protein deposition. Twelve control subjects (54%) had widespread beta/A4 protein deposition but no neocortical neuritic pathology. Of the 34 patients with AD-type changes, 27 (79%) had widespread senile plaques and neurofibrillary tangles, while 7 (21%) had neocortical senile plaques with few neurofibrillary tangles. All demented patients had widespread beta/A4 protein deposition and neocortical tau-immunoreactive, Hicks silver-positive dystrophic neurites. The neurites were found both free in the neuropil as well as surrounding senile plaques. Quantitative analysis showed that dystrophic neurites were significantly increased in patients with AD compared with control subjects and the number of dystrophic neurites and neurofibrillary tangles correlated with the clinical severity of dementia. Widespread cerebral beta/A4 protein deposition may be necessary but by itself is insufficient for the development of dementia in AD.     

Neurobiological correlates of a putative risk allele for Alzheimer's disease on chromosome 12q

OBJECTIVE: To explore the clinical, neuropathologic, and neurochemical correlates of the D12S1045 91 base pair (bp) allele in a group of 50 autopsy-confirmed cases of AD who lacked other concomitant brain diseases. BACKGROUND: In a previous genome survey for novel risk loci for typical-onset (> or =60 years) AD conducted at 10 cM resolution, we detected associations of alleles at six microsatellite loci with AD. These included the 91bp allele of the D12S1045 locus that resides in the telomeric region of 12q. METHODS: Clinical assessment was performed as part of a longitudinal study of AD and related disorders. Standardized pathologic methods, genotyping, morphometry, and neurochemical analyses were performed with postmortem brain tissue. RESULTS: Patients with AD who carried the D12S1045 91bp allele manifested earlier ages at symptomatic onset and death, greater densities of cortical neurofibrillary tangles, and substantially greater reductions in cortical dopamine levels compared to noncarriers. A dosage effect of the number of D12S1045 91bp alleles on cortical dopamine levels was also observed. CONCLUSIONS: Carrying the D12S1045 91bp allele was associated with greater clinical, neuropathologic, and neurochemical severity independent of sex and APOE genotype. These findings suggest that a novel susceptibility gene for AD resides at or in close proximity to the D12S1045 locus.     

The BACE gene: genomic structure and candidate gene study in late-onset Alzheimer's disease

Alzheimer's disease (AD) pathology is characterized by beta-amyloid plaques and neurofibrillary tangles. Studies of autosomal dominant early-onset AD mutations suggest that beta-amyloid overproduction is sufficient to cause AD. Recently, the BACE gene, which encodes beta-secretase, the rate limiting enzyme in beta-amyloid formation, has been identified. Since this gene is a strong candidate gene for late-onset AD because of its function, we have characterized its genomic organization and identified two polymorphisms. Neither of these polymorphisms were associated with AD risk in genetic association studies comparing autopsy-confirmed late-onset AD cases and age-matched non-demented controls. Thus, we find no evidence that this locus influences risk for late-onset AD.     

Time-of-flight secondary ion mass spectrometry (TOF-SIMS) imaging reveals cholesterol overload in the cerebral cortex of Alzheimer disease patients

Although cholesterol has been involved in the pathophysiology of Alzheimer disease (AD), its distribution in the cerebral cortex over the course of AD is unknown. We describe an original method to quantify cholesterol distribution using time-of-flight secondary ion mass spectrometry imaging. Cholesterol was unevenly distributed along the cortical thickness, being more abundant close to the white matter, in both control and AD cases. However, the mean cholesterol signal was significantly higher in the lower half of the cortex in AD samples compared to controls. This increase, when converted into cortical layers, was statistically significant for layers III and IV and did not reach significance in layers V + VI, the variability being too high at the interface between grey and white matter. The density of neurofibrillary tangles and of senile plaques was not statistically linked to the abundance of cholesterol. Cholesterol overload thus appears a new and independent alteration of AD cerebral cortex. The structure in which cholesterol accumulates and the mechanism of this accumulation remain to be elucidated.     

The apolipoprotein E allele epsilon 4 does not correlate with the number of senile plaques or neurofibrillary tangles in patients with Alzheimer's disease.

BACKGROUND AND OBJECTIVES: Apolipoprotein E (apoE) has been implicated in regenerative processes in the brain after trauma, as well as in the pathogenesis of Alzheimer's disease. Inheritance of a specific apo epsilon allele (apo epsilon 4) determines in part the risk and the mean age at onset of Alzheimer's disease. ApoE has been found to bind isoform specifically to beta-amyloid protein, the major component of senile plaques, and to the microtubule associated protein tau, which forms paired helical filaments and neurofibrillary tangles. The aim was to further examine the relation between apo epsilon alleles, especially apo epsilon 4, and the development of neuropathological changes associated with Alzheimer's disease. METHODS: Brains of patients with Alzheimer's disease (n = 44) and vascular dementia (n = 11) and of age matched controls (n = 29) were studied. Senile plaques and neurofibrillary tangles in the hippocampus and frontal cortex were quantified. RESULTS: No correlation was found between the number of apo epsilon 4 alleles and the number of senile plaques and neurofibrillary tangles in the hippocampus or the frontal cortex of patients with Alzheimer's disease, or vascular dementia, or control groups. No significant differences in duration or severity of dementia were found between patients with or. without the apo epsilon 4 allele. No increased frequency of apo epsilon 4 was found in vascular dementia. CONCLUSION AND COMMENT: Although the apo epsilon genotype clearly affects whether Alzheimer's disease will develop or not, the present study suggests that it has no influence on pathology or clinical intellectual status, once the dementia has manifested itself. No increased apo epsilon 4 allele frequency was found in neuropathologically diagnosed patients with vascular dementia in whom concomitant Alzheimer's disease can be excluded.     

Oxidative posttranslational modifications in Alzheimer disease

The distinctive pathological lesions of Alzheimer disease (AD), senile plaques, and neurofibrillary tangles comprise aggregates of insoluble fibrillar protein. We and other investigators recently demonstrated that several mechanisms related to oxidative stress and free-radical reactions could play a crucial role in the pathogenesis of AD and, specifically, in the formation of senile plaques and neurofibrillary tangles (NFT).     

Oxidative posttranslational modifications in Alzheimer disease

The distinctive pathological lesions of Alzheimer disease (AD), senile plaques, and neurofibrillary tangles comprise aggregates of insoluble fibrillar protein. We and other investigators recently demonstrated that several mechanisms related to oxidative stress and free-radical reactions could play a crucial role in the pathogenesis of AD and, specifically, in the formation of senile plaques and neurofibrillary tangles (NFT).     

晚发型阿尔茨海默病β淀粉样蛋白及过磷酸化tau蛋白免疫组织化学分析

目的 探讨中国人晚发型阿尔茨海默病(LOAD)的神经病理学特征,确保其正确诊断.方法 选择经病理证实的8例LOAD患者和5名尤神经系统相关疾病的老年对照者的颞叶脑皮质,为死亡后13～101 h尸检取脑,双侧颞叶皮质取材.常规脱水、透明、石蜡包埋.连续切片,厚度6 μm,β淀粉样蛋白(Aβ)及过磷酸化tau蛋白(AT8)免疫组织化学染色(S/P法),相邻切片作阴性对照.光镜下观察两组颞叶皮质阳性分布情况.结果 LOAD组AB及AT8免疫组织化学染色均为阳性,Aβ阳性表达者分布于皮质各层,大小不一,形态各异,可见早期弥散斑、初级斑和终末斑等;AT8阳性表现为皮质神经元内不同程度神经原纤维缠结、神经毡细丝及老年斑.经半定量统计分析,Aβ免疫组织化学染色LOAD组全部阳性,其中中度阳性(++)5例,强阳性(+++)3例;对照组阳性率为0.AT8免疫组织化学染色LOAD组中度阳性(++)3例,强阳性(+++)5例,阳性率100%;对照组中度阳性(++)1例(1/5),阴性(-)4例.LOAD组与对照组Aβ及AT8染色阳性率比较,差异有统计学意义(χ2=13.000,P=0.001;χ2=9.244,P=0.007).结论 Aβ免疫组织化学染色法能清晰显示各种类型老年斑;AT8免疫组织化学染色法可清晰显示各级神经原纤维缠结的不同变化.两种染色方法 结合使用可提高LOAD患者的诊断率.     

Increased incidence of dementia with Lewy bodies in patients carrying the ɛ4-allele of apolipoprotein E

Background: The apolipoprotein ∈4 (APOE4) allele is a risk factor for Alzheimer's disease, but it remains undetermined whether this allele is related to the pathological development of neurofibrillary tangles (NFT) and the formation of Lewy bodies. Methods: In the present study, we examined the relationship between these changes and the APOE4 allele in 255 consecutive neuropathologically diagnosed cases. APOE genotyping was carried out by the polymerase chain reaction–restriction fragment length polymorphism method. Results: Nearly all our cases of dementia with Lewy bodies (DLB) showed the common form, having numerous senile plaques in the cerebral cortex and NFT in the parahippocampal and hippocampal regions and were also associated with the APOE4 allele. Limbic neurofibrillary tangle dementia (LNTD), characterized by the presence of NFT in limbic areas as well as the absence of senile plaques, did not appear to be associated with the APOE4 allele. Conclusions: The APOE4 allele is a risk factor for DLB as well as Alzheimer's disease and cerebral amyloid angiopathy, but not for LNTD.     

Association of estrogen receptor alpha gene polymorphisms with neurofibrillary tangles

Estrogen receptor alpha (ERalpha) may be implicated in the pathogenesis of Alzheimer's disease (AD). The aim of this study was to clarify the association between ERalpha gene polymorphisms and AD-related pathologic changes. The staging of neurofibrillary tangles (NFT) and senile plaques (SP) was performed according to the method by Braak and Braak and two polymorphisms, PvuII (P or p) and XbaI (X or x), of the ERalpha gene were typed in 551 Japanese cadavers (294 men and 257 women; mean age, 80.8 years). Distributions of the NFT and SP stages significantly correlated with age (NFT: r = 0.306, p < 0.0001; SP: r = 0.237, p < 0.0001) and were significantly higher in patients with the apolipoprotein E epsilon4 allele (p < 0.0001). Possession of the P allele showed a trend to be associated with a more serious NFT stage, but had no relationship with the SP stage. In men, a significant association between PvuII polymorphism and the NFT stage (p = 0.002) was found, revealing a gene- dose effect of the P allele. Similar results were obtained in the men without the epsilon4 allele (p = 0.011). Multiple regression analyses demonstrated that age was the strongest determinant of the NFT stage, possession of the epsilon4 allele was the next strongest, and PvuII polymorphism was the third strongest (p < 0.0001, R(2) = 0.144). The XbaI polymorphism did affect neither the NFT stage nor the SP stage. In conclusion, the PvuII polymorphism of the ERalpha gene is associated with Braak NFT stages and possession of the P allele may act as a risk factor for AD in Japanese men, especially in those without the epsilon4 allele.     

Neuronal loss correlates with but exceeds neurofibrillary tangles in Alzheimer's disease

To assess the relationship between dementia, neuronal loss, and neuropathological findings in Alzheimer's disease (AD), we counted the number of neurons, senile plaques, and neurofibrillary tangles in a high-order association cortex. We studied the superior temporal sulcus of 34 individuals with AD and 17 nondemented control subjects, using statistically unbiased, stereological counting techniques. The number of superior temporal sulcus neurons in nondemented control subjects was stable across the sixth to ninth decades. In AD, more than 50% of the neurons were lost. Both neuronal loss and neurofibrillary tangles increased in parallel with the duration and severity of illness, but the amount of neuronal loss exceeded by manyfold the amount of neurofibrillary tangles accumulated. In contrast to the correlation between neurofibrillary tangels and neuronal loss, the number of senile plaques and the percentage of the superior temporal sulcus that was covered by Aβ (amyloid burden) were not related to neuronal loss, number of neurofibrillary tangles, or duration of disease. Neither the amount nor the rate of neuronal loss in the superior temporal sulcus in AD correlated with apolipoprotein E genotype. These data suggest that neuronal loss in association areas such as the superior temporal sulcus contributes directly to cognitive impairment in AD.     

Apolipoprotein E in Guamanian amyotrophic lateral sclerosis/ parkinsonism-dementia complex: genotype analysis and relationships to neuropathological changes

Apolipoprotein E (Apo E) has been recently identified within amyloid deposits and neurofibrillary tangles in the brains of Alzheimer's disease (AD) patients. A strong association of the Apo E ε4 allele with higher risk of developing AD has also been reported. In the present study, the distribution of Apo E and the possible relationship between Apo E alleles and neuropathological alterations were analyzed in a series of Guamanian amyotrophic lateral sclerosis/parkinsonism-dementia complex (ALS/PDC) cases, a neurodegenerative condition characterized neuropathologically by widespread, severe neurofibrillary tangle formation but rare amyloid deposits. ApoE immunoreactivity was consistently observed in both type of lesions in these cases. Compared to tau protein immunoreactivity, there were generally fewer Apo E-immunoreactive neurofibrillary tangles, particularly in the deep layers of the neocortex and in the hippocampus. Genotype analysis revealed that the ε4 allele frequency was 5.9%, the ε3 allele frequency 88.2%, and the ε2 allele frequency 5.9% in this series. Recent data suggest that the Apo E4 variant may induce amyloidogenesis, while E2 could have a neuroprotective role. However, the rare Guamanian patients with amyloid deposits in cortical areas were not related to the ε4 allele, since all cases with senile plaques were ε3/ε3. In addition, compared to unaffected Guamanian cases and other Asian-Pacific populations previously reported, the observed low frequency of the ε2 allele in the present cases, which may be consistent with the notion that this allele, may represent a neuroprotective factor in several neurodegenerative disorders. The present data indicate that there is a strong interaction between Apo E deposition and neurofibrillary changes in Guamanian ALS-PDC. Received: 22 June 1995 / Revised, accepted: 8 September 1995     

Albumin gene encoding free fatty acid and β-amyloid transporter is genetically associated with Alzheimer disease

Abstract  Alzheimer disease (AD), the major cause of dementia in the elderly, is characterized by β-amyloid deposition in senile plaques and hyperphosphorylated tau in neurofibrillary tangles. Since albumin, binding and transporting free fatty acids is also the major transporter of β-amyloid, we examined the association between the albumin ( ALB ) gene and the occurrence of late-onset AD (LOAD). We found that the allele distribution of the intron 4 microsatellite of the ALB gene showed a significant difference ( P  < 0.05) between LOAD ( n  = 285) and control group ( n  = 656). An allele with 11 CA repeat, termed (CA)₁₁ allele, was significantly predominant in the control group ( P  < 0.005), and the odds ratio carrying the (CA)₁₁ allele was 0.43 ( P  < 0.01, 95% CI = 0.24–0.79). Logistic regression indicated that this effect was independent of age and the ɛ4 dose of the apolipoprotein E gene ( P  < 0.01), while the ALB gene was supposed to be related to aging. Our results indicate that the ALB gene is genetically related with the occurrence of LOAD, supporting the link between fatty acid and β-amyloid transport in the development of LOAD.     

Cerebrovascular Pathology Contributes to the Heterogeneity of Alzheimer's Disease

Heterogeneous pathology in Alzheimer's Disease (AD) is due to variability in the nature and severity of lesions, overlap with other neurodegenerative diseases such as Parkinson's disease, or the co-existence of cerebrovascular disease. In the MGH-ADRC autopsy archives, remote cerebral infarcts (CVA) were reported in 30% of the otherwise uncomplicated AD cases. To determine the potential significance of cerebrovascular lesions in relation to AD, the relative densities (CERAD grading criteria) of Bielschowsky-stained AD lesions and Ab-amyloid immunoreactive plaques were compared among cases of AD+CVA (N=52), AD (N=48), aged controls (NC; N=9), and aged controls with AD lesions (ADC; N=8). The prevalence of the ApoE varepsilon 4 allele was also determined for each group. This study demonstrated: 1) higher densities of Bielschowsky-stained plaques in AD, AD+CVA, and ADC than in NC (P<0.0001); 2) more abundant neurofibrillary tangles in AD relative to all other groups (P<0.0005), and in AD+CVA and ADC relative to NC (P<0.05); and 3) increased densities of Ab-amyloid-immunoreactive plaques in AD relative to AD+CVA (P=0.0003). In AD+CVA, cerebral vascular lesions consisting of remote microscopic cortical and subcortical white matter infarcts, ischemic lesions, and leukoaraiosis were consistently distributed in structures typically damaged by AD neurodegeneration, as well as in the basal ganglia. The ApoE varepsilon 4 allele was more prevalent in the AD+CVA (70%) than in the AD (58%) group (P=0.05). Since the AD and AD+CVA groups had similar degrees of dementia, the results suggest that cerebral vascular lesions in regions typically destroyed by AD may contribute to the clinical manifestations of AD.     

Alzheimer's disease and Lewy body disease: A comparative clinicopathological study

The exact nature of the relationship between Lewy body disease and Alzheimer's disease (AD) is unknown. To investigate this, we compared cases of pure Lewy body disease, mixed Lewy body disease with AD, and pure AD to see what pathological features were shared and how they differed. We counted neurons, Lewy bodies, diffuse and neuritic senile plaques, neurofibrillary tangles, and neuropil threads in the frontal and medial temporal cortex and hippocampus from 5 autopsied cases of Lewy body disease (without AD histopathology), 7 with combined Lewy body disease and AD, 6 with AD, and 5 age-matched normal control subjects. Average neuronal counts in the cases with Lewy body disease were indistinguishable from those of control subjects, but higher than those for AD and combined Lewy body disease and AD. Diffuse plaque densities were similar in all disease forms. Neuritic senile plaques, neurofibrillary tangles, and neuropil threads were numerous in AD and combined Lewy body disease and AD, but sparse or absent in Lewy body disease and controls. Pure Lewy body disease and AD appear to be distinct clinicopathological entities except for the common feature of diffuse plaques in both disorders.     

Genetic association of CDC2 with cerebrospinal fluid tau in Alzheimer's disease

We have recently reported that a polymorphism in the cell division cycle (CDC2) gene, designated Ex6 + 7I/D, is associated with Alzheimer's disease (AD). The CDC2 gene is located on chromosome 10q21.1 close to the marker D10S1225 linked to AD. Active cdc2 accumulates in neurons containing neurofibrillary tangles (NFT), a process that can precede the formation of NFT. Therefore, CDC2 is a promising candidate susceptibility gene for AD. We investigated the possible effects of the CDC2 polymorphism on cerebrospinal fluid (CSF) biomarkers in AD patients. CDC2 genotypes were evaluated in relation to CSF protein levels of total tau, phospho-tau and beta-amyloid(1-42) in AD patients and control individuals, and in relation to the amount of senile plaques and NFT in the frontal cortex and in the hippocampus in patients with autopsy-proven AD and controls. The CDC2 Ex6 + 7I allele was associated with a gene dose-dependent increase of CSF total tau levels (F(2, 626) = 7.0, p = 0.001) and the homozygous CDC2 Ex6 + 7II genotype was significantly more frequent among AD patients compared to controls (p = 0.006, OR = 1.57, 95% CI 1.13-2.17). Our results provide further evidence for an involvement of cdc2 in the pathogenesis of AD.     

脂蛋白脂酶Ser447Stop基因多态与脑梗死的相关性

目的 探讨脂蛋白脂酶(LPL)Ser447Stop基因多态与脑梗死的相关性.方法 受试者共883人,其中脑梗死组563例[包括动脉粥样硬化(AS)性脑梗死329例和腔隙性脑梗死234例],对照组320名,应用聚合酶链反应一限制性片段长度多态性方法,对LPL基因Ser447Stop位点进行基因多态性检测.结果 脑梗死组、AS性脑梗死组和腔隙性脑梗死组LPL Ser447Stop GG+CG基因型频率与对照组相比,差异无统计学意义,AS性脑梗死组G变异等位基因频率(64例,9.7%)与对照组(42例,6.6%)相比差异有统计学意义(X2=3.99,P=0.045).相对于C等位基因,G等位基因的彻值为1.510(95%C/1.012～2.261).结论 LPL Ser447Stop G变异等位基因携带者患AS性脑梗死的危险高于非携带者.G变异等位基因可能是AS性脑梗死高危险性的遗传标志之一.     

GSK-3 inhibitors: a ray of hope for the treatment of Alzheimer's disease?

Alzheimer's disease (AD) is the most common form of dementia affecting more than 15 millions individuals worldwide. While the cause is unknown, there are two major neuropathological abnormalities present in the brains of patients with AD, the extracellular senile plaques and the intracellular neurofibrillary tangles. There is strong evidence that glycogen synthase kinase-3 (GSK-3) plays an important role in AD being involved in the regulation of these neuropathological hallmarks. Increased activity and/or overexpression of this enzyme in AD is associated with increased tau hyperphosphorylation and alterations in amyloid-beta processing that are thought to precede the formation of neurofibrillary tangles and senile plaques, respectively. Furthermore, over activity of GSK-3 is also involved in neuronal loss. These data clearly identify GSK-3 inhibitors as one of the most promising new approaches for the future treatment of AD and a reduction of the aberrant over activity of this enzyme might decrease several aspects of the neuronal pathology in AD. In this review, we provide an overview of the rationale for the development of GSK-3 inhibitors for the treatment of AD, discussing the risks and benefits of this approach.     

Increased neocortical neurofibrillary tangle density in subjects with Alzheimer disease and psychosis

BACKGROUND: Psychosis is common in patients with Alzheimer disease. While the relationship between psychosis and clinical variables has been examined frequently, few studies have examined the relationship between psychosis and the 2 major neuropathological hallmarks of Alzheimer disease: neurofibrillary tangles and senile plaques. We characterized the occurrence of psychosis in relation to dementia severity and determined if subjects with Alzheimer disease and psychosis had a greater neurofibrillary tangle or senile plaque burden than subjects with Alzheimer disease and no psychosis. METHODS: One hundred nine subjects with Alzheimer disease were followed longitudinally with semistructured assessments in order to assign a Clinical Dementia Rating and determine whether psychosis was present. After the subjects died, their brains were obtained for histological examination. Analysis of variance was used to compare the densities of neurofibrillary tangles, total senile plaques, and cored senile plaques in subjects with psychosis vs subjects without psychosis, in several neocortical regions, the hippocampus, and the entorhinal cortex. RESULTS: Psychosis occurred commonly in Alzheimer disease, affecting 63% of subjects. The frequency of psychosis increased with increasing dementia severity. More importantly, we found that subjects with psychosis had a 2.3-fold (95% confidence interval, 1.2-3.9) greater density of neocortical neurofibrillary tangles than did subjects without psychosis. The increase was independent of dementia severity. No similar relationship with psychosis was seen for total senile plaques or cored senile plaques. CONCLUSIONS: The increase in psychosis frequency that occurs with the progression of dementia severity and the independent association between psychosis and neurofibrillary tangle density suggest the possibility that some common underlying process or processes specific to Alzheimer disease may regulate both phenomena. Arch Gen Psychiatry. 2000;57:1165-1173.     

Clinical and neuropathological correlates of apolipoprotein E genotype in dementia with Lewy bodies

Dementia with Lewy bodies (DLB) represents the second commonest cause of dementia in the elderly following Alzheimer's disease (AD). Whilst the presence of Lewy bodies is essential, DLB shares with AD the presence of senile plaques (SP), but neurofibrillary tangles (NFT) are not a necessary feature. The apolipoprotein E (APO E) epsilon4 allele is the most consistently associated genetic risk factor for AD and has also been shown to associate with DLB. We have therefore analysed the APO E epsilon4 allele in a large series of DLB cases coming to autopsy to: (1) determine if the epsilon4 allele describes a similar risk in DLB development as in AD and (2) determine how APO E epsilon4 allele status correlates with clinical and neuropathological findings in DLB, and in AD, as an indication of the role of APO E in underlying disease biology. Both DLB and AD share an increased epsilon4 allele frequency, though in DLB the epsilon2 allele frequency is not reduced and there is a relative lack of epsilon4 homozygotes. In contrast to previous studies, no association of the epsilon4 allele with age at onset or duration of disease was found in either disorders. In DLB cases, overall a significantly shorter duration of illness was observed when compared with AD cases, though no significant effect of the epsilon4 allele on disease onset or duration was seen. The survival rate was reduced by the presence of the epsilon4 allele in DLB, as with AD. No effect on SP or NFT counts was seen with the epsilon4 allele, though DLB cases showed a lower SP burden in addition to the expected lower NFT counts. This study demonstrates that DLB shares the APO epsilon4 allele with AD as a common risk factor, but that there are differences in the way the epsilon4 allele affects the phenotypic expression of disease.