Variant Alzheimer Research Articles

Abnormal Neurites Containing C-Terminally Truncated α-Synuclein Are Present in Alzheimer's Disease without Conventional Lewy Body Pathology

The pathological hallmark of Parkinson's disease and diffuse Lewy body disease (DLBD) is the aggregation of α-synuclein (α-syn) in the form of Lewy bodies and Lewy neurites. Patients with both Alzheimer's disease (AD) and cortical Lewy pathology represent the Lewy body variant of AD (LBV) and constitute 25% of AD cases. C-terminally truncated forms of α-syn enhance the aggregation of α-syn in vitro. To investigate the presence of C-terminally truncated α-syn in DLBD, AD, and LBV, we generated and validated polyclonal antibodies to truncated α-syn ending at residues 110 (α-syn110) and 119 (α-syn119), two products of 20S proteosome-mediated endoproteolytic cleavage. Double immunofluorescence staining of the cingulate cortex showed that α-syn110 and α-syn140 (full-length) aggregates were not colocalized in LBV. All aggregates containing α-syn140 also contained α-syn119; however, some aggregates contained α-syn119 without α-syn140, suggesting that α-syn119 may stimulate aggregate formation. Immunohistochemistry and image analysis of tissue microarrays of the cingulate cortex from patients with DLBD (n = 27), LBV (n = 27), and AD (n = 19) and age-matched controls (n = 15) revealed that AD is also characterized by frequent abnormal neurites containing α-syn119. Notably, these neurites did not contain α-syn ending at residues 110 or 122-140. The presence of abnormal neurites containing α-syn119 in AD without conventional Lewy pathology suggests that AD and Lewy body disease may be more closely related than previously thought.

Paraoxonase-1 polymorphisms in Alzheimer's disease, Parkinson's disease, and AD-PD spectrum diseases.

Paraoxonase-1 (PON1) is a serum arylsulfatase that metabolizes organophosphate pesticides and protects low-density lipoprotein from oxidation. Case-control studies of PON1 genetic variants in Alzheimer's disease (AD) and Parkinson's disease (PD) have revealed some positive albeit inconsistent associations with 2 PON1 coding polymorphisms: Q192R (rs662) and L55M (rs854560). Because AD and PD exist along a spectrum of disorders with shared epidemiologic, clinical, and pathologic features, here we evaluated PON1 variants in a cohort of 746 AD, 566 PD, 132 AD-PD, and 719 cognitively normal age-matched controls. In the combined AD and Caucasian PD cohorts we had 80% power to detect a relative risk of at least 1.25 and 1.35, respectively, for each polymorphism. We found no association between 2 PON1 coding polymorphisms and AD in African Americans or Caucasians, and no association with PD or AD-PD in Caucasians. There was also no evidence of an interaction between PON1 and apolipoprotein E for any of these diseases. Our results suggest that either these functional PON1 polymorphisms are not associated with AD and PD spectrum disorders, or that the relative risk conferred is small.

Does executive impairment define a frontal variant of Alzheimer's disease?

People with Alzheimer's disease (AD) who present with prominent frontal features such as a dysexecutive syndrome may be difficult to differentiate clinically from subjects with frontotemporal lobar degeneration (FTLD). This study was performed to improve the differential diagnosis between AD and FTLD and to better characterize the AD subgroup with greater executive dysfunction. Using a well-defined prospectively studied cohort of cognitively impaired subjects, which included those with AD and with FTLD, we nominated a frontal variant of AD (FvAD) group as those AD subjects with the lowest quartile of scores on the Frontal Assessment Battery (FAB), indicating greatest executive dysfunction, and compared them with the rest of the AD cases (whom we called the AD group) and those with FTLD across several baseline variables including cognitive, functional and behavioral scales. We also compared the changes from baseline for these three groups at 6 and 12 months. Additionally, we controlled for dementia severity by matching AD and FTLD cases on a functional scale, the SMAF, and repeated the same comparisons with these severity-matched groups. The 114 FvAD subjects had a mean age of 78.1 years and Mini-mental State Examination (MMSE) scores of 16.6, and the (remaining) AD group had a mean age of 78.4 years and MMSE of 22.4. There were 30 FTLD subjects with a mean age at baseline of 70.9 years and a mean baseline MMSE of 23.4. The FvAD group was significantly more severely impaired than the other two groups on all baseline assessments except the behavioral scale, the Neuropsychiatric Inventory (NPI), where there was insignificantly less impairment than in the FTLD group. In the analysis of subjects matched at baseline for functional impairment, the FvAD and FTLD groups were not significantly different on most assessment scales although on the FAB, clock-drawing and MMSE the FvAD subjects were still significantly more impaired. These two severity-matched groups were also similar in other baseline characteristics except for older age and less psychotropic use in the FvAD group. The severity-matched FvAD group was significantly different from the AD group in almost all assessment scales. All three unmatched and matched groups declined similarly over 12 months. When groups were not matched for baseline severity, the use of the FAB defined a group of AD subjects with greater executive dysfunction that were distinguished from both the remainder of the AD and FTLD subjects in almost all domains except behavioral disturbance and probably were just more severely affected AD subjects. The FAB is thus more useful as a marker of dementia severity than as a scale to detect a frontal variant of AD or to distinguish AD from FTLD. Controlling for severity, however, did allow the definition of a subgroup of AD subjects that more closely resembled FTLD subjects than the remainder of the AD subjects. It is proposed that subjects with dementia presenting with greater executive impairment but without prominent behavioral symptoms are likely to have AD rather than FTLD, especially if they are quite functionally impaired. With time FTLD subjects develop increasing executive dysfunction and increasingly resemble the more severely affected AD subjects.

Upregulated expression of specific CD44 splice variants in Alzheimer's disease

Upregulated expression of specific CD44 splice variants in Alzheimer's disease

Different implication of NEDD9 genetic variant in early and late-onset Alzheimer's disease

Alzheimer's disease (AD) is a complex and multifactorial progressive neurodegenerative disease. Recently, two studies reported inconsistent results on a possible involvement of the NEDD9 (neural precursor cell expressed, developmentally down-regulated 9, 6p25-p24) as a candidate gene for the risk of developing AD and/or Parkinson's disease (PD). We analyzed the distribution of the rs760678 SNP polymorphism in 735 Italian subjects: 214 unrelated sporadic late-onset AD patients (LOAD, 64.5% females, mean age-at-onset 71.8 ± 5.2 years), 135 early-onset AD patients (EOAD, 57.3% females, mean age-at-onset 57.5 ± 5.5 years) and 386 healthy controls (68.9% females, mean age 83.4 ± 17.9 years; SD). We observed a statistically significant difference between LOAD patients and controls according to genotypes ( P = 0.016) and allele frequency ( P = 0.007); CC genotype was more frequent in LOAD cases (44.4%) than controls (36.0%). No difference after stratification of the data in terms of gender and status of the APOE ɛ4 allele was observed. In conclusion, our data do support an implication of the NEDD9 allelic variant in late-onset AD, with an independent effect of the apolipoprotein E (APOE) ɛ4 allele in the risk of developing AD.

BuChE K variant is decreased in Alzheimer’s disease not in fronto-temporal dementia

Alzheimer's disease (AD) is characterized by a significant reduction in AcetylCholinesterase and an increase in ButyrylCholinesterase (BuChE) activity. The existence of polymorphic regions on the BuChE gene has been previously described; the most frequently found polymorphism is the so-called K variant, which leads to a 30% decreased enzymatic activity. Different studies reported a positive association between K variant and AD, strongest among late-onset AD and Apolipoprotein E (APOE) e4 carriers. We analyzed APOE and BuChE polymorphisms in 167 AD and 59 fronto-temporal dementia (FTD) patients compared with 129 healthy controls (HC). We reported a significantly lower frequency of the BuChE K variant in AD compared with HC and FTD and a significant increased frequency of the K variant in FTD. These results are in agreement with the known increase of the BuChE activity in AD and support the evidence of different molecular pathways involved in the pathogenesis of AD and FTD.

PIN1 gene variants in Alzheimer's disease

BackgroundPeptidyl-prolyl isomerase, NIMA-interacting 1 (PIN1) plays a significant role in the brain and is implicated in numerous cellular processes related to Alzheimer's disease (AD) and other neurodegenerative conditions. There are confounding results concerning PIN1 activity in AD brains. Also PIN1 genetic variation was inconsistently associated with AD risk.MethodsWe performed analysis of coding and promoter regions of PIN1 in early- and late-onset AD and frontotemporal dementia (FTD) patients in comparison with healthy controls.ResultsAnalysis of eighteen PIN1 common polymorphisms and their haplotypes in EOAD, LOAD and FTD individuals in comparison with the control group did not reveal their contribution to disease risk.In six unrelated familial AD patients four novel PIN1 sequence variants were detected. c.58+64C>T substitution that was identified in three patients, was located in an alternative exon. In silico analysis suggested that this variant highly increases a potential affinity for a splicing factor and introduces two intronic splicing enhancers. In the peripheral leukocytes of one living patient carrying the variant, a 2.82 fold decrease in PIN1 expression was observed.ConclusionOur data does not support the role of PIN1 common polymorphisms as AD risk factor. However, we suggest that the identified rare sequence variants could be directly connected with AD pathology, influencing PIN1 splicing and/or expression.

Involvement of paraoxonase 1 genetic variants in Alzheimer’s disease neuropathology

Evidence suggests that the genes involved in brain lipid homeostasis are of particular relevance for Alzheimer's disease (AD) etiology. Among these genes, that encoding paraoxonase 1 (PON1) has gained newfound interest from a public health perspective, as recent studies have suggested that PON1 L55M and Q192R genetic variants might affect individual susceptibility to environmental events, such as exposure to cholinesterase inhibitors. Cholinesterase inhibitor therapy being the treatment of choice for patients with mild to moderate AD, we sought to answer two main questions: (i) are these genetic variants associated with increased AD risk, earlier age of onset/death, or shorter AD duration; and (ii) do they affect the neuropathological hallmarks of AD? This genetic study used a large cohort of clinical and autopsy-confirmed AD cases and age-matched, cognitively intact controls from the Douglas Hospital Brain Bank, Quebec, Canada (n = 1066). The evidence presented here suggests multiple gender-specific effects of PON1 polymorphisms on AD etiopathology. The L55M Met allele exerts an AD risk-enhancing effect only in men (P < 0.001), whereas both men and women carrying the M55M/Q192Q genotype exhibit increased survival (2.5 years, P < 0.05) and later age of onset (1.5 years, P < 0.05). These genetic variants are also individually and significantly associated, sometimes in opposite directions for both genders, with beta-amyloid levels (P < 0.001), senile plaque accumulation (P < 0.001) and choline acetyltransferase activity (P < 0.05) in, respectively, two of two, five of six, and three of six brain areas. These results suggest an involvement of the PON1 gene in AD etiopathology and responses to treatment.

AKINETOPSIA IN THE POSTERIOR CORTICAL VARIANT OF ALZHEIMER DISEASE

Akinetopsia is a rare condition in which patients cannot perceive motion.1 Akinetopsia has occurred from bilateral cortical lesions involving the temporo-parieto-occipital junction.1,2 This report describes 2 patients with akinetopsia from neurodegenerative disease. They had double vision, and proved to have directional akinetopsia with persistence of successive stills from moving images as part of posterior cortical atrophy (PCA) or visual variant Alzheimer disease (AD).3,4 ### Case reports. #### Case 1. A 71-year-old right-handed woman had a 3-year progressive decline in the ability to visually localize objects. She could not find objects in her home, on countertops, in her wallet, or if dropped. She also had double vision. Leftward moving objects were perceived as 2 or more successive images occurring side by side. She did not have polyopsia on viewing static objects or on moving her eyes. The patient also had a decline in recent memory, numerical ability, and instrumental activities of daily living. Past medical history included recent cataract surgery in an attempt to fix her visual problems, and her medications were donepezil and memantine. On examination, she scored 21/30 on the Mini-Mental State Examination (MMSE). Language was fluent with good auditory comprehension, repetition, and naming. On a verbal learning task, the patient recalled 0/10 words after a …

Positron Emission Tomography in Diagnosis of Visual Variant Alzheimer Disease

A 65-year-old man with a 3-year history of difficulty seeing had normal ophthalmologic and neurologic examinations except for impaired visual spatial and perceptual function. Brain MRI failed to disclose any structural abnormalities, but positron emission tomography (PET) performed 2 weeks later showed prominent hypometabolism in the parieto-occipital regions bilaterally. These findings were considered consistent with the visual variant of Alzheimer disease (VVAD). Although the dissociation between normal structural and abnormal functional imaging has been reported before in VVAD, this patient is a reminder that PET may be useful to confirm the diagnosis before the disease becomes advanced.

Lewy Body Variant of Alzheimer's Disease: Selective Neocortical Loss of t-SNARE Proteins and Loss of MAP2 and α-Synuclein in Medial Temporal Lobe

Lewy bodies (LBs) appear in the brains of nondemented individuals and also occur in a range of neurodegenerative disorders, such as dementia with Lewy bodies (DLB) and Parkinson's disease. A number of people with a definite diagnosis of Alzheimer's disease (AD) also exhibit these intraneuronal inclusions in allo- and/or neocortical areas. The latter, referred to as Lewy body variant of AD (LBV), bears a clinical resemblance to AD in terms of age at onset, duration of illness, cognitive impairment, and illness severity. Since the presence of LBs is accompanied by neuronal cytoskeleton changes, it is possible that the latter may influence neuronal connectivity via alterations to the synaptic network. To address this, we examined the expression of synaptic proteins (synaptophysin, syntaxin, SNAP-25, and α-synuclein) and two cytoskeletal proteins (tau and MAP2) in the brain tissue of subjects enrolled in a population-based autopsy study (n = 47). They were divided into groups with no memory problems (control group, n = 15), LBV (n = 5), AD devoid of LBs (n = 17), cerebrovascular dementia (n = 3), and mixed dementia (n = 7). The LBV and AD groups had a similar degree of cognitive impairment and neuropathological staging in terms of Braak staging and CERAD score. In comparison with the control group and the dementia groups without LBs, the LBV group had significantly lower levels of syntaxin and SNAP-25 (23%) in the neocortex, and depletion of MAP2 (64%), SNAP-25 (34%), and α-synuclein (44%) proteins in the medial temporal lobes. These findings suggest that the t-SNARE complex deficit present in LBV may be associated with the presence of LB-related pathology and may explain the more profound cholinergic loss seen in these patients.

P2-033: Pet amyloid ligand [11C]PIB uptake shows predominantly striatal increase in variant Alzheimer's disease

P2-033: Pet amyloid ligand [11C]PIB uptake shows predominantly striatal increase in variant Alzheimer's disease

PET amyloid ligand [11C]PIB uptake shows predominantly striatal increase in variant Alzheimer's disease

Variant Alzheimer's disease (VarAD) with spastic paraparesis and presenile dementia is associated with certain mutations of the presenilin 1 (PS-1) gene, particularly those leading to deletion of exon 9 (PS-1Delta E9). VarAD is neuropathologically characterized by the presence of unusually large, Abeta42 positive, non-cored 'cotton wool' plaques (CWPs), also devoid of dystrophic neurites. The aim of the present study was to find out whether [(11)C]PIB would show increased uptake and serve as an in vivo biomarker of amyloid accumulation in VarAD. A further aim was to assess the correspondence of the [(11)C]PIB binding to the amount and type of Abeta deposits in another group of deceased VarAD patients' brains. We studied four patients with VarAD and eight healthy controls with PET using [(11)C]PIB as tracer. Parametric images were computed by calculating the region-to-cerebellum and region-to-pons ratio in each voxel over 60-90 min. Group differences in [(11)C]PIB uptake were analysed with automated region-of-interest (ROI) analysis. [(11)C]PIB uptake was compared to the immunohistochemically demonstrated deposition of Abeta in the brains of another group of four deceased VarAD patients. Patients with VarAD had significantly higher [(11)C] PIB uptake than the control group in the striatum (caudate nucleus and putamen), anterior and posterior cingulate gyrus, occipital cortex and thalamus. In the caudate and putamen [(11)C]PIB uptake, expressed as region-to-cerebellum ratio, was on the average 43% greater than the mean of the control group. The increases in the anterior (28%) and posterior (27%) cingulate gyrus, occipital cortex (21%) and thalamus (14%) were smaller. All VarAD patients showed this similar topographical pattern of increased [(11)C]PIB uptake. The results were essentially similar when the uptake was expressed as region-to-pons ratios. [(11)C]PIB imaging shows increased uptake in patients with VarAD especially in the striatum, and it can be used to detect amyloid accumulation in vivo in these patients. The pattern of increased [(11)C]PIB uptake is different from that described in sporadic Alzheimer's disease and resembles that seen in Alzheimer's disease patients with certain presenilin-1 mutations or amyloid precursor protein gene duplication showing predominantly striatal increase in [(11)C]PIB uptake.

Clinical Criteria for the Diagnosis of Alzheimer Disease: Still Good After All These Years

To examine the impact of newer neuropathological techniques on the power of National Institute of Neurological and Communicative Disorders and Stroke-AD and Related Disorders Association criteria for Alzheimer disease (AD) to detect AD at later postmortem study. We examined clinical and postmortem diagnoses of persons evaluated postmortem with thioflavin-S staining for plaques and tangles and immunohistochemical staining techniques for alpha synuclein, uhiquitin, and tau protein. Alzheimer Disease Center. Clinically evaluated persons for whom tissue diagnosis was available. Of 313 evaluees, 166 met criteria for probable AD. An additional 59 subjects had clinical diagnoses that included AD, e.g., possible AD, Lewy body variant of AD, AD and Parkinsonism, and mixed AD and vascular dementia. Of the 166 probable AD cases, 147 of 166 (88.6%) met pathologic criteria for AD. When all five AD groups were combined, 194 of 225 subjects (86.2%) met pathologic criteria for AD. There were five cases diagnosed pathologically as tangle-only dementia, which was considered a variant of AD. A pathologic diagnosis of Lewy body variant of AD was made in 56 (17.9%) of cases, including 44 of 313 (14.1%) cases diagnosed as probable or possible AD. Pure dementia with Lewy bodies was seen in 13 (4.2%). There were 9 (2.9%) cases of mixed AD and vascular dementia, and 37 (11.4%) cases of frontotemporal dementia. McKhann et al. criteria for probable and possible AD are valid for AD but do not exclude additional Lewy body pathology.

Enhanced Accumulation of Phosphorylated α-Synuclein and Elevated β-Amyloid 42/40 Ratio Caused by Expression of the Presenilin-1 ΔT440 Mutant Associated with Familial Lewy Body Disease and Variant Alzheimer's Disease

Mutations in the PSEN1 gene encoding presenilin 1 (PS1) are linked to a vast majority of pedigrees with early-onset, autosomal dominant forms of familial Alzheimer's disease (FAD). Lewy body (LB) pathology is frequently found in the brains of FAD patients harboring PSEN1 mutations. We recently reported on a novel PS1 mutation with the deletion of threonine at codon 440 (deltaT440) in a familial case diagnosed as having the neocortical type of dementia with LBs (DLB) and variant AD. In this report, we investigated the possible involvement of PS1 deltaT440 mutation in aberrant alpha-synuclein accumulation. We established cell lines that stably express either wild-type (WT) PS1 or the FAD-linked PS1 H163R, E280A, deltaE9, and PS1 deltaT440 mutants and now demonstrate that the expression of the PS1 deltaT440 mutant led to a marked elevation in the ratio of beta-amyloid (Abeta) 42/40 peptides in a conditioned medium. More importantly, we report here that the levels of phosphorylated alpha-synuclein increase in neuronal and non-neuronal cells expressing the PS1 deltaT440 mutant compared with cells that express WT PS1 or the PS1 H163R and E280A variants that are not associated with LB pathology. This finding is consistent with our demonstration of elevated levels of phosphorylated alpha-synuclein in the detergent-resistant fraction prepared from a patient's brain with PS1 deltaT440 mutation. These observations raise the intriguing suggestion that the mechanism(s) by which the PS1 deltaT440 mutant causes DLB and variant AD are by enhancing the phosphorylation of alpha-synuclein and the ratio of Abeta(42/40) peptides, respectively, in the brain.

Amyloid Peptide Toxicity in an Animal Model of Alzheimer Disease

Amyloid Peptide Toxicity in an Animal Model of Alzheimer Disease

Single molecule profiling of tau gene expression in Alzheimer’s disease

Tau is a microtubule-associated protein that is important for establishing and maintaining neuronal morphology. In addition to its role in normal cells, tau protein is involved in many neurodegenerative diseases, e.g. Alzheimer's disease (AD) and frontotemporal dementia, as the main component of intraneuronal aggregates. Alternative splicing of tau gene in the brain can give rise to at least six protein variants. A causative role of skewed tau exon 10 inclusion has been defined in frontotemporal dementia; however, no link was established between the aberrant splicing of tau and AD. Here, we applied a single-molecule-based technology, polymerase colony or polony, to simultaneously monitor tau splicing variant and haplotype profile in sporadic AD and normal brains. We found that the coordinated expression of tau exons 2 and 10 is altered in AD. Additional investigations of cis and trans mechanisms of this observation revealed a decreased protein expression of a known tau splicing factor, htra2-beta-1 in AD, thereby implicating a trans mechanism. Our results demonstrate that dysregulation of combinatorial splicing might serve as a signature for aging-related diseases, and the polony assay could be widely adapted for the study of other tauopathies. Furthermore, splicing-based therapeutics is an emerging area of drug development, and a well-defined and quantitative assay for monitoring single-gene transcriptome will be relevant for such development.

Neuropathology, biochemistry, and biophysics of α‐synuclein aggregation

Aggregation of alpha-synuclein, an abundant and conserved pre-synaptic brain protein, is implicated as a critical factor in several neurodegenerative diseases. These diseases, known as synucleinopathies, include Parkinson's disease, dementia with Lewy bodies (LBs), diffuse LB disease, the LB variant of Alzheimer's disease, multiple system atrophy, and neurodegeneration with brain iron accumulation type I. Although the precise nature of in vivoalpha-synuclein function remains elusive, considerable knowledge has been accumulated about its structural properties and conformational behavior. alpha-Synuclein is a typical natively unfolded protein. It is characterized by the lack of rigid, well-defined, 3-D structure and possesses remarkable conformational plasticity. The structure of this protein depends dramatically on its environment and it accommodates a number of unrelated conformations. This paper provides an overview of the biochemistry, biophysics, and neuropathology of alpha-synuclein aggregation.

Neurophysiologic analyses of low- and high-level visual processing in Alzheimer disease

We developed visual motion evoked potential (EP) measures related to navigational impairment in Alzheimer disease (AD) and have now applied these methods to explore the role of elementary perceptual and attentional mechanisms mediating these effects. Older adult (OA) control subjects and AD patients underwent visual motion perceptual testing, attentional performance monitoring, and basic neuropsychological and visual assessments. We recorded stationary pattern onset and visual motion onset EPs as well as behavioral event-related potentials during centered visual fixation. Psychophysical assessment demonstrated visual motion perceptual impairments in patients with AD, half of whom also showed low sensitivity in the attentional task. The low sensitivity AD patients had small pattern onset and absent motion onset EPs, whereas the high sensitivity AD patients had large pattern onset EPs and normal motion onset EPs. We conclude that visual evoked potentials (EPs) are abnormal in all patients with Alzheimer disease (AD): Those with small pattern and motion onset EPs may have greater AD pathology in visual cortex, whereas those with larger pattern onset EPs may have greater AD pathology in higher centers. These findings highlight the utility of visual EPs in distinguishing between syndromic variants of AD associated with particular patterns of functional decline.

The Association Between Genetic Variants in SORL1 and Alzheimer Disease in an Urban, Multiethnic, Community-Based Cohort

To investigate the association between Alzheimer disease (AD) and variant alleles in SORL1 using a series of single nucleotide polymorphisms (SNPs) in an urban, multiethnic, community-based population. We used a nested case-control analysis in a population-based, prospective study of aging and dementia in Medicare recipients, 65 years and older. Northern Manhattan, NY. There were 296 patients with probable AD and 428 healthy, elderly controls. The participants were African American (34%), Caribbean Hispanic (51%), or non-Hispanic white (15%). We genotyped all 29 SNPs in SORL1 that were examined in the earlier report. We assessed allelic association with AD using standard case-control methods, which included apolipoprotein E genotype as a covariate. Several individual SNPs and SNP haplotypes were significantly associated with AD in this prospectively collected community-based cohort, confirming the previously reported positive association of SORL1 with AD. Single nucleotide polymorphism 12, near the 5' region, was associated with AD in African American and Hispanic individuals. Two SNPs in the 3' region were also associated with AD in African American (SNP 26) and non-Hispanic white (SNP 20) individuals. A single haplotype in the 3' region was associated with AD in Hispanic individuals. However, several different haplotypes were associated with AD in African American and white individuals, including the TTC haplotypes at SNPs 23 through 25 (P = .035), which was significantly associated with AD in the North European white individuals in our previous report. This study confirms the association between genetic variants in SORL1 and AD. While the associations observed in these data sets overlap with those previously reported, the finding of novel SNP and haplotype associations suggests that there may be extensive allelic heterogeneity in SORL1. Broad regions of the SORL1 gene will therefore need to be scrutinized for functional pathogenic variants.