Educational attainment and ability in young adults following acquired brain injury.

PURPOSE: To compare the educational levels of clients with brain injury, acquired during working age who received neurorehabilitation between 2002 and 2013 with two governmental reports examining educational levels of attainment in the general public. METHODS: Results from national skills numeracy and literacy assessments undertaken by clients with acquired brain injury (ABI) on admission to the centre between 2002 and 2013 were compared with the results from two national reports examining educational attainment in people in further education with and without long term disabilities, as part of an ongoing review/audit of the service. RESULTS: ABI resulted in lower levels of literacy and numeracy compared to the general public; women with ABI performed more poorly on the numeracy assessment compared to the literacy assessment; and clients with ABI had a disproportionately reduced level of literacy, resulting in a more even pattern of attainment on the numeracy and literacy assessments whereas the general public scored more highly on the literacy assessment. CONCLUSION: ABI adversely affects both literacy and numeracy skills. It is important that the effect of ABI on numeracy and literacy is considered during vocational counselling and rehabilitation as a person's premorbid education level may be an overestimation of their abilities.

Long term efficacy of an integrated neurological and vocational rehabilitation programme for young adults with acquired brain injury.

PURPOSE: To characterise and determine the pre-injury, injury and post-injury factors associated with vocational outcome 1-9 years post-discharge from a mixed therapy/educational/vocational rehabilitation (VR) residential programme. METHODS: 119 clients of working age when they acquired their brain injury and who had attended the centre between 2002 and 2011 were followed up at least 1 year post-discharge to determine their vocational outcome as part of an ongoing review/audit of the service. All clients had had a severe/very severe brain injury. Clients were classified as having a positive vocational outcome (working-paid/voluntary, full/part-time or undertaking full or part-time vocationally related education) or negative vocational outcome (undertaking neither work nor education). RESULTS: Over half of the clients attained a positive vocational outcome. Length of time since discharge did not differ between those clients with a positive or negative vocational outcome. Vocational outcome was predicted by cognitive and motor ability at discharge, and gender. Together these variables correctly classified the vocational outcome of 76 % of the clients. CONCLUSION: Clients with severe/very severe brain injury can attain a positive vocational outcome following intensive neurorehabilitation consisting of traditional therapies in addition to educational and VR.

Dementia in Down's syndrome: an MRI comparison with Alzheimer's disease in the general population.

BACKGROUND: Down's syndrome (DS) is the most common genetic cause of intellectual disability. People with DS are at an increased risk of Alzheimer's disease (AD) compared to the general population. Neuroimaging studies of AD have focused on medial temporal structures; however, to our knowledge, no in vivo case-control study exists comparing the anatomy of dementia in DS to people with AD in the general population. We therefore compared the in vivo brain anatomy of people with DS and dementia (DS+) to those with AD in the general population. METHOD: Using MRI in 192 adults, we compared the volume of whole brain matter, lateral ventricles, temporal lobes and hippocampus in DS subjects with and without dementia (DS+, DS-), to each other and to three non-DS groups. These included one group of individuals with AD and two groups of controls (each age-matched for their respective DS and general population AD cohorts). RESULTS: AD and DS+ subjects showed significant reductions in the volume of the whole brain, hippocampus and temporal lobes and a significant elevation in the volume of the lateral ventricle, compared to their non-demented counterparts. People with DS+ had a smaller reduction in temporal lobe volume compared to individuals with AD. CONCLUSIONS: DS+ and AD subjects have a significant reduction in volume of the same brain regions. We found preliminary evidence that DS individuals may be more sensitive to tissue loss than others and have less 'cognitive reserve'.

Increase in functional abilities following a residential educational and neurorehabilitation programme in young adults with acquired brain injury.

OBJECTIVES: To characterize and determine the pre-injury and injury-related variables that are linked to the extent of functional recovery following rehabilitation at a mixed therapy and educational residential programme and whether these variables differ for traumatic brain injury (TBI) and non traumatic brain injury (nonTBI). METHODS: 106 young adults (age 16-36 years) with moderate-to-severe TBI who had attended and been discharged from the centre since 2002 were included. Clients received 5 hours of education and/or therapy each day. Functional level was assessed using the FIM + FAM. Regression analysis was used to determine possible predictors of functional independence at discharge. MAIN OUTCOMES AND RESULTS: Clients with TBI and nonTBI made clinically and statistically significant improvements in their functional abilities during their neurorehabilitation. For the combined TBI and nonTBI group, FIM + FAM scores at discharge were predicted by FIM + FAM at admission and length of stay. These two predictors explained 80% of the variance in the FIM + FAM score at discharge. CONCLUSION: Both clients with TBI and nonTBI benefited from a mixed inpatient neurorehabilitation programme. This benefit was predicted by their functional abilities at admission and the length of stay. These findings are of importance as it becomes increasingly necessary to demonstrate who will benefit from residential intensive neurorehabilitation as opposed to community therapy.

Magnetic resonance imaging and magnetic resonance spectroscopy for detection of early Alzheimer's disease.

Alzheimer's disease is the most common form of neurodegenerative disorder and early detection is of great importance if new therapies are to be effectively administered. We have investigated whether the discrimination between early Alzheimer's disease (AD) and elderly healthy control subjects can be improved by adding magnetic resonance spectroscopy (MRS) measures to magnetic resonance imaging (MRI) measures. In this study 30 AD patients and 36 control subjects were included. High resolution T1-weighted axial magnetic resonance images were obtained from each subject. Automated regional volume segmentation and cortical thickness measures were determined for the images. 1H MRS was acquired from the hippocampus and LCModel was used for metabolic quantification. Altogether, this yielded 58 different volumetric, cortical thickness and metabolite ratio variables which were used for multivariate analysis to distinguish between subjects with AD and Healthy controls. Combining MRI and MRS measures resulted in a sensitivity of 97% and a specificity of 94% compared to using MRI or MRS measures alone (sensitivity: 87%, 76%, specificity: 86%, 83% respectively). Adding the MRS measures to the MRI measures more than doubled the positive likelihood ratio from 6 to 17. Adding MRS measures to a multivariate analysis of MRI measures resulted in significantly better classification than using MRI measures alone. The method shows strong potential for discriminating between Alzheimer's disease and controls.

Down syndrome with and without dementia: an in vivo proton Magnetic Resonance Spectroscopy study with implications for Alzheimer's disease.

It is poorly understood why people with Down syndrome (DS) are at extremely high-risk of developing Alzheimer's disease (AD) compared to the general population. One explanation may be related to their extra copy of risk factors modulated by chromosome 21. Myo-inositol (mI), whose transporter gene is located on chromosome 21, has been associated with dementia in the non-DS population; however, nobody has contrasted brain mI in DS with (DS+) and without (DS-) dementia to other non-DS groups. Our primary aim was to compare the hippocampal concentration of mI ([mI]) and other brain metabolites such as N-acetylaspartate (NAA; a proxy measure of neuronal density and mitochondrial function) in DS+, DS-, and age-matched healthy controls using proton Magnetic Resonance Spectroscopy (((1))H-MRS). We compared hippocampal [mI] and other metabolites in 35 individuals with genetically-confirmed DS [DS+ (n=17, age=53±6) and DS- (n=18, age=47±8)] to age-matched healthy controls (n=13, age=51±10) adjusting for proportion of the MRS voxel occupied by cerebrospinal spinal fluid, and gray/white matter. DS+ had a significantly higher [mI] than both DS- and healthy controls. In contrast neither DS+ nor DS- differed significantly from controls in [NAA] (although NAA in DS+ was significantly lower than DS-). Our secondary aim of comparing brain metabolites in DS+ and DS- to Alzheimer's disease (AD; n=39; age=77±5) revealed that the DS+ group had significantly elevated [mI] compared to AD or DS-. [mI] may modify risk for dementia in this vulnerable population.

Hippocampal proton MR spectroscopy in early Alzheimer's disease and mild cognitive impairment.

Proton magnetic resonance spectroscopy ((1)H-MRS) studies have previously reported reduced brain N-acetyl aspartate (NAA) and increased myo-inositol (mI) in people with established Alzheimer's disease (AD). The earliest structure affected by AD is the hippocampus but relatively few studies have examined its neuronal integrity by MRS in AD and fewer still in people with amnestic mild cognitive impairment (MCI). We measured the hippocampal concentration of NAA, mI, choline (Cho) and creatine + phosphocreatine (Cr + PCr) in 39 patients with AD, 21 subjects with MCI and 38 age matched healthy elderly controls. Patients with AD had a significantly lower hippocampal [NAA] than controls, with subjects with MCI intermediate between the other two groups. [NAA] was positively correlated with memory in the impaired groups. Using mean hippocampal [NAA] and [Cr + PCr] we correctly classified 72% of people with AD, and 75% of controls. Reductions in [NAA] can be detected in the hippocampi of subjects with MCI and hippocampal [NAA] and [Cr + PCr] can distinguish between mild AD and normal elderly controls.

Maturation of limbic regions in Asperger syndrome: a preliminary study using proton magnetic resonance spectroscopy and structural magnetic resonance imaging.

People with autistic spectrum disorders (ASD, including Asperger syndrome) may have developmental abnormalities in the amygdala-hippocampal complex (AHC). However, in vivo, age-related comparisons of both volume and neuronal integrity of the AHC have not yet been carried out in people with Asperger syndrome (AS) versus controls. We compared structure and metabolic activity of the right AHC of 22 individuals with AS and 22 healthy controls aged 10-50 years and examined the effects of age between groups. We used structural magnetic resonance imaging (sMRI) to measure the volume of the AHC, and magnetic resonance spectroscopy ((1)H-MRS) to measure concentrations of N-acetyl aspartate (NAA), creatine+phosphocreatine (Cr+PCr), myo-inositol (mI) and choline (Cho). The bulk volume of the amygdala and the hippocampus did not differ significantly between groups, but there was a significant difference in the effect of age on the hippocampus in controls. Compared with controls, young (but not older) people with AS had a significantly higher AHC concentration of NAA and a significantly higher NAA/Cr ratio. People with AS, but not controls, had a significant age-related reduction in NAA and the NAA/Cr ratio. Also, in people with AS, but not controls, there was a significant relationship between concentrations of choline and age so that choline concentrations reduced with age. We therefore suggest that people with AS have significant differences in neuronal and lipid membrane integrity and maturation of the AHC.

Combining MRI and MRS to distinguish between Alzheimer's disease and healthy controls.

Alzheimer's disease (AD) is the most common neurodegenerative disorder among the elderly, and early detection is of great importance if new therapies are to be effectively administered. We have used multivariate data analysis (orthogonal partial least squares to latent structures (OPLS) analysis) to investigate whether the discrimination between AD and elderly healthy control subjects can be improved by adding magnetic resonance spectroscopy (MRS) measures to magnetic resonance imaging (MRI). In this study, 30 AD patients and 36 control subjects were included (mean (SD) age=77(5) and 77(5) years, MMSE=23(4) and 29(1) respectively). High resolution T1-weighted axial magnetic resonance images were obtained from each subject. Automated regional volume segmentation and cortical thickness measures were determined for the images. 1H MRS was acquired from the hippocampus and LCModel was used for metabolite quantification. Altogether, this yielded 54 different volumetric, cortical thickness and metabolite ratio variables which were used for multivariate analysis. All analyses were performed using seven-fold-cross-validation. Combining MRI and MRS measures resulted in a sensitivity of 97% and a specificity of 94% compared to using MRI or MRS measures alone (sensitivity: 93%, 76%, specificity: 86%, 83% respectively). Adding the MRS measures to the MRI measures more than doubled the positive likelihood ratio from 7 to 17. Adding MRS measures to a multivariate analysis of MRI measures resulted in significantly better classification than using MRI measures alone. The OPLS method shows strong potential for discriminating between Alzheimer's disease and controls.

Association of plasma clusterin concentration with severity, pathology, and progression in Alzheimer disease.

CONTEXT: Blood-based analytes may be indicators of pathological processes in Alzheimer disease (AD). OBJECTIVE: To identify plasma proteins associated with AD pathology using a combined proteomic and neuroimaging approach. DESIGN: Discovery-phase proteomics to identify plasma proteins associated with correlates of AD pathology. Confirmation and validation using immunodetection in a replication set and an animal model. SETTING: A multicenter European study (AddNeuroMed) and the Baltimore Longitudinal Study of Aging. PARTICIPANTS: Patients with AD, subjects with mild cognitive impairment, and healthy controls with standardized clinical assessments and structural neuroimaging. MAIN OUTCOME MEASURES: Association of plasma proteins with brain atrophy, disease severity, and rate of clinical progression. Extension studies in humans and transgenic mice tested the association between plasma proteins and brain amyloid. RESULTS: Clusterin/apolipoprotein J was associated with atrophy of the entorhinal cortex, baseline disease severity, and rapid clinical progression in AD. Increased plasma concentration of clusterin was predictive of greater fibrillar amyloid-beta burden in the medial temporal lobe. Subjects with AD had increased clusterin messenger RNA in blood, but there was no effect of single-nucleotide polymorphisms in the gene encoding clusterin with gene or protein expression. APP/PS1 transgenic mice showed increased plasma clusterin, age-dependent increase in brain clusterin, as well as amyloid and clusterin colocalization in plaques. CONCLUSIONS: These results demonstrate an important role of clusterin in the pathogenesis of AD and suggest that alterations in amyloid chaperone proteins may be a biologically relevant peripheral signature of AD.

Are abnormal premorbid personality traits associated with Alzheimer's disease? - A case-control study.

OBJECTIVE: To examine the association between premorbid personality traits, social networks and AD, using a case-control design, and two informant-based retrospective assessments of premorbid personality. METHODS: Cases consisted of 217 Subjects diagnosed with probable late onset Alzheimer's disease (160 females and 57 males). Recruitment was from both community and nursing home settings. Controls consisted of 76 unaffected siblings (44 females and 32 males) of patients with AD. Both cases and controls received informant ratings of premorbid personality. RESULTS: A selection of abnormal personality traits were over represented in the AD group. AD was particularly associated with Cluster A personality disorder traits (Paranoid, Schizoid, Schizotypal). AD cases had correspondingly sparser social networks. CONCLUSIONS: There is an association between abnormal personality traits and AD. Individuals with AD also appear to have had lower levels of social interactivity.

Education, occupation and retirement age effects on the age of onset of Alzheimer's disease.

OBJECTIVE: To determine the effects of early life education, mid life employment and later life retirement age on the age of onset (AOO) of Alzheimer's disease (AD). METHODS: Multiple regression analyses were carried out using data for 1320 probable AD cases, of which 382 were males with employment and retirement age data, using informant based information on education and employment. RESULTS: No relation was found between years of education, best qualification obtained, or employment variables in males and the AOO of AD. A significant effect of later retirement age in delaying the AOO of AD was seen in males. CONCLUSIONS: In this study no effect of education or employment was seen, although this may be due to limited variance in the study population. The significant effect of retirement age may have several explanations, the most interesting of which would be the suggestion that active employment later in life allows an individual to prolong their cognitive assets above the threshold for dementia.

Proteome-based identification of plasma proteins associated with hippocampal metabolism in early Alzheimer's disease.

BACKGROUND AND METHODS: There is an urgent need for peripheral surrogates of Alzheimer's disease (AD) that accurately reflect disease state and severity as well as correlate with key features of its neuropathology. The aim of this study was to identify plasma proteins associated with known in vivo markers of disease activity. In an earlier proteomic study of plasma, we discovered a panel of 15 proteins that were differentially expressed in AD and further validated complement factor-H (CFH) and alpha-2-macroglobulin (A2M) as AD-specific plasma biomarkers. In the present study, we extended these findings by testing the associations of these plasma proteins with neuro-imaging measures of disease progression in AD. We combined (1)H-magnetic resonance spectroscopy of the hippocampus and MRI-based hippocampal volumetry with proteomic analysis of plasma in early AD and mild cognitive impairment (MCI) to achieve this goal. Using (1)H-magnetic resonance spectroscopy, we derived estimates of the hippocampal metabolite ratio N-acetylaspartate/myo-inositol (NAA/mI), a biochemical measure that is associated with cognitive decline in early AD. We also undertook a proteomic analysis of plasma in these individuals using two-dimensional gel electrophoresis (2DGE). RESULTS: We observed that two plasma proteins previously shown to be differentially expressed in AD, complement factor-H (CFH) and alpha-2-macroglobulin (A2M) showed significant positive correlations with hippocampal NAA/mI ratio in AD. CONCLUSIONS: The association of plasma CFH and A2M with hippocampal NAA/mI in this cohort of AD subjects suggests that these proteins may reflect disease progression in early AD. These findings warrant validation in large population-based datasets.

Diagnosing Alzheimer's disease--non-clinicians and computerised algorithms together are as accurate as the best clinical practice.

BACKGROUND: An accurate diagnosis of Alzheimer's disease and an exclusion of other dementias is important in many clinical studies. Obtaining such a clinical diagnosis in epidemiological studies and clinical trials that recruit large numbers of patients is time consuming. OBJECTIVES: To construct an algorithm using a limited number of data points to generate a diagnosis of the commonest forms of dementia using information collected by non clinicians. METHODS: We constructed a computer algorithm to generate a diagnosis of Alzheimer's disease (AD), Dementia with Lewy Bodies (DLB), frontotemporal dementia (FTD), vascular dementia or to flag the case as needing a clinical review based on a limited number of data points taken from a largely structured interview using widely used scales. The diagnosis generated in life by the algorithm in a prospective, longitudinal study was compared to definitive diagnosis at post mortem. RESULTS: Post mortem diagnosis was available for 43 cases. The positive predictive value of the algorithm was greater than 95%. AD was diagnosed by the algorithm and at post mortem in 36 of the cases. Two cases with FTD were wrongly diagnosed as having AD by the algorithm, five cases were flagged as needing a clinical review due to concomitant medical conditions of whom four had AD and one, who had been diagnosed clinically as having AD, was diagnosed on post mortem with corticobasal degeneration. CONCLUSIONS: A combination of non-clinical researchers, a structured interview and a computerised algorithm is as effective at identifying AD as highly trained and skilled clinicians.

Premorbid personality and behavioral and psychological symptoms in probable Alzheimer disease.

OBJECTIVES: Previous research investigating the influence of premorbid personality on behavioral and psychological symptoms in dementia (BPSD) has produced mixed findings. Addressing some limitations of previous studies, the authors aimed to investigate whether some of the common individual symptoms of BPSD (depression, anxiety, irritability, and aggression) were associated with key aspects of previous personality (neuroticism and agreeableness); and also to perform an exploratory investigation into the broader influence of personality factors on behavioral and psychological syndromes. METHODS: Two hundred eight patients with a diagnosis of probable Alzheimer disease were assessed for the presence of BPSD over the disease course using the caregiver-rated Neuropsychiatric Inventory (NPI). One or two knowledgeable informants rated patients' midlife personalities using a retrospective version of the NEO-FFI questionnaire. RESULTS: Premorbid neuroticism was correlated with anxiety and total NPI score, although not with depression. Premorbid agreeableness was negatively correlated with agitation and irritability. Principal components analysis of the 10 NPI behavioral domains identified three syndromes: "agitation/apathy," "psychosis," and "affect." In stepwise linear regression analyses, including personality domains from the Five-Factor Model and a range of potential confounders as independent variables; the only significant personality predictor of a behavioral syndrome was "agitation/apathy," predicted by lower premorbid agreeableness. CONCLUSION: Lower premorbid agreeableness is associated with agitation and irritability symptoms in Alzheimer disease and also predicts an "agitation/apathy" syndrome. The relationship between premorbid neuroticism and BPSD is less straightforward, and premorbid neuroticism does not appear to be associated with depression in Alzheimer disease or predict an "affect" syndrome.

Four components describe behavioral symptoms in 1,120 individuals with late-onset Alzheimer's disease.

OBJECTIVES: To investigate behavioral components of Alzheimer's disease (AD) and to analyze behavioral components in relation to disease severity, apolipoprotein E genotype (APOE), sex, years of education, age at onset, and cognitive impairment. DESIGN: Cross-sectional study. SETTING: Data were collected from community-dwelling individuals and those residing in nursing homes. PARTICIPANTS: A total of 1,120 individuals meeting National Institute of Neurological and Communicative Disorders and Stroke/Alzheimer's Disease and Related Disorders Association criteria for late-onset probable AD. MEASUREMENTS: Behavioral symptoms were assessed using the Neuropsychiatric Inventory. First-order polychoric correlations, controlling for disease severity, between the 12 symptom domain scores were estimated, and the resulting matrix underwent principal components analysis. RESULTS: Four interpretable components were identified: behavioral dyscontrol (euphoria, disinhibition, aberrant motor behavior, and sleep and appetite disturbances), psychosis (delusions and hallucinations), mood (depression, anxiety, and apathy), and agitation (aggression and irritability). Scores on the four components were associated with severity of cognitive impairment. Higher behavioral dysfunction, agitation, and mood component scores were associated with lower age at onset. Behavioral dysfunction and mood component scores were associated with sex. None of the components were associated with age at assessment, years of education, or number of APOE epsilon4 alleles. CONCLUSION: Four behavioral components were identified that were comparable with those observed previously. Future analysis of these components will strengthen understanding of the underlying pathology of behavioral symptoms and AD.

The NEO-FFI is a reliable measure of premorbid personality in patients with probable Alzheimer's disease.

AIM: To assess the inter-informant reliability, intra-informant reliability and internal consistency of the NEO-FFI as a measure of premorbid personality in patients with Alzheimer's Disease (AD). SUBJECTS: One hundred and five persons with NINCDS-ADRDA probable AD for the assessment of inter-informant reliability and internal consistency, and 30 for the assessment of intra-informant reliability. METHODS: Premorbid personality was rated retrospectively by close relatives remembering the patient as he/she had been when aged in his/her forties. One hundred and five AD patients were rated by two separate informants. Thirty AD patients were rated by the same informant on separate occasions one year apart. RESULTS: Inter-informant reliability for the five domain scores of the NEO-FFI was shown to range from fair to good when measured using the single measure Intraclass Correlation Co-efficient (ICC) (0.52-0.64), and to range from good to excellent when measured using the average ICC (0.68-0.78). Intra-informant reliability for four out of the five domains was shown to be excellent when measured using the single ICC (0.81-0.92), and good for the remaining domain (0.72). Intra-informant reliability was found to be excellent for all five domains when measured using the average ICC (0.84-0.96). Internal consistency of the five domains was good. CONCLUSIONS: The NEO-FFI can be used reliably to measure premorbid personality in patients with probable AD. It may be useful to maximise reliability by using a mean domain score based on questionnaires completed by two or more informants who knew the patient well earlier in life.

Polymorphisms in the phosphate and tensin homolog gene are not associated with late-onset Alzheimer's disease.

The varepsilon4 allele of the APOE locus is the only confirmed risk factor for late-onset Alzheimer's disease (LOAD). The phosphate and tensin homolog (PTEN) gene is both a biological and positional candidate gene for LOAD. Eight polymorphisms spanning this gene were selected from dbSNP and genotyped in pooled DNA samples of both cases and controls. No evidence for association with LOAD was obtained in this study although further investigation revealed low levels of linkage disequlibrium (LD) between the genotyped SNPs. Our results suggest that it is unlikely that genetic variation within the PTEN gene contributes to risk of LOAD.

A scan of chromosome 10 identifies a novel locus showing strong association with late-onset Alzheimer disease.

Strong evidence of linkage to late-onset Alzheimer disease (LOAD) has been observed on chromosome 10, which implicates a wide region and at least one disease-susceptibility locus. Although significant associations with several biological candidate genes on chromosome 10 have been reported, these findings have not been consistently replicated, and they remain controversial. We performed a chromosome 10-specific association study with 1,412 gene-based single-nucleotide polymorphisms (SNPs), to identify susceptibility genes for developing LOAD. The scan included SNPs in 677 of 1,270 known or predicted genes; each gene contained one or more markers, about half (48%) of which represented putative functional mutations. In general, the initial testing was performed in a white case-control sample from the St. Louis area, with 419 LOAD cases and 377 age-matched controls. Markers that showed significant association in the exploratory analysis were followed up in several other white case-control sample sets to confirm the initial association. Of the 1,397 markers tested in the exploratory sample, 69 reached significance (P < .05). Five of these markers replicated at P < .05 in the validation sample sets. One marker, rs498055, located in a gene homologous to RPS3A (LOC439999), was significantly associated with Alzheimer disease in four of six case-control series, with an allelic P value of .0001 for a meta-analysis of all six samples. One of the case-control samples with significant association to rs498055 was derived from the linkage sample (P = .0165). These results indicate that variants in the RPS3A homologue are associated with LOAD and implicate this gene, adjacent genes, or other functional variants (e.g., noncoding RNAs) in the pathogenesis of this disorder.

Genetic association of the APP binding protein 2 gene (APBB2) with late onset Alzheimer disease.

Alzheimer disease (AD) is a complex neurodegenerative disorder predisposed by multiple genetic factors. Mutations in amyloid beta precursor protein (APP) are known to be associated with autosomal dominant, early onset familial AD and possibly also late onset AD (LOAD). A number of genes encoding proteins capable of binding to APP have been identified, but their contribution to AD pathobiology remains unclear. Conceivably, mutations in these genes may play a role in affecting AD susceptibility, which appears to be substantiated by some genetic studies. Here we report results of the first genetic association study with APBB2, an APP binding protein (also known as FE65L), and LOAD, in three independently collected case-control series totaling approximately 2,000 samples. Two SNPs were significantly associated with LOAD in two sample series and in meta-analyses of all three sample sets (for rs13133980: odds ratio [OR](hom)=1.36 [95% CI: 1.05-1.75], OR(het)=1.32 [95% CI: 1.04-1.67], minor allele frequency=43%, P=0.041; and for hCV1558625: OR(hom)=1.37 [95% CI: 1.06-1.77], OR(het)=1.02 [95% CI: 0.82-1.26], minor allele frequency=48%, P=0.026). One of these SNPs, located in a region conserved between the human and mouse genome, showed a significant interaction with age of disease onset. For this marker, the association with LOAD was most pronounced in subjects with disease onset before 75 years of age (OR(hom)=2.43 [95% CI: 1.61-3.67]; OR(het)=2.15 [95% CI: 1.46-3.17]; P=0.00006) in the combined sample set. Our data raise the possibility that genetic variations in APBB2 may affect LOAD susceptibility.