Autopsy-confirmed Alzheimer's Disease Cases Research Articles

Prevalence, risk factors, and impact of anxiety in early Alzheimer disease: a retrospective study of an autopsy-confirmed cohort.

Anxiety is a neuropsychiatric symptom (NPS) of Alzheimer disease (AD) patients which has been studied primarily in prospective and retrospective studies of clinically diagnosed AD. However, this can be confounded by other primary etiologies. Moreover, anxiety has not been comprehensively studied in autopsy-confirmed AD cases across subjective cognitive decline (SCD), mild cognitive impairment (MCI), and dementia stages. We conducted a retrospective longitudinal analysis of 212 participants with autopsy-confirmed AD, followed from 1986-2013 at the NYU Alzheimer's Disease Research Center with staging via the Global Deterioration Scale and NPS assessed via BEHAVE-AD. We found that anxiety varied uniquely with stage and was the most common NPS in SCD and MCI (35-40% prevalence). ApoE4 carriage associated with a higher rate of anxiety only at mild dementia. Anxiety in SCD associated with cerebral amyloid angiopathy and arteriosclerosis on brain autopsy, but there were no such associations with concomitant neuropathology at MCI and mild dementia. Anxiety associated with increased progression rate (∼2.5-fold) from SCD to MCI/dementia stages, but not from MCI to dementia. These results suggest an important relationship between anxiety and AD, especially at the preclinical stage. This warrants further study of anxiety as a possible modifiable factor of disease experience and course.

The SERPINA5 coding variant E228Q does not contribute to clinicopathologic characteristics in Alzheimer's disease: A cross-sectional study.

We previously demonstrated that increased expression of the SERPINA5 gene is associated with hippocampal vulnerability in Alzheimer's disease (AD) brains. SERPINA5 was further demonstrated to be a novel tau-binding partner that colocalizes within neurofibrillary tangles. Our goal was to determine whether genetic variants in the SERPINA5 gene contributed to clinicopathologic phenotypes in AD. To screen for SERPINA5 variants, we sequenced 103 autopsy-confirmed young-onset AD cases with a positive family history of cognitive decline. To further assess the frequency of a rare missense variant, SERPINA5 p.E228Q, we screened an additional 1114 neuropathologically diagnosed AD cases. To provide neuropathologic context in AD, we immunohistochemically evaluated SERPINA5 and tau in a SERPINA5 p.E228Q variant carrier and a matched noncarrier. In the initial SERPINA5 screen, we observed 1 individual with a rare missense variant (rs140138746) that resulted in an amino acid change (p.E228Q). In our AD validation cohort, we identified an additional 5 carriers of this variant, resulting in an allelic frequency of 0.0021. There was no significant difference between SERPINA5 p.E228Q carriers and noncarriers in terms of demographic or clinicopathologic characteristics. Although not significant, on average SERPINA5 p.E228Q carriers were 5 years younger at age of disease onset than noncarriers (median: 66 [60-73] vs 71 [63-77] years, P = .351). In addition, SERPINA5 p.E228Q carriers exhibited a longer disease duration than noncarriers that approached significance (median: 12 [10-15]) vs 9 [6-12] years, P = .079). More severe neuronal loss was observed in the locus coeruleus, hippocampus, and amygdala of the SERPINA5 p.E228Q carrier compared to noncarrier, although no significant difference in SERPINA5-immunopositive lesions was observed. Throughout the AD brain in either carrier or noncarrier, areas with early pretangle pathology or burnt-out ghost tangle accumulation did not reveal SERPINA5-immunopositive neurons. Mature tangles and newly formed ghost tangles appeared to correspond well with SERPINA5-immunopositive tangle-bearing neurons. SERPINA5 gene expression was previously associated with disease phenotype; however, our findings suggest that SERPINA5 genetic variants may not be a contributing factor to clinicopathologic differences in AD. SERPINA5-immunopositive neurons appear to undergo a pathologic process that corresponded with specific levels of tangle maturity.

Cell type-specific gene expression changes in Alzheimer's patients with varying levels of cerebral amyloid angiopathy.

Tau neurofibrillary tangles and senile plaques comprised of insoluble amyloid beta are the major histopathological hallmarks of Alzheimer's disease (AD). More than 85% of autopsy-confirmed AD cases also exhibit some degree of cerebral amyloid angiopathy (CAA), which is characterized by amyloid beta peptide deposits predominantly in blood vessels in the meningeal and intracerebral blood vessels. Consequently, CAA predisposes individuals with AD to cerebral infarction and hemorrhages, accounting for ∼20% of cases in the elderly, which could lead to faster cognitive decline through neurovascular pathway dysfunction. We sought to identify cellular composition changes and characterize cell type-specific expression associated with CAA pathology in AD patients. Using 10x Genomics single nuclei RNA sequencing, we profiled nuclei from frozen post-mortem temporal cortex tissue of 80 individuals with neuropathologic diagnosis of AD and varying levels of CAA, ranging from zero to severe CAA pathology. Braak and Thal measures were also obtained. Downstream analyses were performed in R using Seurat v3.2.3. Quality control filtering based on percentage of genes mapped to the mitochondrial genome and number of genes and UMIs detected resulted in 135,092 nuclei for analysis. Differential gene expression analyses were performed using R package MAST. We identified 30 clusters which were annotated using established cell type marker genes. There were 3 oligodendrocyte, 14 neuronal (2 excitatory and 3 inhibitory), 5 microglial, 3 endothelial, 4 astrocyte and 1 oligodendrocyte precursor cell cluster. We observed a significant increase in microglial cell proportions with increasing CAA severity, for 3 of the microglial clusters. Conversely, the excitatory neuronal proportion were decreased in individuals with more severe CAA. Further investigation is ongoing to identify the genes underlying the dysregulation of these cell types in CAA. We observed cellular proportion changes for multiple cell types with increasing CAA severity. Additional analyses to determine the effects of CAA independent of AD severity will be performed by adjusting for Braak and Thal measures. Deeper characterization of cell type-specific expression profiles is expected to provide novel insights into cell-type specific transcriptome changes associated with vascular risk factors in AD.

Genome-wide analysis identifies novel genetic variants and unique biological pathways associated with AD-related proteins in the brain.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder neuropathologically characterized by amyloid-β (Aβ) plaques and neurofibrillary tangles. Assessment of AD-related endophenotypes can reveal novel insights into aspects of the heterogeneity of AD. We hypothesize that, amongst AD patients, the levels and solubility of AD-related proteins are influenced by genetic variants; identifying these may provide key insights into disease pathogenesis. To test this, we performed a genome-wide association study (GWAS) for the levels of five AD-related proteins (apoE, Aβ40, Aβ42, tau, and p-tau) in the brain. Genome-wide genotypes were collected from 441 autopsy-confirmed AD cases on the Infinium Omni2.5Exome-8 v1.3 genotyping array, imputed to the haplotype reference consortium (HRC) panel, and quality filtered. Temporal cortex levels of the five AD-related proteins from three fractions, i.e. buffer-soluble (TBS), detergent-soluble (Triton-X=TX), and insoluble (Formic acid=FA) were measured by ELISA. Using linear regression, genetic variants were tested for association with each biochemical measure, and the Aβ40/42 ratio. Pathway analysis was done using GSA-SNP2 to identify enriched Gene Ontology (GO) terms. We identified 9 unique GWS variants (genome-wide significant, p<2.89E-08), 2 at the APOE locus and 7 novel. Variants within the APOE locus were significantly associated with Aβ40 levels in the TX and FA fractions, the Aβ40/42 ratio in the FA fraction, and apoE levels in the TBS and FA fractions. Of the novel GWS variants, four were associated with Aβ40 residing on chromosomes 17 (TBS), 3, 4, and 15 (TX), and three with apoE levels on chromosomes 19 (TBS), 7, and 14 (TX). Pathway analysis revealed both shared and distinct pathways significantly enriched for the GWAS results. Although all biochemical measures tested reflect proteins core to AD pathology, our results strongly suggest each have unique genetic factors and enriched pathways which influence their brain levels. Furthermore, discovery of genetic factors that underlie specific biochemical outcomes may lead to the identification of novel genes that influence biochemical properties of AD proteins. These findings can enhance our understanding of the pathophysiology of proteostasis in AD and may have implications for other neurodegenerative diseases also characterized by abnormal protein accumulation in the brain.

Increased Inflammation and Unchanged Density of Synaptic Vesicle Glycoprotein 2A (SV2A) in the Postmortem Frontal Cortex of Alzheimer's Disease Patients.

Sections from the middle frontal gyrus (Brodmann area 46) of autopsy-confirmed Alzheimer’s disease (AD) patients and non-demented subjects were examined for the prevalence of hallmark AD pathology, including amyloid-β (Aβ) plaques, phosphorylated tau (pTau) tangles, neuroinflammation and synaptic loss (n = 7 subjects/group). Dense-core deposits of Aβ were present in all AD patients (7/7) and some non-demented subjects (3/7), as evidenced by 6E10 immunohistochemistry. Levels of Aβ immunoreactivity were higher in AD vs. non-AD cases. For pTau, AT8-positive neurofibrillary tangles and threads were exclusively observed in AD patient tissue. Levels of [3H]PK11195 binding to the translocator protein (TSPO), a marker of inflammatory processes, were elevated in the gray matter of AD patients compared to non-demented subjects. Levels of [3H]UCB-J binding to synaptic vesicle glycoprotein 2A (SV2A), a marker of synaptic density, were not different between groups. In AD patients, pTau immunoreactivity was positively correlated with [3H]PK11195, and negatively correlated with [3H]UCB-J binding levels. No correlation was observed between Aβ immunoreactivity and markers of neuroinflammation or synaptic density. These data demonstrate a close interplay between tau pathology, inflammation and SV2A density in AD, and provide useful information on the ability of neuroimaging biomarkers to diagnose AD dementia.

Pathologically Confirmed Alzheimer's Disease in APOE ɛ2 Homozygotes is Rare but Does Occur.

Homozygous APOEɛ4 status is a well-known risk factor in the development of Alzheimer's disease (AD). However, other genotypes of APOE have not yet been found to have equal clinical significance. There is a paucity of reports regarding clinically or pathologically described AD in APOEɛ2 homozygotes compared to the other alleles. To notify clinicians that patients with homozygous APOEɛ2 are also at risk of developing AD based on results from the largest prospectively gathered registry of brain samples to date. We queried the National Alzheimer's Coordinating Center (NACC) database for autopsy-confirmed AD cases. Of the Uniform Data Set (UDS) participants who are deceased, 5,779 were diagnosed with dementia at their last UDS visit prior to death, and autopsy data is available for 3,518. Of the brains in the NACC database with pathologically confirmed dementia, seven were found to be homozygous for APOEɛ2, which represents only 0.2% of the autopsy-confirmed sample. Furthermore, pathology-confirmed AD represents 29% (2/7) of the APOEɛ2/ɛ2 patients diagnosed with dementia. Although rare, autopsy-confirmed AD can be present in APOEɛ2/ɛ2 carriers.

Differential clinicopathologic and genetic features of late-onset amnestic dementias.

Hippocampal sclerosis of the elderly (HpScl) and Alzheimer's disease (AD), especially the limbic-predominant subtype (LP-AD), are amnestic syndromes that can be difficult to distinguish. To complicate matters, a subset has concomitant HpScl and AD (HpScl-AD). We examined a large cohort of autopsy-confirmed cases of HpScl, HpScl-AD, LP-AD, and typical AD to identify distinct clinical, genetic, and pathologic characteristics. HpScl cases were significantly older at death and had a substantially slower rate of cognitive decline than the AD subtypes. Genetic analysis revealed that the AD groups (AD, LP-AD, and HpScl-AD) were more likely to be APOE ε4 carriers. In contrast, the HpScl groups (HpScl and HpScl-AD) were more likely to exhibit genetic variants in GRN and TMEM106B that are associated with frontotemporal lobar degeneration. The HpScl groups had a high frequency of TDP-43 pathology that was most often Type A morphology and distribution, while typical AD and LP-AD had a significantly lower frequency of TDP-43 pathology that was most often Type B. These results suggest that HpScl and AD are pathologically and genetically distinct and non-synergistic neurodegenerative processes that present with amnestic dementia. Pure HpScl and HpScl with concomitant AD occur most often in elderly individuals.

Early Visuospatial Deficits Predict the Occurrence of Visual Hallucinations in Autopsy-Confirmed Dementia With Lewy Bodies

The current study explored the value of visuospatial findings for predicting the occurrence of visual hallucinations (VH) in a sample of patients with dementia with Lewy bodies (DLB) compared with patients with Alzheimer disease (AD). PARTICIPANTS/MEASUREMENTS: Retrospective analysis of 55 autopsy-confirmed DLB and 55 demographically similar, autopsy-confirmed AD cases determined whether severe initial visuospatial deficits on the WISC-R Block Design subtest predicted the development of VH. Visuospatial deficits were considered severe if Block Design z scores were 2.5 or more standard deviations below the mean of a well-characterized normal control group (severe visuospatial deficits [severe-VIS]; DLB: n = 35, AD: n = 26) and otherwise were considered mild (mild visuospatial deficits [mild-VIS]; DLB: n = 20, AD: n = 29). Forty percent of the severe-VIS DLB group had baseline VH compared with 0% of mild-VIS DLB patients. Only 8% of the severe-VIS and 3% mild-VIS AD patients had baseline VH. During the follow-up period (mean = 5.0 years), an additional 61% of the severe-VIS but only 11% of the mild-VIS DLB patients developed VH. In that period, 38% of the severe-VIS and 20% of the mild-VIS AD patients developed VH. After considering initial MMSE score and rate of decline, logistic regression analyses found that performance on Block Design significantly predicted the presence of VH in the DLB group but not the AD group. The presence of early, severe deficits on neuropsychological tests of visuospatial skill increases the likelihood that patients with suspected DLB will develop the prototypical DLB syndrome. The presence of such deficits may identify those DLB patients whose syndrome is driven by α-synuclein pathology rather than AD pathology and may inform treatment plans as well as future research.

Pooled-DNA sequencing identifies novel causative variants in PSEN1, GRN and MAPT in a clinical early-onset and familial Alzheimer's disease Ibero-American cohort

IntroductionSome familial Alzheimer's disease (AD) cases are caused by rare and highly-penetrant mutations in APP, PSEN1, and PSEN2. Mutations in GRN and MAPT, two genes associated with frontotemporal dementia (FTD), have been found in clinically diagnosed AD cases. Due to the dramatic developments in next-generation sequencing (NGS), high-throughput sequencing of targeted genomic regions of the human genome in many individuals in a single run is now cheap and feasible. Recent findings favor the rare variant-common disease hypothesis by which the combination effects of rare variants could explain a large proportion of the heritability. We utilized NGS to identify rare and pathogenic variants in APP, PSEN1, PSEN2, GRN, and MAPT in an Ibero-American cohort.MethodsWe performed pooled-DNA sequencing of each exon and flanking sequences in APP, PSEN1, PSEN2, MAPT and GRN in 167 clinical and 5 autopsy-confirmed AD cases (15 familial early-onset, 136 sporadic early-onset and 16 familial late-onset) from Spain and Uruguay using NGS. Follow-up genotyping was used to validate variants. After genotyping additional controls, we performed segregation and functional analyses to determine the pathogenicity of validated variants.ResultsWe identified a novel G to T transition (g.38816G>T) in exon 6 of PSEN1 in a sporadic early-onset AD case, resulting in a previously described pathogenic p.L173F mutation. A pathogenic p.L392V mutation in exon 11 was found in one familial early-onset AD case. We also identified a novel CC insertion (g.10974_10975insCC) in exon 8 of GRN, which introduced a premature stop codon, resulting in nonsense-mediated mRNA decay. This GRN mutation was associated with lower GRN plasma levels, as previously reported for other GRN pathogenic mutations. We found two variants in MAPT (p.A152T, p.S318L) present only in three AD cases but not controls, suggesting that these variants could be risk factors for the disease.ConclusionsWe found pathogenic mutations in PSEN1, GRN and MAPT in 2.33% of the screened cases. This study suggests that pathogenic mutations or risk variants in MAPT and in GRN are as frequent in clinical AD cases as mutations in APP, PSEN1 and PSEN2, highlighting that pleiotropy of MAPT or GRN mutations can influence both FTD and AD phenotypic traits.

Normalization of gene expression using SYBR green qPCR: A case for paraoxonase 1 and 2 in Alzheimer's disease brains

Validating the expression stability of reference genes is crucial for reliable normalization of real-time quantitative PCR (qPCR) data, but relatively few studies have investigated this issue in brain human tissues. The present study thus aimed at identifying in human post-mortem brain tissues a set of suitable endogenous reference genes (ERG) for the expression analysis of potential candidate genes associated with Alzheimer's disease (AD). The mRNA levels of ten common ERGs (ACTB, GAPDH, GPS1, GUSB, M-RIP, PGK1, POL2RF, PPIA, UBE2D2, and YES1) were determined in the frontal cortex of autopsy-confirmed AD and non-demented control cases ( n = 20) using SYBR Green technology. Then, these levels were ranked according to their expression stability using three software applications: geNorm, NormFinder and BestKeeper. Whereas PPIA and UBE2D2 were among the ERGs with the most reliable expression, ACTB was the worst. Subsequently, using PPIA and UBE2D2 as ERGs for normalization, the mRNA levels of paraoxonase 1 (PON1) and paraoxonase 2 (PON2) were quantified in the frontal cortex of AD and control cases ( n = 80) and analyzed using the REST 2009 program. Our results indicate that both paraoxonases are expressed in the human frontal cortex and that PON2 but not PON1 mRNA levels are up-regulated in AD relative to non-demented controls. However, re-analysis of the results by ANCOVA indicated that the significance of the difference between AD and control groups depended upon the ERG used for normalization. The use of a computational method allowing the inclusion of possible confounding factors is thus recommended for the analysis of data.

Dementia

Reprinted with permission from Christopher M. Filley, MD While much neuroscientific research remains focused on finding better treatments for Alzheimer disease (AD), important work is contributing to progress in understanding related aspects of AD, and other dementias as well. This review considers 5 areas in which recent developments have informed clinical practice in the dementias. The topics were selected because they frequently arise in discussions with colleagues and patients, and concern practical issues in dementia diagnosis and prevention that require attention while the search for more effective treatments continues. A major goal of current research in AD is the discovery of biomarkers that can identify patients at an early stage and facilitate treatment at a time when it can be most effective. One of the categories of biomarkers involves neuroimaging, and medial temporal atrophy on magnetic resonance imaging (MRI), reduced glucose metabolism in temporoparietal cortices on positron emission tomography (PET) scans, and imaging of brain amyloid using PET with an agent such as Pittsburgh compound B have attracted attention. The other important biomarker category is biochemical testing, the most highly touted of which is a profile in the cerebrospinal fluid (CSF) of low β-amyloid protein 1–42 (Aβ1–42), high total tau protein (T-tau), and elevated phosphorylated tau protein 181 (P-tau). In a much-discussed recent report examining CSF diagnosis of AD and other conditions, DeMeyer and colleagues1 found that this profile was present in 90% of patients with probable AD, 72% of those with mild cognitive impairment (MCI), and 36% of normal subjects. Additional analyses showed that 64 of 68 autopsy-confirmed AD cases had the profile (94% sensitivity), and that in a cohort of 57 MCI cases followed for up to 5 years, the profile had 100% sensitivity in predicting progression to AD.1 In light of this and other studies, …

Diagnosis-Independent Alzheimer Disease Biomarker Signature in Cognitively Normal Elderly People

To identify biomarker patterns typical for Alzheimer disease (AD) in an independent, unsupervised way, without using information on the clinical diagnosis. Mixture modeling approach. Alzheimer's Disease Neuroimaging Initiative database. Cognitively normal persons, patients with AD, and individuals with mild cognitive impairment. Cerebrospinal fluid-derived beta-amyloid protein 1-42, total tau protein, and phosphorylated tau(181P) protein concentrations were used as biomarkers on a clinically well-characterized data set. The outcome of the qualification analysis was validated on 2 additional data sets, 1 of which was autopsy confirmed. Using the US Alzheimer's Disease Neuroimaging Initiative data set, a cerebrospinal fluid beta-amyloid protein 1-42/phosphorylated tau(181P) biomarker mixture model identified 1 feature linked to AD, while the other matched the "healthy" status. The AD signature was found in 90%, 72%, and 36% of patients in the AD, mild cognitive impairment, and cognitively normal groups, respectively. The cognitively normal group with the AD signature was enriched in apolipoprotein E epsilon4 allele carriers. Results were validated on 2 other data sets. In 1 study consisting of 68 autopsy-confirmed AD cases, 64 of 68 patients (94% sensitivity) were correctly classified with the AD feature. In another data set with patients (n = 57) with mild cognitive impairment followed up for 5 years, the model showed a sensitivity of 100% in patients progressing to AD. The mixture modeling approach, totally independent of clinical AD diagnosis, correctly classified patients with AD. The unexpected presence of the AD signature in more than one-third of cognitively normal subjects suggests that AD pathology is active and detectable earlier than has heretofore been envisioned.

Cerebrospinal fluid biomarker signature in Alzheimer's disease neuroimaging initiative subjects.

Develop a cerebrospinal fluid biomarker signature for mild Alzheimer's disease (AD) in Alzheimer's Disease Neuroimaging Initiative (ADNI) subjects. Amyloid-beta 1 to 42 peptide (A beta(1-42)), total tau (t-tau), and tau phosphorylated at the threonine 181 were measured in (1) cerebrospinal fluid (CSF) samples obtained during baseline evaluation of 100 mild AD, 196 mild cognitive impairment, and 114 elderly cognitively normal (NC) subjects in ADNI; and (2) independent 56 autopsy-confirmed AD cases and 52 age-matched elderly NCs using a multiplex immunoassay. Detection of an AD CSF profile for t-tau and A beta(1-42) in ADNI subjects was achieved using receiver operating characteristic cut points and logistic regression models derived from the autopsy-confirmed CSF data. CSF A beta(1-42) was the most sensitive biomarker for AD in the autopsy cohort of CSF samples: receiver operating characteristic area under the curve of 0.913 and sensitivity for AD detection of 96.4%. In the ADNI cohort, a logistic regression model for A beta(1-42), t-tau, and APO epsilon 4 allele count provided the best assessment delineation of mild AD. An AD-like baseline CSF profile for t-tau/A beta(1-42) was detected in 33 of 37 ADNI mild cognitive impairment subjects who converted to probable AD during the first year of the study. The CSF biomarker signature of AD defined by A beta(1-42) and t-tau in the autopsy-confirmed AD cohort and confirmed in the cohort followed in ADNI for 12 months detects mild AD in a large, multisite, prospective clinical investigation, and this signature appears to predict conversion from mild cognitive impairment to AD.

Association of distinct variants in SORL1 with cerebrovascular and neurodegenerative changes related to Alzheimer disease.

Single-nucleotide polymorphisms (SNPs) in 2 distinct regions of the gene for the sortilin-related receptor (SORL1) (bounded by consecutively numbered SNPs 8-10 and 22-25) were shown to be associated with Alzheimer disease (AD) in multiple ethnically diverse samples. To test the hypothesis that SORL1 is associated with brain magnetic resonance imaging (MRI) measurements of atrophy and/or vascular disease. We evaluated the association of 30 SNPs spanning SORL1 with MRI measures of general cerebral atrophy, hippocampal atrophy, white matter hyperintensities, and overall cerebrovascular disease in 44 African American and 182 white sibships from the MIRAGE Study. We performed single- and 3-SNP haplotype association analyses using family-based tests. Haplotypes found to be significantly associated with at least 1 MRI trait were tested for association with 6 pathological traits in a separate sample of 69 white patients with autopsy-confirmed AD. In white patients, white matter hyperintensities were associated with multiple markers in the region encompassing SNPs 6 to 10, whereas cerebral and hippocampal atrophy were associated with markers from the region including SNPs 21 to 26. Examination of specific 3-SNP haplotypes from these 2 regions in the autopsy-confirmed cases of AD revealed association of white matter disease with SNPs 8 to 10 and association of hippocampal atrophy with SNPs 22 to 26. The haplotype CGC at SNPs 8 to 10 was associated with fewer white matter changes in the clinical (P<.001) and autopsy (P=.02) samples. Variants of SORL1 previously associated with AD are also associated with MRI and neuropathological measures of neurodegenerative and cerebrovascular disease. These findings not only support the hypothesis that multiple areas in SORL1 are of functional importance but also raise the possibility that multiple SORL1 variants influence amyloid precursor protein or endothelial lipoprotein processing or both in different regions of the brain.

Altered fMRI activation during mental rotation in those at genetic risk for Alzheimer disease

This study was undertaken to examine differential functional MRI patterns in those at genetic risk for Alzheimer disease (AD), specifically investigating parietal lobe activation, a brain region with changes noted in the early stages of AD. This study uses functional MRI to investigate blood oxygenation level dependent changes in the parietal lobe in a high-risk sample of 18 asymptomatic offspring of autopsy-confirmed AD cases, compared to 15 matched controls. The cognitive activation paradigm was a mental rotation task, which requires individuals to rotate three-dimensional cube stimuli to judge their similarity. We found no differences in either reaction time or performance accuracy between groups. However, the at-risk individuals showed increases in activation in the right superior parietal lobule (BA 7), the right insula (BA 13), the right middle frontal gyrus (BA 10), and the right inferior frontal gyrus (BA 47). We present evidence for a compensatory mechanism for those at increased risk for Alzheimer disease (AD). This study examines and confirms parietal changes with increased risk for late-onset AD, despite normal cognitive performance. Added to the previous findings from this group, these results demonstrate the sensitivity of functional imaging measures to brain changes that are not yet reflected in cognitive performance, which may ultimately serve as an important indicator of disease.

ASSOCIATION BETWEEN GENETIC VARIANTS IN SORL1 AND AUTOPSY-CONFIRMED ALZHEIMER DISEASE

Genetic variants within two distinct regions of SORL1 have recently been associated with both familial and sporadic Alzheimer disease (AD) in multiple cohorts composed of more than 6,000 individuals.1 The original report was subsequently confirmed in an independent cohort of unrelated patients with probable AD and healthy elderly control subjects from a prospective study in multiethnic communities in northern Manhattan.2 To extend these results, we investigated a series of autopsy-confirmed cases with AD (n = 103) of white, non-Hispanic origin, and compared them with controls (n = 93) from similar ethnic origins. These analyses revealed that the same alleles in a haplotype in the 5′ region of the gene and a haplotype in the same 3′ region are associated with autopsy-proven AD. ### Methods. Frozen brain tissue was obtained from 103 autopsy-confirmed cases of AD and from 17 elderly control subjects with a normal postmortem examination and without a history of dementia or another neurologic disorder. To augment the number of controls from the same ethnic background, we included 76 nondemented elderly participants who have been followed prospectively at approximately 18-month intervals as part of a study of …

Sporadic cerebral amyloid angiopathy is not a frequent cause of spontaneous brain hemorrhage

The retrospective study of a consecutive autopsy series of 1100 elderly subjects (mean age 78.3 +/- 6.8 SD years), revealed sporadic cerebral amyloid angiopathy (CAA) in 50.0% and in 95.7% of autopsy-confirmed cases of Alzheimer disease (AD). Apolipoprotein (APOE) epsilon 3/4 and epsilon 4/4 were significantly more frequent in AD than in controls, and were associated with more severe degrees of CAA. Spontaneous (non-traumatic) intracerebral hemorrhages (ICH) (excluding microbleeds and hemorrhagic infarctions) were seen in 5.4% and only in 3.3% of AD cases. CAA was found in 50.6% of brains without and in 42.4% with ICH, the latter showing a significantly higher frequency of severe degrees of CAA. ICH was related to CAA in 42.4%, whilst no such relation was seen in 57.6%. Patients with CAA were older, showed a higher frequency of clinical dementia and pathologically confirmed AD, but signs of hypertension (history and/or autopsy) occurred in 40%, compared with 80% in those with non-CAA-related ICHs. CAA-related ICH more frequently involved in cerebral lobes or hemispheres, whilst non-CAA-related ones were more often located in the basal ganglia and brainstem. The data of a lower prevalence of CAA in cases with than without ICH and of ICH with and without CAA do not support the concept that CAA represents the most important risk factor for ICH in the aged, probably because of other risk factors including hypertension.

A 50-Year-Old Man With Acute-Onset Generalized Seizure

A 50-Year-Old Man With Acute-Onset Generalized Seizure

Contributors to white matter damage in the frontal lobe in Alzheimer's disease

Abnormalities of cerebral white matter are present in a majority of patients with Alzheimer's disease (AD) and probably contribute to motor dysfunction and cognitive impairment. The white matter abnormalities are usually attributed to degenerative vascular disease and cerebral amyloid angiopathy (CAA) but the evidence is scanty or inconclusive. In the present study we examined sections of frontal lobe from 125 autopsy-confirmed cases of AD and assessed the relationship of degenerative large and small vessel disease, CAA, parenchymal Abeta load and APOE genotype, to several objective measures of white matter damage: extent of immunolabelling for glial fibrillary acidic protein (GFAP), axonal accumulation of amyloid precursor protein (APP), axon density in superficial and deep white matter, and intensity of staining for myelin. We found no association between atherosclerosis, arteriolosclerosis, CAA or APOE genotype and white matter damage. However, labelling of white matter for GFAP correlated strongly with the parenchymal Abeta load (P = 0.0003) and with APP accumulation (P = 0.008). Our findings suggest that severity of frontal white matter damage in AD is closely related to parenchymal Abeta load and that in most cases the contribution of degenerative vascular disease, CAA and APOE is relatively minor.

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 β protein (Aβ). 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 Aβ 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, Aβ (Aβ 40 and Aβ 42) load, tau load or extent of amyloid angiopathy did not differ between D/D, I/D and I/I genotype groups, though Aβ 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 Aβ or tau deposited in the brain.