Volume 24, Number 1, April 2011

Pages 1-2
George Perry, Xiongwei Zhu
Mark Anthony Smith (19652010): Visionary, Alzheimer Researcher, and Editor-in-Chief of the Journal of Alzheimer's Disease

Pages 3-10
Ming Chen, Jerome J Maleski, Darrell R Sawmiller
Scientific Truth or False Hope? Understanding Alzheimer’s Disease from an Aging Perspective
Abstract: In this paper, we argue that the current official definition for Alzheimer’s disease is misleading, since it defines senile dementia (SD), a long-known incurable senile/geriatric condition, as a discrete/curable disease. This optimistic definition was incepted in the 1970s amid the public’s fear of the upcoming SD crisis and desperate hope for a cure. Scientifically, however, it has overturned Alois Alzheimer’s age-based concept for disease classification—the essence of modern Geriatric Medicine and the National Institute of Aging. Thus, the current definition for SD, though socially and politically appealing, would be scientifically flawed. As an authoritative study guideline, it has caused profound and far-reaching confusions in research by misleading attention to the presumptive pathogenic/erroneous factors as drug targets for “silver bullets”. Such well-intentioned studies would generate numerous data, but render SD a scientific and logical enigma. In this context we discuss: 1) why and how senile conditions including SD differ from discrete diseases by origin, thus also by study paradigm and intervention strategy; 2) why senile conditions may not be explained by abnormal/pathogenic factors, but logically should be explained by “normal” elements in life, perhaps advanced aging plus risk factors; and 3) why the “amyloid-β toxicity” controversy, a simple scientific issue, has lasted for so long. Finally, we ask: can scientific inquiry preserve its integrity and objectivity under social pressure? It appears that these fundamental questions warrant serious attention if the scientific nature of SD is to be eventually understood.

Pages 11-13
     Peter J. Whitehouse, Daniel R. George, Simon D'Alton
     Describing the dying days of "Alzheimer's disease"

Pages 15-24
Marc Gleichmann, Vivian W. Chow, Mark P. Mattson (Handling Associate Editor: Gregory Brewer)
Homeostatic Disinhibition in the Aging Brain and Alzheimer’s Disease
Abstract: In this article, we propose that impaired efficiency of glutamatergic synaptic transmission and a compensatory reduction in inhibitory neurotransmission, a process called homeostatic dishinhibition, occurs in the aging brain and more dramatically in Alzheimer’s disease (AD). Homeostatic disinhibition may help understand certain features of the aging brain and AD, including: 1) the increased risk for epileptic seizures, especially in the early phase of the disease; 2) the reduced ability to generate γ-oscillations; and 3) the increase in neuronal activity as measured by functional MRI. Homeostatic disinhibition may be the major mechanism that activates cognitive reserve. Modulating neuronal activity may therefore be a viable therapeutic strategy in AD that can complement existing anti-amyloid strategies. Specifically, enhancing endogenous glutamatergic synaptic transmission through increased co-agonist signaling or through positive allosteric modulation of metabotropic glutamatergic receptors appears as an attractive strategy. Alternatively, further reduction of GABAergic signaling may work as well, although care has to be taken to prevent epileptic seizures.

Pages 25-34
Abhay P. Sagare, Rashid Deane, Henrik Zetterberg, Anders Wallin, Kaj Blennow, Berislav V. Zlokovic
Impaired lipoprotein receptor-mediated peripheral binding of plasma amyloid-β is an early biomarker for mild cognitive impairment preceding Alzheimer’s disease
Abstract: Soluble circulating low density lipoprotein receptor-related protein-1 (sLRP) provides key plasma binding activity for Alzheimer’s disease (AD) amyloid-β peptide (Aβ). sLRP normally binds 70-90% of plasma Aβ preventing free Aβ access to the brain. In AD, Aβ binding to sLRP is compromised by increased levels of oxidized sLRP which does not bind Aβ. Here, we determined plasma oxidized sLRP and Aβ40/42 sLRP-bound, other proteins-bound and free plasma fractions, cerebrospinal fluid (CSF) tau/Aβ42 ratios, and mini-mental state examination (MMSE) scores in patients with mild cognitive impairment (MCI) who progressed to AD (MCI-AD, n=14), AD (n=14) and neurologically healthy controls (n=14) recruited from the Göteborg MCI study. In MCI-AD patients prior to conversion to AD and AD patients, the respective increases in oxidized sLRP and free plasma Aβ40 and Aβ42 levels were 4.9 and 3.7-fold, 1.8, and 1.7-fold and 4.3 and 3.3-fold (p < 0.05, ANOVA with Tuckey post-hoc test). In MCI-AD and AD patients increases in oxidized sLRP and free plasma Aβ40 and Aβ42 correlated with increases in CSF tau/Aβ42 ratios and reductions in MMSE scores (p < 0.05, Pearson analysis). A heterogeneous group of ‘stable’ MCI patients that was followed over 2-4 years (n=24) had normal CSF tau/Aβ42 ratios but increased oxidized sLRP levels (p< 0.05, Student’s t test). Data suggests that a deficient sLRP-Aβ binding might precede and correlate later in disease with an increase in the tau/Aβ42 CSF ratio and global cognitive decline in MCI individuals converting into AD, and therefore is an early biomarker for AD-type dementia.

Pages 35-45
Katie Palmer, Federica Lupo, Roberta Perri, Giovanna Salamone, Lucia Fadda, Carlo Caltagirone, Massimo Musicco, Luca Cravello
Predicting disease progression in Alzheimer’s disease: the role of neuropsychiatric syndromes on functional and cognitive decline
Abstract: Patients with Alzheimer’s disease (AD) have heterogeneous rates of disease progression. The aim of the current study is to investigate whether neuropsychiatric disturbances predict cognitive and functional disease progression in AD, according to failure theory. We longitudinally examined 177 memory-clinic AD outpatients (mean age=73.1, SD=8.1; 70.6% women). Neuropsychiatric disturbances at baseline were categorized into five syndromes. Patients were followed for up to two years to detect rapid disease progression defined as a loss of ≥1 abilities in Activities of Daily living (ADL) or a drop of ≥5 points on Mini-Mental State Examination (MMSE). Hazard ratios (HR) were calculated with Gompertz regression, adjusting for sociodemographics, baseline cognitive and functional status, and somatic comorbidities. Most patients (74.6%) exhibited one or more neuropsychiatric syndromes at baseline. The most common neuropsychiatric syndrome was Apathy (63.8%), followed by Affective (37.3%), Psychomotor (8.5%), Manic (7.9%), and Psychotic (5.6%) syndromes. The variance between the observed (Kaplen Meier) and predicted (Gompertz) decline for disease progression in cognition (0.30, CI=0.26-0.35), was higher than the variance seen for functional decline (0.22, CI=0.18-0.26). After multiple adjustment, patients with the Affective syndrome had an increased risk of functional decline (HR=2.0; CI=1.1-3.6), whereas the risk of cognitive decline was associated with the Manic (HR=3.2, CI=1.3-7.5) syndrome. In conclusion, specific neuropsychiatric syndromes are associated with functional and cognitive decline during the progression of AD, which may help with the long-term planning of care and treatment. These results highlight the importance of incorporating a thorough psychiatric examination in the evaluation of AD patients.

Pages 47-59
Andrew D. Watt, Keyla A. Perez, Noel G. Faux, Kerryn E. Pike, Christopher C. Rowe, Pierrick Bourgeat, Olivier Salvado, Colin L. Masters, Victor. L. Villemagne, Kevin J. Barnham
Increasing the predictive accuracy of amyloid-β blood-borne biomarkers in Alzheimer’s disease
Abstract: Diagnostic measures for Alzheimer’s disease (AD) commonly rely on evaluating the levels of amyloid-β (Aβ) peptides within the cerebrospinal fluid (CSF) of affected individuals. These levels are often combined with levels of an additional non-Aβ marker to increase predictive accuracy. Recent efforts to overcome the invasive nature of CSF collection led to the observation of Aβ species within the blood cellular fraction, however, little is known of what additional biomarkers may be found in this membranous fraction. The current study aimed to undertake a discovery-based proteomic investigation of the blood cellular fraction from AD patients (n = 18) and healthy controls (HC; n = 15) using copper immobilized metal affinity capture and Surface Enhanced Laser Desorption/Ionisation Time-Of-Flight Mass Spectrometry. Three candidate biomarkers were observed which could differentiate AD patients from HC (ROC AUC > 0.8). Bivariate pairwise comparisons revealed significant correlations between these markers and measures of AD severity including; MMSE, composite memory, brain amyloid burden, and hippocampal volume. A partial least squares regression model was generated using the three candidate markers along with blood levels of Aβ. This model was able to distinguish AD from HC with high specificity (90%) and sensitivity (77%) and was able to separate individuals with mild cognitive impairment (MCI) who converted to AD from MCI non-converters. While requiring further characterization, these candidate biomarkers reaffirm the potential efficacy of blood-based investigations into neurodegenerative conditions. Furthermore, the findings indicate that the incorporation of non-amyloid markers into predictive models, function to increase the accuracy of the diagnostic potential of Aβ.

Supplementary Data for Watt et al. article (PDF)

Pages 61-75
Cláudia P. Figueiredo, Maíra A. Bicca, Alexandra Latini, Rui Daniel S. Prediger, Rodrigo Medeiros, João B. Calixto (Handling Associate Editor: William Grant)
Folic acid plus α-tocopherol mitigates amyloid-β-induced neurotoxicity through modulation of mitochondrial complexes activity
Abstract: Early symptoms of Alzheimer’s disease (AD) have been attributed to amyloid-β (Aβ) toxicity. The pathophysiology of AD is complex and involves several different biochemical pathways, including defective Aβ protein metabolism, neuroinflammation, oxidative processes, and mitochondrial dysfunction. In the current study, we assessed the molecular mechanisms, mainly the modifications in the activity of mitochondrial complexes, whereby the association of folic acid and α-tocopherol protects mice against the Aβ-induced neurotoxicity. Oral treatment with folic acid (50 mg/kg) plus α-tocopherol (500 mg/kg), once a day during 14 consecutive days, protected mice against the Aβ1–40-induced cognitive decline, synaptic loss, and neuronal death. However, chronic treatment comprising folic acid plus α-tocopherol was ineffective on Aβ-induced glial cell activation, suggesting that the effect of this treatment is independent of anti-inflammatory features. Interestingly, the results obtained in our study suggest that mitochondrial energy metabolism is impaired by the Aβ peptide, and upregulation of mitochondrial genes may be a compensatory response, as demonstrated by the increase in mitochondrial complexes I, II, and IV activity, in the hippocampus of mice, after Aβ1-40 injection. Of note, the chronic treatment comprising folic acid plus α-tocopherol prevented the increase in the activity of mitochondrial complexes I and IV induced by Aβ1-40. Together, these results show the antioxidant effect of the combination of folic acid and α-tocopherol, as observed by the decrease in NO generation from iNOS and nNOS, preventing an increase in the activity of mitochondrial complexes, mainly I and IV, and the neuronal death induced by the Aβ1-40 peptide.

Pages 77-84
Rukhsana Sultana, Patrizia Mecocci, Francesca Mangialasche, Roberta Cecchetti, Mauro Baglioni, D. Allan Butterfield (Handling Associate Editor: William Banks)
Increased Protein and Lipid Oxidative Damage in Mitochondria Isolated from Lymphocytes from Patients with Alzheimer’s Disease: Insights into the Role of Oxidative Stress in Alzheimer’s Disease and Initial Investigations into a Potential Biomarker for This Dementing Disorder Abstract: Alzheimer’s disease (AD) is histopathologically characterized by the presence of senile plaques, neurofibrillary tangles, and synapse loss. The main component of senile plaques is amyloid β-peptide (Aβ), which has been shown to induce oxidative stress in in vitro and in vivo studies. AD is associated with elevated levels of oxidative damage in brain and peripheral lymphocytes. Further Aβ has been found to be accumulated in mitochondria, which might contribute to the reported alterations in the mitochondrial morphology, and impaired mitochondrial energy metabolism in AD brain. Biomarkers are desperately needed for earlier diagnosis of AD and to monitor efficacy of new therapies. Hence, in the present study we show that markers of oxidative damage are elevated in mitochondria isolated from AD lymphocytes suggesting that these oxidative stress indices potentially could serve as a viable biomarker for AD.

Pages 85-100
Rui Liu, Tiantai Zhang, Haiguang Yang, Xi Lan, Jian Ying, Guanhua Du
The flavonoid apigenin protects brain neurovascular coupling against amyloid-β25-35-induced toxicity in mice
Abstract: Apigenin, one of the most common flavonoids, has demonstrated anti-inflammatory, anticarcinogenic, and free radical-scavenging activities. Recent studies revealed its protective effects against amyloid-β (Aβ)-induced neurotoxicity, but the mechanism was unclear. In the present study, we aimed to explore the anti-amnesic and protective effects of apigenin against Aβ25-35-induced toxicity and the underlying mechanisms in the cerebral cortex in mice. The learning and memory impairments, changes in morphology of major components of neurovascular unit, ultrastructural changes and oxidative stress of cerebral cortex, cerebrovascular dysfunction, and neuronal changes were detected after oral administration of apigenin continuously for 8 days. Our results demonstrate that oral administration of apigenin for Aβ25-35-induced amnesic mice conferred robust neurovascular coupling protection, involving improvement of the learning and memory capabilities, maintenance of neurovascular unit integrity, modulation of microvascular function, reduction of neurovascular oxidative damage, increase of regional cerebral blood flow, improvement of cholinergic system involving the inhibition of AChE activity and elevation of ACh level, and modification of BNDF, TrkB, and phospho-CREB levels.

Pages 101-108
Rui Zhou, Juan Deng, Meng Zhang, Hua-Dong Zhou,Yan-Jiang Wang
Association between Bone Mineral Density and the Risk of Alzheimer’s Disease
Abstract: Alzheimer’s disease (AD) and osteoporosis are common chronic degenerative disorders which are strongly associated with advanced age. Some studies suggest that low bone mineral density (BMD) is related to the increased risk of AD. We conducted a 5-year prospective study to exam the association between BMD and the risk of AD in a cohort of Chinese elderly people. Of 3263 community residents aged 65 years and over, 2019 were enrolled into the study and followed up annually for 5 years. At baseline demographic data, smoking and drinking status, medical history, cognitive status, and blood samples were collected. BMD was measured by dual energy X-ray absorptiometry (DEXA) scanning at baseline and during follow-up. Cox proportional hazards analysis was used to evaluate the association with BMD and incidence of AD. Over the follow-up of 5 years, AD developed in 132 subjects. Baseline BMD, bone loss rate, current smoking, and daily drinking were associated with increased risk of AD, while higher baseline plasma leptin level was associated with decreased risk of AD, in both women and men. Low BMD and increased loss rate of BMD were associated with higher risk of AD. Cigarette smoking, alcohol drinking, and lower leptin level are risk factors for AD. Uncovering the relation linking osteoporosis and AD is important for understanding the pathogenesis and developing therapeutic strategies for these two common disorders afflicting elderly people.

Pages 109-123
Connor Keller, Ahmadul Kadir, Anton Forsberg, Omar Porras, Agneta Nordberg
Long-term effects of Galantamine treatment on brain functional activities as measured by PET in Alzheimer’s Disease patients
Abstract: The effects of galantamine (16 to 24 mg/day) treatment on brain functional activities (blood flow and glucose metabolism) were examined in 18 patients with mild Alzheimer’s disease (AD) in relation to brain acetylcholinesterase (AChE) activity and nicotinic receptors and cognitive function. The study consisted of an initial double-blind phase of three months (short-term) followed by an open-label phase up until twelve months after the beginning of the study (long-term). The AD patients underwent positron emission tomography (PET) studies with the tracers [15O]-H2O for measurement of regional cerebral blood flow (rCBF) at baseline, 3 weeks, 3 and 12 months treatment, and [18F]-fluoro-deoxyglucose (FDG) for measurement of regional cerebral metabolic rate for glucose (rCMRglc) at baseline and 12 months. A battery of neuropsychological assessments was performed on each patient in order to follow changes in cognition during the treatment period. Throughout the study, different cortical areas showed significant increases in rCBF after galantamine treatment. rCBF positively correlated with AChE activity,nicotinic receptor activity, and cognition. In addition to these positive changes, an increase in rCMRglc in the frontal brain region and stabilization in other cortical areas was observed after 12 months galantamine treatment. This stabilization in rCMRglc was also correlated with a stabilization of cognition. Our results ultimately suggest that treatment with galantamine has a long-term positive effect on brain perfusion and rCMRglc and stabilizes cognition.

Pages 125-136
Samuel R Chamberlain, Andrew D Blackwell, Pradeep J. Nathan, Geoff Hammond, Trevor W Robbins, John R Hodges, Albert Michael, James M Semple, Edward T Bullmore*, Barbara J Sahakian* (Handling Associate Editor: Paulo Caramelli) *Joint senior authors
Differential cognitive deterioration in dementia: a two year longitudinal study
Abstract: The ability to predict cognitive deterioration in patients with dementia holds valuable potential for clinical trials and early intervention. This study identified cognitive domains deteriorating differentially over time as well as baseline predictors of subsequent cognitive decline in patients referred to a memory clinic. Twenty-six subjects with Alzheimer’s disease (AD) and 43 subjects with Subjective Memory Impairment (SMI) were entered into a longitudinal study in which cognitive function was assessed at baseline and at 8-monthly intervals for 2 years, using a range of well-validated measures. Thirty-seven patients with depression and 39 healthy controls were also longitudinally assessed. AD was associated with disproportionate deterioration over time on general measures of cognitive function, multiple measures of mnemonic processing, mental fluency (letter and category), and aspects of motor speed. SMI showed restricted relative cognitive deterioration on general measures of cognitive function, on a subset of memory measures, and on letter but not category fluency. Secondary analysis showed that earliest detectable ADAS-cog and MMSE decline in AD was at 16 months, while several specific neuropsychological indices were sensitive as early as 8 months (graded naming test, semantic naming, and the category/letter fluency tests). In combination, baseline/early changes in cognitive performance, alongside clinical measures, predicted 48% of disease progression over two years in memory impaired patients as a whole. These findings have implications for identifying patients likely to benefit from disease modifying agents, and for designing, powering, enriching, and implementing future clinical trials. Follow-up studies in independent populations are needed to validate predictive algorithms identified.

Supplementary Data for Chamberlain et al. article (PDF)

Pages 137-149
Matthew Schrag, Andrew Crofton, Matthew Zabel, Arshad Jiffry, David Kirsch, April Dickson, Xiao Wen Mao, Harry V. Vinters, Dylan W. Domaille, Christopher J. Chang, Wolff Kirsch (Handling Associate Editor: Othman Ghribi)
Effect of cerebral amyloid angiopathy on brain iron, copper, and zinc in Alzheimer’s disease
Abstract: Cerebral amyloid angiopathy (CAA) is a vascular lesion associated with Alzheimer’s disease (AD) present in up to 95% of AD patients and produces MRI-detectable microbleeds in many of these patients.  It is possible that CAA-related microbleeding is a source of pathological iron in the AD brain.  Because the homeostasis of copper, iron, and zinc are so intimately linked, we determined whether CAA contributes to changes in the brain levels of these metals.  We obtained brain tissue from AD patients with severe CAA to compare to AD patients without evidence of vascular amyloid-β.  Patients with severe CAA had significantly higher non-heme iron levels.  Histologically, iron was deposited in the walls of large CAA-affected vessels.  Zinc levels were significantly elevated in grey matter in both the CAA and non-CAA AD tissue, but no vascular staining was noted in CAA cases.  Copper levels were decreased in both CAA and non-CAA AD tissues and copper was found to be prominently deposited on the vasculature in CAA.  Together, these findings demonstrate that CAA is a significant variable affecting transition metals in AD.

Pages 151-160
Andrea Tales, Antony J Bayer, Judy Haworth, Robert J. Snowden, Michelle Philips, Gordon Wilcock
Visual search in mild cognitive impairment: A longitudinal study
Abstract: In the study of Alzheimer’s disease, a multidisciplinary research approach has identified significant abnormality in several areas of visual and visual attention-related brain function in addition to those typically measured as part of clinical diagnosis. This raises the possibility that a similar approach applied to amnestic mild cognitive impairment (aMCI) will increase our understanding of its theoretical and clinical constructs, particularly if functions whose integrity is heterogeneous with respect to etiological outcome can be found. In this study we examined visual search performance (the brain’s ability to search effectively throughout the environment for a particular object) in aMCI compared to healthy aging. Cross-sectionally, visual search performance in aMCI was significantly poorer than in healthy aging, with greater intra-group performance heterogeneity in the aMCI compared to the healthy older adult group. This outcome illustrates that although individuals within an aMCI group ostensibly have the same condition they can differ substantially with respect to the integrity of aspects of brain function. Such findings may have implications for the clinical management of the individual patient. The results from the longitudinal aspect of this study also illustrate how heterogeneity in the performance of brain operations other than memory in aMCI may help to inform the likelihood of their developing dementia, as those patients who were diagnosed with dementia within 2.5 years of baseline measurement showed significantly poorer visual search performance compared to those who did not.

Pages 161-174
Carlos Ramirez, Inmaculada Tercero, Antonia Pineda, Javier S. Burgos
Simvastatin is the statin that most efficiently protects against kainate-induced excitotoxicity and memory impairment
Abstract: Statins have recently been shown to act as protectants against several neuropathological conditions. They have received special attention in the field of Alzheimer's disease (AD), where epidemiological studies indicating a lower prevalence of AD/dementia in statin-prescribed populations. Excitotoxicity, which derives from the overstimulation of glutamate receptors, is a major cause of neuron death in several neurological diseases, including AD and epilepsy. We have carried out a comparative study to investigate the effects of all the commercially available statins (simvastatin, lovastatin, fluvastatin, pravastatin, and atorvastatin) on neuron damage and memory impairment. To this end, we studied neurodegeneration in a mouse model by systemic administration of kainate. Simvastatin was the most effective statin in reducing the deleterious effects caused by kainate, including the severity of seizures, excitotoxicity, oxidative damage, neuritic dystrophy and apoptosis in the hippocampus and other limbic structures of the brain cortex. Lovastatin was the second most efficient statin in preventing seizures and histopathological signs of excitotoxicity, whilst fluvastatin, pravastatin, and atorvastatin showed neither antiepileptic nor neuroprotective effects. Only simvastatin enhanced episodic-like memory. To the best of our knowledge this is the first in vivo study to analyze the neuroprotective effect of all the commercially available statins. Our results suggest that both simvastatin and lovastatin (but especially simvastatin) may well have therapeutic potential in the treatment of neurodegenerative diseases involving excitotoxicity and memory impairment, including AD.

Pages 175-185
Serena Bucossi, Mariacarla Ventriglia, Valentina Panetta, Carlo Salustri, Patrizio Pasqualetti, Stefania Mariani, Mariacristina Siotto, Paolo Maria Rossini, Rosanna Squitti
Copper in Alzheimer’s Disease: A Meta-Analysis of Serum, Plasma, and Cerebrospinal Fluid Studies
Abstract: There is an ongoing debate on the involvement of systemic copper (Cu) dysfunctions in Alzheimer’s disease (AD), and clinical studies comparing Cu levels in serum, plasma, and cerebrospinal fluid (CSF) of AD patients with those of healthy controls have delivered non-univocal and often conflicting results. In an attempt to evaluate whether Cu should be considered a potential marker of AD, we applied meta-analysis to a selection of 26 studies published in the literature. Meta-analysis is a quantitative method that combines the results of independent reports to distinguish between small effects and no effects, random variations, variations in sample used, or in different analytical approaches. The subjects’ sample obtained by merging studies was a pooled total of 761 AD subjects and 664 controls for serum Cu studies, 205 AD subjects and 167 controls for plasma Cu, and of 116 AD subjects and 129 controls for CSF Cu. Our meta-analysis of serum data showed that AD patients have higher levels of serum Cu than healthy controls. Plasma data did not allow conclusions, due to their high heterogeneity, but the meta-analysis of the combined serum and plasma studies confirmed higher Cu levels in AD. The analysis of CSF data, instead, revealed no difference between AD patients and controls.

Pages 187-196
Dushyant P. Purohit, Nirmala O. Batheja, Mary Sano, Kusum D. Jashnani, Rajesh N. Kalaria, Arivarasan Karunamurthy, Shalinder Kaur, Asha S. Shenoy, Kathleen Van Dyk, James Schmeidler, Daniel P. Perl (Handling Associate Editor: Robert Friedland)
Profiles of Alzheimer’s disease-related pathology in an aging urban population sample
Abstract: Systematic studies on Alzheimer’s disease (AD) -related pathology that complement clinical and epidemiological data on dementia from low and middle income countries are rare.  We report the first large study on AD-related pathology in autopsy service-derived brains from an urban center in India, a low/middle income country, and compare findings with a similar sample from New York.  Amyloid-β plaques and neurofibrillary tangles were assessed in 91 brain specimens derived from hospital autopsy cases from Mumbai, India (age 60+ years; mean age 71.1 years, ±8.3 SD; range 60-107 years) and compared with identically examined age-matched sample obtained in New York.   These cases had no known clinical history of dementia.   Our study showed that in comparison with the New York sample, the mean brain weight of the Mumbai sample was lower (p=0.013) and mean diffuse plaque density was higher (p=0.019), while differences in mean density and counts of neurofibrillary tangles and neuritic plaques were not statistically significant (p>0.05).  Our findings indicate that the burden of AD-related pathology was approximately equivalent in Mumbai and New York samples, which is at variance with expected lower AD- related lesion burden based on the clinical/epidemiological studies suggesting lower prevalence of AD in India.