Alzheimer Disease: Silverman JM

Rosendorff C, Beeri MS, Silverman JM. · Department of Medicine, Mount Sinai School of Medicine, New York, NY, USA. · Am J Geriatr Cardiol. · Pubmed #17483665 No free full text.

Abstract: There is now sizable literature on the association between traditional cardiovascular risk factors and Alzheimer's disease (AD). Based on epidemiologic studies, both cross-sectional and longitudinal, there are statistically significant correlations between the prevalence of AD and diabetes, hypercholesterolemia, hypertension, hyperhomocysteinemia, dietary saturated fats, cholesterol, antioxidants, alcohol consumption, smoking, physical activity, the presence of atrial fibrillation, atherosclerotic disease, and the plasma concentration of some hemostatic factors. Most of the cardiovascular risk factors found to be associated with AD are age-dependent, and the prevalence of AD increases with age. Therefore, the association could simply be attributed to aging. On the other hand, the common pathogenetic mechanisms for the generation of both atherosclerotic disease and AD, such as inflammation and the generation of free radicals, suggest a causal link. If this is the case, the identification of modifiable risk factors for dementia becomes a research priority and early intervention aimed at reducing those cardiovascular risk factors a therapeutic imperative.

Beeri MS, Schmeidler J, Silverman JM, Gandy S, Wysocki M, Hannigan CM, Purohit DP, Lesser G, Grossman HT, Haroutunian V. · Mount Sinai School of Medicine, Department of Psychiatry, One Gustave Levy Place, Box 1230, New York, NY 10029, USA. · Neurology. · Pubmed #18765651 No free full text.

Abstract: OBJECTIVE: To examine the association between treatment for diabetes and Alzheimer disease (AD) neuropathology. METHODS: This postmortem study matched 124 subjects with diabetes to 124 without diabetes from the Mount Sinai School of Medicine Brain Bank, on age (mean = 81.2 + 9.3), sex (57.3% F), and severity of dementia (Clinical Dementia Rating [CDR] 2.4 + 1.7). Densities of neuritic plaques (NPs) and of neurofibrillary tangles (NFTs) were assessed in several neocortical regions and in the hippocampus, entorhinal cortex, and amygdala. Diabetic subjects were classified according to their recorded lifetime antidiabetic medications: none (n = 29), insulin only (n = 49), diabetes medications other than insulin only (n = 28), or concomitant use of both insulin and any oral antidiabetic medications (n = 18). For each dependent variable, analysis of covariance controlling for age at death, sex, and CDR distinguished among the nondiabetic patients and four diabetic subgroups. RESULTS: There were differences among the five groups for NP ratings in the entorhinal cortex (p = 0.003), amygdala (p = 0.009), and overall NP (p = 0.014) as well as counts of NPs in all regions examined (p values ranging from 0.009 to 0.04). NP ratings in the hippocampus (p = 0.057) and the combined neocortical measure (p = 0.052) approached significance. In each analysis, the concomitant medication group had significantly fewer NPs (approximately 20%) than any of the other groups, which were relatively similar. No significant NFT differences were found. CONCLUSION: The results of this study suggest that the combination of insulin with other diabetes medication is associated with substantially lower neuritic plaque density consistent with the effects of both on the neurobiology of insulin.

Fillenbaum GG, van Belle G, Morris JC, Mohs RC, Mirra SS, Davis PC, Tariot PN, Silverman JM, Clark CM, Welsh-Bohmer KA, Heyman A. · Center for the Study of Aging and Human Development, Duke University Medical Center, Durham, NC, USA. · Alzheimers Dement. · Pubmed #18631955 No free full text.

Abstract: The Consortium to Establish a Registry for Alzheimer's Disease (CERAD) was funded by the National Institute on Aging in 1986 to develop standardized, validated measures for the assessment of Alzheimer's disease (AD). The present report describes the measures that CERAD developed during its first decade and their continued use in their original and translated forms. These measures include clinical, neuropsychological, neuropathologic, and behavioral assessments of AD and also assessment of family history and parkinsonism in AD. An approach to evaluating neuroimages did not meet the standards desired. Further evaluations that could not be completed because of lack of funding (but where some materials are available) include evaluation of very severe AD and of service use and need by patient and caregiver. The information that was developed in the U.S. and abroad permits standardized assessment of AD in clinical practice, facilitates epidemiologic studies, and provides information valuable for individual and public health planning. CERAD materials and data remain available for those wishing to use them.

Schnaider Beeri M, Silverman JM, Schmeidler J, Wysocki M, Grossman HZ, Purohit DP, Perl DP, Haroutunian V. · Department of Psychiatry, Mount Sinai School of Medicine, New York, NY 10029, USA. · Dement Geriatr Cogn Disord. · Pubmed #18367838 links to  free full text

Abstract: AIMS: To assess the relationships between early and late antemortem measures of dementia severity and Alzheimer disease (AD) neuropathology severity. METHODS: 40 residents of a nursing home, average age at death 82.0, participated in this longitudinal cohort study with postmortem assessment. Severity of dementia was measured by Clinical Dementia Rating (CDR) at two time points, averaging 4.5 and 1.0 years before death. Densities of postmortem neuritic plaques (NPs) and neurofibrillary tangles (NFTs) were measured in the cerebral cortex, hippocampus, and entorhinal cortex. RESULTS: For most brain areas, both early and late CDRs were significantly associated with NPs and NFTs. CDRs assessed proximal to death predicted NFTs beyond the contribution of early CDRs. NPs were predicted by both early and late CDRs. NPs were predictive of both early and late CDRs after controlling for NFTs. NFTs were only associated significantly with late CDR in the cerebral cortex after controlling for NPs. CONCLUSIONS: Even if assessed several years before death, dementia severity is associated with AD neuropathology. NPs are more strongly associated with dementia severity than NFTs. NFTs consistently associate better with late than early CDR, suggesting that these neuropathological changes may occur relatively later in the course of the disease.

Silverman JM, Schmeidler J, Schnaider-Beeri M, Grossman HT, Luo X, West R, Lally RC, Wang JY. · Department of Psychiatry, Mount Sinai School of Medicine, New York, New York 10029, USA. · Am J Med Genet B Neuropsychiatr Genet. · Pubmed #18161858 No free full text.

Abstract: Life expectancy is a familial trait. However, the effectiveness of using the age at death of a deceased parent to estimate life expectancy in their offspring can vary depending on whether death in the parent was due to extrinsic versus intrinsic causes, as well as demographic characteristics such as sex. While Alzheimer's disease (AD) risk increases with increased age, mortality for individuals with AD is increased in contrast to comparably aged individuals without AD. Yet in most cases it is not the defining neuropathology of AD that directly terminates life but instead conditions and illnesses extrinsic to AD pathology that nevertheless have increased likelihood in its presence. For this reason, we hypothesized that offspring of AD mothers would have greater longevity than offspring of mothers without AD (insufficient numbers prevented a comparable analysis using fathers with AD). The longevity of 345 offspring of 100 deceased 60+ year old AD mothers was compared with 5,465 offspring in 1,312 deceased 60+ year old non-AD mothers. We used a proportional hazards model that accounted for clustered (nonindependent) observations due to the inclusion of several offspring from the same family. In both an unadjusted model and one that adjusted for the age at death in the mother, and the sex and birth year in the offspring we found evidence for increased longevity in the offspring of AD mothers. The results suggest that, in addition to genes that might directly affect pathways leading to AD, there may be familial/genetic factors not connected to specific pathophysiological processes in AD but instead associated with increased longevity that contribute to the familial aggregation observed in AD.

Silverman JM, Schnaider-Beeri M, Grossman HT, Schmeidler J, Wang JY, Lally RC. · Department of Psychiatry, Mount Sinai School of Medicine, New York, New York 10029, USA. · Am J Med Genet B Neuropsychiatr Genet. · Pubmed #18023042 No free full text.

Abstract: Survival from Alzheimer's disease (AD) and other dementias into late old age may be a useful phenotype for genetic studies of successful cognitive aging. To support molecular genetics studies for successful cognitive aging, we conducted a two-stage study to determine an optimal age phenotype for successful cognitive aging. First, risk of AD was evaluated, through informant interviews, in 4,794 parents and siblings of 976 elderly nondemented probands who were divided into three different proband age groups: those aged 60-74, 75-89, and 90+. Relatives of probands aged 90+ had a significantly lower risk than the relatives of the other two proband groups. Second, this sample was combined with an earlier sample (combined nondemented elderly probands: n = 2,025; relatives: n = 10,506), and a series of proband age groups (i.e., 75-79, 80-84, 85-89, 90+) were used to determine which optimally identifies a group of relatives with low AD risk. Using the relatives of the nondemented proband aged 60-74 as the reference group, there were reductions in cumulative risk among relatives of probands aged 85-89 and 90+, but only the latter group also showed significant reductions to the relatives of probands aged 75-79, 80-84, and 85-89. This pattern of results varied little by sex. Finally, cumulative AD risk curves were similar between relatives of probands aged 90-94 and 95+. These results suggest that age 90 is an optimal age threshold to use for both men and women in genetic studies seeking to identify genes associated with successful cognitive aging.

Beeri MS, Schmeidler J, Sano M, Wang J, Lally R, Grossman H, Silverman JM. · Mount Sinai School of Medicine, Department of Psychiatry, One Gustave Levy Place, Box 1230, New York, NY 10029, USA. · Neurology. · Pubmed #17000969 No free full text.

Abstract: OBJECTIVE: To evaluate the performance of nondemented subjects 85 years and older on the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) neuropsychological battery, and to assess its relationship with sociodemographic variables. METHODS: We studied 196 subjects enrolled in an Alzheimer's Disease Research Center study who had a complete CERAD neuropsychological assessment. We used multiple regression analysis to predict performance on the neuropsychological tests from age, education, and sex. Eight representative hypothetical individuals were created (for example, an 87-year-old man, with high education). For each test, estimates of performance at the 10th, 25th, 50th, and 75th percentiles were reported for the eight representative hypothetical individuals. RESULTS: Mean age was 89.2 years (SD = 3.2), mean years of education was 14.9 (SD = 3.2), and 66% of the sample were women. For 11 of the 14 neuropsychological tests, there was a significant multiple regression model using education, age, and sex as predictors. Neither the models nor the predictors used individually were significant for Delayed Recall, Savings, or correct Recognition. Among the significant results, seven had education as the strongest predictor. Lower age and higher education were associated with better performance. Women performed better than men in three of four tests with significant results for sex. CONCLUSIONS: In a sample of oldest old whose primary language is English, neuropsychological testing is influenced mainly by education and age. Cutoff scores based on younger populations and applied to the oldest old might lead to increased false-positive misclassifications.

Beeri MS, Rapp M, Silverman JM, Schmeidler J, Grossman HT, Fallon JT, Purohit DP, Perl DP, Siddiqui A, Lesser G, Rosendorff C, Haroutunian V. · Department of Psychiatry, The Mount Sinai School of Medicine, New York, NY, USA. · Neurology. · Pubmed #16682673 No free full text.

Abstract: OBJECTIVE: To examine the associations between postmortem Alzheimer disease (AD) neuropathology and autopsy-verified cardiovascular disease. METHODS: The authors examined 99 subjects (mean age at death = 87.6; SD = 8.7) from the Mount Sinai School of Medicine Department of Psychiatry Brain Bank who were devoid of cerebrovascular disease-associated lesions or of non-AD-related neuropathology. Density of neuritic plaques (NPs) and neurofibrillary tangles (NFTs) as well as coronary artery and aortic atherosclerosis, left ventricular wall thickness, and heart weight were measured. Partial correlations were used to assess the associations of the four cardiovascular variables with NPs and NFTs in the hippocampus, entorhinal cortex, and multiple regions of the cerebral cortex after controlling for age at death, sex, dementia severity, body mass index, and ApoE genotype. These analyses were also repeated separately for ApoE4 carriers and noncarriers. RESULTS: The extent of coronary artery disease and to a lesser extent atherosclerosis were significantly associated with the density of cardinal neuropathologic lesions of AD in this autopsy sample (significant correlations between 0.22 and 0.29). These associations were more pronounced for the ApoE4 allele carriers (n = 42; significant correlations between 0.34 and 0.47). CONCLUSIONS: The degree of coronary artery disease is independently associated with the cardinal neuropathological lesions of Alzheimer disease. These associations are primarily attributable to individuals with the ApoE4 allele.

Beeri MS, Silverman JM, Davis KL, Marin D, Grossman HZ, Schmeidler J, Purohit DP, Perl DP, Davidson M, Mohs RC, Haroutunian V. · Department of Psychiatry, Mount Sinai School of Medicine, New York, USA. · J Gerontol A Biol Sci Med Sci. · Pubmed #15933386 No free full text.

Abstract: BACKGROUND: In cross-sectional and longitudinal studies, type 2 diabetes has been positively associated with the risk of Alzheimer's disease (AD). The present descriptive study compared diabetic and nondiabetic subjects on the severity of neuritic plaques and neurofibrillary tangles (NFTs) in the cerebral cortex and in the hippocampus. METHODS: The study included specimens from 385 consecutive autopsies of residents of a nursing home (15.8% diabetics). Mean age at death = 84 years [standard deviation (SD) = 10], 66% were female, Clinical Dementia Rating mean = 3.0 (SD = 1.6), and 32.5% had an APOE4 allele. Additional analyses limited the sample to 268 subjects (14.1% diabetics) without neuropathology other than AD. RESULTS: Analyses of covariance controlling for age at death, dementia severity (Clinical Dementia Rating score), and APOE4 allele indicated that diabetics had significantly fewer neuritic plaques (p =.008) and NFTs (p =.047) in the cerebral cortex than did nondiabetics. In the hippocampus, diabetics had significantly lower plaque ratings than did nondiabetics (p =.019), but the lower ratings of NFTs did not achieve statistical significance (p =.082). In the entire sample, diabetics had significantly less AD-associated neuropathology in all four analyses. CONCLUSIONS: These results raise the possibility that the varied associations observed between diabetes and AD may be specific to as yet ill-defined subgroups of dementia and diabetic patients or may be more characteristic of younger patients than of those who survive to a mean age of 84 years. Future studies are encouraged to examine a variety of other characteristics such as age that may interact with diabetes affecting the incidence of AD.

Silverman JM, Ciresi G, Smith CJ, Marin DB, Schnaider-Beeri M. · Department of Psychiatry, Mount Sinai School of Medicine, New York, NY 10029, USA. · Arch Gen Psychiatry. · Pubmed #15867110 links to  free full text

Abstract: CONTEXT: The role of genetic factors in Alzheimer disease (AD) varies across the late life span, complicating efforts to quantify the risk of AD for relatives of probands with AD. OBJECTIVES: To visualize the changing levels of familial risk according to proband onset age and the age of the at-risk relative and to determine the familiality of age at onset in AD. DESIGN: A retrospective, informant-based family study. SETTING, PATIENTS, AND OTHER PARTICIPANTS: Siblings and parents of probands with AD (relatives = 4687; probands = 904), ascertained at geriatric clinic and nursing home settings, and of elderly probands without dementia (relatives = 7649; probands = 1525) who were spouses of probands, participants at senior centers, or nursing home residents without dementia. MAIN OUTCOME MEASURES: Informant-based assessments of AD in the relatives were used to generate 3-dimensional surfaces representing the patterns of risk of AD across the late life span depending on the specific onset age of the proband with AD (or assessment age of the elderly proband without dementia). We then constructed a 3-dimensional, age-specific, 10-year hazard rate ratio (HRR) surface representing the relative risk of AD in relatives of probands with AD with smoothly shifting levels of onset age compared with relatives of elderly probands without dementia. RESULTS: The HRR surface peaked (HRR, 13.0) for younger sexagenarian relatives related to probands with AD with onset age in their early 60s. The HRRs dropped sharply both as the proband age at onset and the age of the relative increased. For relatives aged in their late 80s, the HRR fell lower than 2.0 regardless of proband onset age and their lower-limit 95% confidence intervals were less than 1.0. CONCLUSIONS: The role of genetic risk factors decreases with increasing onset age of the proband with AD regardless of the age of the relatives themselves. The familiality of onset age is greatly reduced at later ages. The role of environmental risk factors in AD likely increases with onset age.

Beeri MS, Davidson M, Silverman JM, Noy S, Schmeidler J, Goldbourt U. · Mt. Sinai School of Medicine, Department of Psychiatry, One Gustave Levy Place, Box 1230, New York, NY 10029, USA. · Am J Geriatr Psychiatry. · Pubmed #15703320 No free full text.

Abstract: OBJECTIVE: Structural and functional brain reserves, thought to develop in childhood and adolescence, may be critical in determining the age at onset of cognitive impairment. Body height is affected by childhood conditions that promote growth. The authors examine the relationship of height in midlife and subsequent dementia, Alzheimer disease (AD), and vascular dementia. METHODS: Dementia was evaluated from 1999 to 2001 in 1,892 men age 76 to 95. Height had been measured when these men participated in the Israeli Ischemic Heart Disease project in 1963. Age, socioeconomic status (SES), and area of birth were also assessed in 1963. RESULTS: Older men and those with lower SES tended to be shorter. Relative to the shortest quartile, controlling for age, SES, and area of birth, the other quartiles had lesser respective odds ratios for dementia as a whole, AD, and vascular dementia. CONCLUSION: Height was inversely associated with dementia, AD, and vascular dementia in a male sample. Since height is associated with childhood nutrition and may be associated with other risk factors for dementia, efforts to improve early life conditions that maximize body growth may diminish or delay the onset of dementia in later life.

Silverman JM, Smith CJ, Marin DB, Mohs RC, Propper CB. · Department of Psychiatry, Box 1230, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, NY 10029, USA. · Arch Gen Psychiatry. · Pubmed #12578437 links to  free full text

Abstract: BACKGROUND: The incidence of Alzheimer disease (AD) peaks after 85 years of age. Although genetic factors are implicated in AD with substantially earlier onset, the familial characteristics of high-incidence very late-onset AD (VLOAD, defined here as AD with onset age >/=85 years) remain unknown. METHODS: We collected information pertaining to the cognitive status and demographics of 809 parents and siblings of 144 VLOAD probands, 4235 parents and siblings of 793 earlier-onset AD probands, and 7646 parents and siblings of 1493 nondemented elderly probands. Cumulative risks and 5-year interval-specific hazard rate ratios were calculated for AD in relatives of the 2 AD proband groups and relatives of the nondemented elderly group. RESULTS: The cumulative risk for AD in the relatives of VLOAD probands was significantly different than that in the relatives of earlier-onset AD probands (P<.001), but not in the relatives of nondemented elderly probands. Also, the relatives of earlier-onset AD probands had hazard rate ratios ranging from 19.7 in those aged 50 to 54 years to 1.2 in those aged 90 to 94 years. Rates successively dropped as age intervals increased. CONCLUSIONS: At least through the middle of the ninth decade of life, relatives of VLOAD probands have a lower risk for AD than those of earlier-onset AD probands. In addition, the relatively increased risk of relatives of earlier-onset AD probands is highest at younger ages and diminishes with increasing age. In counseling family members of patients with AD concerned about their own risk, the onset age of the patient and the age of the concerned relative should be considered. Very late-onset AD may be a good target for investigating environmental factors associated with AD.

Silverman JM, Smith CM, Marin DB, Schmeidler J, Birstein S, Lantz M, Davis KL, Mohs RC. · Department of Psychiatry, Mt. Sinai School of Medicine, New York, NY 10029, USA. · Int J Geriatr Psychiatry. · Pubmed #10918344 No free full text.

Abstract: Studies of the familial aggregation of Alzheimer's disease have primarily used samples ascertained from tertiary care clinics which may not be representative of many AD patients, for example those residing at geriatric nursing homes. Survival analysis was used to investigate whether estimates of familial aggregation of AD based on a clinic-based AD proband (C-AD) sample (probands: N=544; first degree relatives; N=4267) differ from one ascertained at a nursing home (NH-AD; probands: N=225; first degree relatives; N=1772). The cumulative survival from AD was significantly worse in relatives of the C-AD probands and the overall relative risk (RR) of AD in this group was greater than twice that of relatives of the NH-AD probands. However, age at onset in C-AD probands was significantly earlier than in the NH-AD group and in both groups this factor was negatively associated with familial aggregation. When, for this reason, the proband samples were matched one-to-one by age at onset, dropping those probands with no match, the two curves were close to identical and the RR for the C-AD group of relatives was 1.0 The results suggest that estimates of familial risk of AD based on C-AD samples are not applicable and overestimate the extent of increased risk for relatives of more prevalent, later onset AD probands. However, the overestimate can be explained by the typically earlier age at onset in C-AD samples as opposed to a sampling bias related to the proband's family history status per se. The relationship between onset age and familial aggregation suggests that no single estimate of the age-dependent risk (survival curve) is uniformly appropriate for relatives of AD probands.

Ehrenkrantz D, Silverman JM, Smith CJ, Birstein S, Marin D, Mohs RC, Davis KL. · Department of Psychiatry, Mt. Sinai School of Medicine, New York, New York 10029, USA. · Am J Med Genet. · Pubmed #10402505 No free full text.

Abstract: Recent evidence for mitochondrial mutations associated with Alzheimers disease (AD) suggests the possibility of maternal transmission of this illness. We investigated this hypothesis by examining, in a variety of ways, the risk of a primary progressive dementia (PPD) in the parents (n = 650) and siblings (n = 1,220) of 325 AD probands. The results did not support maternal transmission in AD: The mothers of AD probands were not at greater risk of PPD than the fathers or the sisters of AD probands; the offspring of affected mothers were not at greater risk than the offspring of affected fathers or families with no affected parent; and, after selecting those proband families with evidence for increased familial loading, such families did not more frequently have affected mothers than fathers. In contrast, the cumulative risk of PPD in fathers of AD probands, while similar to that of mothers, was significantly increased over the brothers of AD probands. In addition, the cumulative risk curve of PPD in the offspring of affected fathers was significantly higher than the offspring of no affected parents. While no evidence for maternal transmission in AD was observed, unexpectedly, we did find evidence of increased paternal transmission.

Silverman JM, Smith CJ, Marin DB, Birstein S, Mare M, Mohs RC, Davis KL. · Department of Psychiatry, Mt. Sinai School of Medicine, One Gustave L. Levy Place, New York, NY 10029, USA. · Am J Hum Genet. · Pubmed #10053018 links to  free full text

Abstract: Elderly individuals who lived beyond the age of 90 years without dementia were hypothesized to have increased concentrations of genetic protective factors against Alzheimer disease (AD), conferring a reduced liability for this disease relative to less-aged nondemented elderly. However, testing this hypothesis is complicated by having to distinguish such a group from those who may lack genetic risk factors for AD, have had protective environmental exposures, or have escaped dementia for other reasons. Probands carrying genetic protective factors, however, should have relatives with lower illness rates not only for earlier-onset disease, when genetic risk factors are a strong contributing factor to the incidence of AD, but also for later-onset disease, when the role of these factors appears to be markedly diminished. AD dementia was assessed through family informants in 6,660 first-degree relatives of 1,049 nondemented probands aged 60-102 years. The probands were grouped by age (60-74, 75-89, and 90-102 years), and the cumulative survival from AD and 10-year-age-interval hazard rates of AD were calculated in their first-degree relatives. Cumulative survival from AD was significantly greater in the relatives of the oldest proband group (aged 90-102 years) than it was in the two younger groups. In addition, the reduction in the rate of illness for this group was relatively constant across the entire late life span. The results suggest that genetic factors conferring a lifelong reduced liability of AD may be more highly concentrated among nondemented probands aged >/=90 years and their relatives. Efforts to identify protective allele-bearing genes that are associated with very late-onset AD should target the families of nonagenarians and centenarians.

Samuels SC, Silverman JM, Marin DB, Peskind ER, Younki SG, Greenberg DA, Schnur E, Santoro J, Davis KL. · Department of Psychiatry, Mount Sinai School of Medicine, New York, NY, USA. · Neurology. · Pubmed #10025785 No free full text.

Abstract: OBJECTIVES: We examined the relationship between CSF amyloid beta peptide (A beta) concentration and AD severity in 31 probable AD patients and explored whether APOE genotype modifies this relationship. BACKGROUND: A beta deposition in AD brains has been correlated with disease severity and with APOE-epsilon4 allele frequency. Few studies have examined the effects of APOE genotype on the relationship between CSF A beta and disease severity in an antemortem sample. METHODS: Patients carried the clinical diagnosis of probable AD and did not have serious medical illness, current or past diagnosis of mood disorder, schizophrenia or alcoholism, or current psychotic features. The Mini-Mental State Examination (MMSE) was administered to the patient within 3 months of CSF collection. CSF was analyzed for A beta1-40 and A beta1-42 by sandwich ELISAs, and APOE genotype was determined by PCR run from blood. Correlations were performed between MMSE score and A beta1-40 and A beta1-42 concentrations while controlling for potential confounding variables. RESULTS: CSF measures of A beta1-40 and A beta1-42 concentrations were correlated with each other (r = 0.56, df = 28, p < 0.01). CSF A beta1-40 and A beta1-42 concentrations were positively correlated with MMSE score. The negative association between CSF A beta measures and disease severity remained significant after controlling for age (A beta1-40 and MMSE score: r = 0.46, df = 28, p = 0.01; A beta1-42 and MMSE score: r = 0.35, df = 28, p = 0.05). Among the APOE-epsilon3/3 homozygotes there was a significant positive correlation only between A beta1-42 and MMSE score (A beta1-42, r = 0.94, p = 0.02; A beta1-40, r = 0.79, p = 0.11). CONCLUSIONS: We hypothesize that an increased deposition of A beta in plaques results in decreased CSF A beta concentration. The stronger relationship between MMSE score and CSF A beta, specifically in APOE-epsilon3/3 homozygotes, suggests that patients with APOE-epsilon3/3 genotype may have different pathogenic mechanisms than the other genotypes for A beta deposition or clearance.