Alzheimer Disease: Zonderman AB

Jarvik L, LaRue A, Blacker D, Gatz M, Kawas C, McArdle JJ, Morris JC, Mortimer JA, Ringman JM, Ercoli L, Freimer N, Gokhman I, Manly JJ, Plassman BL, Rasgon N, Roberts JS, Sunderland T, Swan GE, Wolf PA, Zonderman AB. · Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, CA 90095, USA. · Alzheimer Dis Assoc Disord. · Pubmed #18317242 No free full text.

Abstract: Children of persons with Alzheimer disease (AD), as a group, face an increased risk of developing AD. Many of them, throughout their adult lives, seek input on how to reduce their chances of one day suffering their parent's fate. We examine the state of knowledge with respect to risk and protective factors for AD and recommend a research agenda with special emphasis on AD offspring.

Beydoun MA, Lhotsky A, Wang Y, Dal Forno G, An Y, Metter EJ, Ferrucci L, O'Brien R, Zonderman AB. · Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, Maryland 21224, USA. · Am J Epidemiol. · Pubmed #18835864 No free full text.

Abstract: Adiposity status and change are potential risk factors for Alzheimer's disease (AD). The authors used data on 2,322 participants in the Baltimore Longitudinal Study of Aging to analyze the relation between AD incidence and adiposity in Cox proportional hazards models, with adjustment for sociodemographic factors and smoking status. Body mass index (BMI; weight (kg)/height (m)(2)) and waist circumference at specific ages were predicted by empirical Bayes estimators from mixed-effects regression models. After a median of 23.4 years of follow-up between 1958 and 2006, 187 participants developed AD. Among men, being underweight (BMI <or=18.5) at age 30, 40, or 45 years increased the likelihood of AD (hazard ratio (HR) = 5.76, 95% confidence interval (CI): 2.07, 16.00); among women, being obese (BMI >or=30) at age 30, 40, or 45 years and jointly centrally obese (waist circumference >or=80th percentile) at age 30, 35, or 50 years increased AD risk (HR = 6.57, 95% CI: 1.96, 22.02). Women who lost weight (BMI change <10th percentile) between ages 30 and 45 years were also at increased risk (HR = 2.02, 95% CI: 1.06, 3.85). Weight gain among men (BMI change >90th percentile) between ages 30 and 50 years increased AD risk (HR = 3.70, 95% CI: 1.43, 9.56). Future studies should identify age- and gender-specific optimal weights and weight-loss strategies for preventing AD and investigate potential mechanisms.

Iacono D, O'Brien R, Resnick SM, Zonderman AB, Pletnikova O, Rudow G, An Y, West MJ, Crain B, Troncoso JC. · Division of Neuropathology, Department of Pathology, School of Medicine, Johns Hopkins University, Baltimore, Maryland 21205, USA. · J Neuropathol Exp Neurol. · Pubmed #18520776 links to  free full text

Abstract: The pathologic changes of Alzheimer disease (AD) evolve very gradually over decades before the disease becomes clinically manifest. Thus, it is not uncommon to find substantial numbers of Abeta plaques and neurofibrillary tangles in autopsy brains of older subjects with documented normal cognition, a state that we define as asymptomatic AD (ASYMAD). The goal of this study is to understand the morphometric substrate of ASYMAD subjects compared with mild cognitive impairment and definite AD cases. We used designed-based stereology to measure the volumes of neuronal cell bodies, nuclei, and nucleoli in 4 cerebral regions: anterior cingulate gyrus, posterior cingulate gyrus, primary visual cortex, and CA1 of hippocampus. We examined and compared autopsy brains from 4 groups (n = 15 each) of participants in the Baltimore Longitudinal Study of Aging: ASYMAD, mild cognitive impairment, AD, and age-matched controls. We found significant hypertrophy of the neuronal cell bodies, nuclei, and nucleoli of CA1 of hippocampus and anterior cingulate gyrus neurons in ASYMAD subjects compared with control and mild cognitive impairment cases. In the posterior cingulate gyrus and primary visual cortex, the hypertrophy was limited to the nuclei and nucleoli. The hypertrophy of cortical neurons and their nuclei and nucleoli in ASYMAD may represent an early reaction to the presence of neurotoxic Abeta or tau, or a compensatory mechanism that prevents the progression of the disease into dementia.

Szekely CA, Green RC, Breitner JC, Østbye T, Beiser AS, Corrada MM, Dodge HH, Ganguli M, Kawas CH, Kuller LH, Psaty BM, Resnick SM, Wolf PA, Zonderman AB, Welsh-Bohmer KA, Zandi PP. · Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA. · Neurology. · Pubmed #18509093 No free full text.

Abstract: INTRODUCTION: Observational studies show reduced incidence of Alzheimer dementia (AD) in users of nonsteroidal anti-inflammatory drugs (NSAIDs). One hypothesis holds that the subset of NSAIDs known as selective A beta(42)-lowering agents (SALAs) is responsible for this apparent reduction in AD risk. METHODS: We pooled individual-level data from six prospective studies to obtain a sufficient sample to examine AD risk in users of SALA vs non-SALA NSAIDs. RESULTS: Of 13,499 initially dementia-free participants (70,863 person-years), 820 developed incident AD. Users of NSAIDs (29.6%) showed reduced risk of AD (adjusted hazard ratio [aHR] 0.77, 95% CI 0.65-0.91). The point estimates were similar for SALAs (aHR 0.87, CI 0.72-1.04) and non-SALAs (aHR 0.75, CI 0.56-1.01). Because 573 NSAID users (14.5%) reported taking both a SALA and non-SALA, we examined their use alone and in combination. Resulting aHRs were 0.82 (CI 0.67-0.99) for SALA only, 0.60 (CI 0.40-0.90) for non-SALA only, and 0.87 (CI 0.57-1.33) for both NSAIDs (Wald test for differences, p = 0.32). The 40.7% of participants who used aspirin also showed reduced risk of AD, even when they used no other NSAIDs (aHR 0.78, CI 0.66-0.92). By contrast, there was no association with use of acetaminophen (aHR 0.93, CI 0.76-1.13). CONCLUSIONS: In this pooled dataset, nonsteroidal anti-inflammatory drug (NSAID) use reduced the risk of Alzheimer dementia (AD). However, there was no apparent advantage in AD risk reduction for the subset of NSAIDs shown to selectively lower A beta(42), suggesting that all conventional NSAIDs including aspirin have a similar protective effect in humans.

Troncoso JC, Zonderman AB, Resnick SM, Crain B, Pletnikova O, O'Brien RJ. · Department of Pathology, Johns Hopkins University, Baltimore, MD, USA. · Ann Neurol. · Pubmed #18496870 links to  free full text

Abstract: OBJECTIVE: To define the magnitude and mechanism of the effect of brain infarcts on the odds of dementia in a prospective study. METHODS: We examined the effects of brain infarcts and Alzheimer's disease (AD) pathology on the risk for dementia in 179 subjects from the Baltimore Longitudinal Study of Aging Autopsy Program. All subjects had longitudinal clinical and cognitive evaluations, and underwent postmortem examination of the brain. RESULTS: Brain infarcts were common in our cohort, and both symptomatic and asymptomatic infarcts conferred a significant increase in the odds of dementia. Risk factors for stroke in the absence of an infarct did not increase the odds of dementia, which was quantitatively related to the number but not the size of hemispheral infarcts; deep subcortical infarcts conferred no increased risk for dementia. The contribution of microscopic infarcts to dementia was significant and equivalent to that of macroscopic infarcts. In subjects with intermediate AD pathology scores, a single macroscopic hemispheral infarct was sufficient to cause dementia. A logistic regression model of the effect of infarcts and AD pathology on dementia indicated that AD pathology alone accounts for 50% of the dementia seen in this cohort, and that hemispheral infarcts alone or in conjunction with AD pathology account for 35%. INTERPRETATION: Cerebrovascular disease is a significant and potentially preventable cause of dementia in the Baltimore Longitudinal Study of Aging. Burden and location of infarcts are significantly associated with cognitive decline.

Grober E, Hall CB, Lipton RB, Zonderman AB, Resnick SM, Kawas C. · Department of Neurology, Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, New York 10467, USA. · J Int Neuropsychol Soc. · Pubmed #18282324 No free full text.

Abstract: In the Baltimore Longitudinal Study of Aging (BLSA), we examined the temporal unfolding of declining performance on tests of episodic memory (Free Recall on the Free and Cued Selective Reminding Test), executive function (Category Fluency, Letter Fluency, and Trails), and Verbal Intelligence (Nelson, 1982; American Version of the Nelson Adult Reading Test [AMNART]) before the diagnosis of dementia in 92 subjects with incident Alzheimer's disease (AD) followed for up to 15 years before diagnosis. To examine the preclinical onset of cognitive decline, we aligned subjects at the time of initial AD diagnosis and examined the cognitive course preceding diagnosis. We found that declines in performance on tests of episodic memory accelerated 7 years before diagnosis. Declining performance on tests of executive function accelerated 2-3 years before diagnosis, and verbal intelligence declined in close proximity to diagnosis. This cognitive profile is compatible with pathologic data suggesting that structures which mediate memory are affected earlier than frontal structures during the preclinical onset of AD. It also supports the view that VIQ as estimated by the AMNART does not decline during the preclinical onset of AD.

Morgan MD, Mielke MM, O'Brien R, Troncoso JC, Zonderman AB, Lyketsos CG. · Johns Hopkins University, Baltimore, MD 21224, USA. · Alzheimer Dis Assoc Disord. · Pubmed #17804951 links to  free full text

Abstract: The prevalence of major depression is increased in Alzheimer disease (AD), but currently the basis of this association remains unclear. The present study examined rates of depression in 4 groups of participants with postmortem examination from the Baltimore Longitudinal Study of Aging: (1) cognitively normal controls with no Alzheimer pathology, (2) cognitively normal individuals with Alzheimer pathology, (3) individuals with mild cognitive impairment plus Alzheimer pathology, (4) individuals with clinical diagnoses of dementia plus Alzheimer pathology. Depressive symptoms were assessed using the Center for Epidemiologic Studies Depression Scale. Individuals with Alzheimer pathology but no cognitive decline before death had significantly lower rates of depression than cognitively normal controls with no Alzheimer pathology and individuals with Alzheimer pathology plus clinical diagnoses of dementia. These findings suggest that depression is a risk factor for AD in the presence of AD pathology, but depression is not a risk factor for AD pathology.

Riudavets MA, Iacono D, Resnick SM, O'Brien R, Zonderman AB, Martin LJ, Rudow G, Pletnikova O, Troncoso JC. · Division of Neuropathology, Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. · Neurobiol Aging. · Pubmed #17599696 links to  free full text

Abstract: This study focuses on the morphometric changes of neurons in asymptomatic Alzheimer's disease (AD), a state characterized by the presence of AD lesions in subjects without cognitive impairment. In autopsy brains, we used stereological methods to compare the cell body and nuclear volumes of anterior cingulate gyrus (ACG) and CA1 hippocampal neurons in asymptomatic AD subjects (n=9), subjects with AD dementia (AD, n=8), mild cognitive impairment (MCI, n=9), and age-matched controls (controls, n=9). In ACG, we observed a significant decrease in the neuronal volume of MCI and AD compared to controls; by contrast, no atrophy was present in asymptomatic AD. Moreover, we found a significant increase in nuclear volume in asymptomatic AD compared to controls (P<0.001), MCI (P<0.01) and AD (P<0.001) brains. Similar results were found in the CA1 region of the hippocampus. This nuclear hypertrophy may represent an early neuronal reaction to Abeta or Tau, or a compensatory mechanism which forestalls the progression of AD and allows the brain to resist the development of dementia.

Driscoll I, Resnick SM, Troncoso JC, An Y, O'Brien R, Zonderman AB. · Laboratory of Personality and Cognition, National Institute on Aging, National Institutes of Health, Johns Hopkins University School of Medicine, Baltimore, MD, USA. · Ann Neurol. · Pubmed #17192929 No free full text.

Abstract: OBJECTIVE: Some individuals who are asymptomatic for dementia while alive have substantial Alzheimer's disease (AD) neuropathology at autopsy. We investigated whether cognitive trajectories differ between clinically normal elderly individuals with and without AD neuropathology and how they compare with trajectories of clinically impaired individuals before dementia diagnosis. METHODS: Eighty-one elderly participants in the Baltimore Longitudinal Study of Aging (BLSA) were followed prospectively with neurological and neuropsychological assessments before autopsy evaluation at death. Trajectories of cognitive change were estimated for a number of domains using cognitive data before a clinical diagnosis of dementia. RESULTS: Clinically normal elderly individuals with and without AD-type neuropathology have similar cognitive trajectories across different cognitive domains. In contrast, individuals with mild cognitive impairment/AD show steeper rates of longitudinal decline in several aspects of cognition compared with clinically normal elderly individuals regardless of whether the latter have AD neuropathology. Moreover, the cognitive differences between impaired and unimpaired groups can be detected years before a diagnosis of dementia. INTERPRETATION: Clinically normal individuals with and without AD neuropathology do not differ in rates of cognitive decline across a number of cognitive domains. Understanding the factors that protect some individuals with AD pathology from cognitive impairment may contribute to the maintenance of cognitive health in the elderly.

Zonderman AB. · National Institute on Aging, Laboratory of Personality & Cognition, Cognition Section, Baltimore, Maryland 21224, USA. · J Geriatr Psychiatry Neurol. · Pubmed #16306238 links to  free full text

Abstract: Longitudinal studies offer opportunities for studying children whose parents have Alzheimer's disease. The Baltimore Longitudinal Study of Aging (BLSA) has examined adult cognitive performance but has not systematically recruited participants' children. We initiated studies of dementia in the 1980s. This work suggested that hormone replacement and use of nonsteroidal anti-inflammatory drugs reduced the risk of Alzheimer's disease and that risk for Alzheimer's disease could be predicted from cognitive performance as many as 20 years prior to its onset. More recently, we showed that premorbid levels of free testosterone were lower in men who developed Alzheimer's disease and premorbid depressive symptomatology was a risk for Alzheimer's disease in men but not women as many as 6 years before the onset of dementia. Participants in the BLSA include family members with a variety of degrees of relationship, but there is no systematic effort to collect data from relatives of participants.

Brant LJ, Sheng SL, Morrell CH, Zonderman AB. · Gerontology Research Center, National Institute on Aging, 5600 Nathan Shock Drive, Baltimore, MD 21224, USA. · J Clin Epidemiol. · Pubmed #15939221 No free full text.

Abstract: BACKGROUND: This article presents a computerized method to help predict individuals at risk for developing Alzheimer's disease (AD). This would be a valuable tool for clinicians in developing treatment plans for potential AD patients. Using the initial level and rates of change in visual memory performance, such a method could predict potential AD patients in a fast and inexpensive manner. A longitudinal case-control study of 52 female and 145 male participants was performed in a gerontology research center using premorbid tests of visual memory and neurologic examinations to identify individuals with and without dementia and AD. METHODS: The classification method for each individual starts on the second examination and proceeds to compute that person's risk of AD one examination at a time based on all the follow-up information of the remaining individuals. RESULTS: By performing a crossvalidation study, the optimal combination of sensitivity and specificity derived from a receiver operating characteristic (ROC) curve showed 65% of the Alzheimer cases and 75% of the noncases were correctly classified for females, while 65 and 60% of cases and noncases, respectively, were correctly classified for males. CONCLUSION: Longitudinal measurements of cognition can be useful in detecting the presence of AD.

Dal Forno G, Palermo MT, Donohue JE, Karagiozis H, Zonderman AB, Kawas CH. · Clinical Neurosciences, University Campus BioMedico and Associazione Fatebenefratelli per la Ricerca (A.Fa.R.), Via dei Compositori 130-132, 00128 Rome, Italy. · Ann Neurol. · Pubmed #15732103 No free full text.

Abstract: Depression associates with increased risk for dementia and Alzheimer's disease (AD), although it is unclear whether it represents an actual risk factor or a prodrome. To determine the relative hazard of premorbid depressive symptomatology for development of dementia and AD, we studied risk for incident dementia and AD over a 14-year period in 1,357 community-dwelling men and women participating in the 40-year prospective Baltimore Longitudinal Study of Aging. Screening for depressive symptoms, comprehensive medical and neuropsychological evaluations were prospectively collected every 2 years. Time-dependent proportional hazards of development of AD or dementia were calculated separately for men and women, with symptoms of depression detected at 2-, 4-, and 6-year intervals before onset of dementia symptoms. Vascular risk factors were analyzed as covariates. Premorbid depressive symptoms significantly increased risk for dementia, particularly AD in men but not in women. Hazard ratios were approximately two times greater than for individuals without history of depressive symptoms, an effect independent of vascular disease. We conclude that the impact of depressive symptoms on risk for dementia and AD may vary with sex. Further studies assessing separately the role of depression as a risk factor in men and women are necessary.

Moffat SD, Zonderman AB, Metter EJ, Kawas C, Blackman MR, Harman SM, Resnick SM. · Laboratory of Personality and Cognition, National Institute on Aging, Intramural Research Program, Baltimore, MD 21224, USA. · Neurology. · Pubmed #14745052 No free full text.

Abstract: OBJECTIVE: To investigate the relationships between age-associated decreases in endogenous serum total testosterone (T) and a free T index (FTI) in men and the subsequent development of Alzheimer disease (AD). METHOD: The authors used a prospective, longitudinal design with follow-up in men since 1958. Participants were from the Baltimore Longitudinal Study of Aging, a community-dwelling volunteer sample with baseline ages of 32 to 87 years. All subjects were free of AD at baseline T assessment. Five hundred seventy-four men assessed at multiple time points were followed for a mean of 19.1 years (range, 4 to 37 years). Diagnoses of AD were based on biennial physical, neurologic, and neuropsychological evaluations. RESULTS: Diagnosis of AD was associated inversely with FTI by itself and after adjustments for age, education, smoking status, body mass index, diabetes, any cancer diagnoses, and hormone supplements. In separate analyses, total T and sex hormone binding globulin were not significant predictors after adjustment with covariates. Increases in the FTI were associated with decreased risk of AD (hazard ratio = 0.74; 95% CI = 0.57 to 0.96), a 26% decrease for each 10-nmol/nmol FTI increase. CONCLUSIONS: Calculated free testosterone concentrations were lower in men who developed Alzheimer disease, and this difference occurred before diagnosis. Future research may determine whether higher endogenous free testosterone levels offer protection against a diagnosis of Alzheimer disease in older men.

Kawas CH, Corrada MM, Brookmeyer R, Morrison A, Resnick SM, Zonderman AB, Arenberg D. · Alzheimer's Disease Research Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA. · Neurology. · Pubmed #12682311 No free full text.

Abstract: BACKGROUND: Recent studies have suggested that AD may reflect a chronic process that begins many years before the clinical expression of dementia. The current study examines premorbid Benton Visual Retention Test (BVRT) and Wechsler Adult Intelligence Scale-vocabulary (WAIS-voc) test scores in order to determine whether long-term deficits in these tests can predict the development of AD decades later in the Baltimore Longitudinal Study of Aging (BLSA). METHOD: Participants are volunteers from the BLSA, a multidisciplinary study of normal aging conducted by the National Institute on Aging. A total of 1,425 BLSA participants who were older than 60 years were included in the analyses. Cox proportional hazards models were used to estimate the relative risk of developing AD associated with BVRT and WAIS-voc scores at different time periods up to 20 years before the diagnosis of AD. RESULTS: The relative risks for 6 or more BVRT errors vs less than 6 errors at 1 to 3, 3 to 5, 5 to 10, and 10 to 15 years before the diagnosis of AD were 5.69, 2.11, 1.76, and 1.83 (p < 0.05). The relative risk for 15 or more years before diagnosis was not significant (p > 0.10). WAIS-voc scores were not significantly associated with the risk of AD in any time period. CONCLUSIONS: A greater number of errors on the BVRT is associated with an increased risk of AD up to 15 years later. Poor visual memory performance may represent an early expression of AD years before diagnosis. This result suggests the need to continue to revise views on the natural history of AD and the possibility of an increased window of opportunity for preventive treatment before definitive diagnosis.

Moffat SD, Szekely CA, Zonderman AB, Kabani NJ, Resnick SM. · Gerontology Research Center, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA. · Neurology. · Pubmed #10891924 No free full text.

Abstract: The epsilon4 allele of the apolipoprotein E (APOE) gene confers an increased risk for the development of AD. The authors compared longitudinal rates of change in hippocampal volume as a function of APOE genotype in nondemented elderly individuals. Rate of volumetric loss was significantly greater among epsilon4+ compared with epsilon4- individuals. These results indicate that individuals positive for the APOE epsilon4 allele may show a greater rate of hippocampal atrophy than their epsilon4- counterparts, even in the absence of a diagnosis of AD.