Alzheimer Disease: Sager MA

Ries ML, Carlsson CM, Rowley HA, Sager MA, Gleason CE, Asthana S, Johnson SC. · William S. Middleton Memorial Veterans Hospital Geriatric Research Education and Clinical Center, Madison, Wisconsin 53705, USA. · J Am Geriatr Soc. · Pubmed #18410325 links to  free full text

Abstract: Given the predicted increase in prevalence of Alzheimer's disease (AD) in the coming decades, early detection and intervention in persons with the predementia condition known as mild cognitive impairment (MCI) is of paramount importance. Recent years have seen remarkable advances in the application of neuroimaging and other biomarkers to the study of MCI. This article reviews the most recent developments in the use of magnetic resonance imaging (MRI) to characterize brain changes and to prognosticate clinical outcomes of patients with MCI. The review begins with description of methods and findings in structural MRI research, delineating findings regarding both gross atrophy and microstructural brain changes in MCI. Second, we describe the most recent findings regarding brain function in MCI, enumerating findings from functional MRI and brain perfusion studies. Third, we will make recommendations regarding the current clinical use of MRI in identification of MCI. As a conclusion, we will look to the future of neuroimaging as a tool in early AD detection.

Shelton P, Schraeder C, Dworak D, Fraser C, Sager MA. · Outcomes/Performance and Improvement, Coordinated Care Services, Mahomet, Illinois 61853, USA. · J Am Geriatr Soc. · Pubmed #11843991 No free full text.

Abstract: OBJECTIVES: The purpose of this study is to examine the effect of the Medicare Alzheimer's Disease Demonstration and Evaluation (MADDE) conducted in Illinois on the use of health services and Medicare expenditures by caregivers of persons with dementia. DESIGN: Prospective randomized clinical trial. SETTING: The MADDE (1989-1994), Illinois site. PARTICIPANTS: A cohort of 412 Medicare-eligible caregivers of persons with dementia. MEASUREMENTS: Medicare claims files provided data on the number of hospitalizations, hospital bed days, emergency department visits, and total Medicare Part A expenditures. RESULTS: After adjustment for baseline variables, the caregivers in the treatment group, when compared with those in the comparison group, had a lower likelihood of any hospitalization during the study period (odds ratio 0.58 (95% confidence interval (CI)=0.35-0.97), P= .037) and a reduced, but not significant, likelihood of emergency department use (odds ratio 0.66 (95% CI=0.40-1.08), P= .095). For those who were hospitalized, there were no significant differences between the treatment and comparison group caregivers in the number of hospitalizations, hospital length of stay, or Medicare payments. CONCLUSION: These results suggest that enhanced chronic illness case management directed at persons with dementia and their caregivers can reduce the need for acute hospital care.

Weimer DL, Sager MA. · Robert M. La Follette School of Public Affairs, University of Wisconsin-Madison, Madison, WI, USA. · Alzheimers Dement. · Pubmed #19362885 No free full text.

Abstract: BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disease that places substantial burdens on those who provide support for family members with declining cognitive and functional abilities. Many AD patients eventually require formal long-term care services because of the absence, exhaustion, or inability of family members to provide care. The costs of long-term care, and especially nursing home care, often deplete private financial resources, placing a substantial burden on state Medicaid programs. Current evidence suggests that pharmacological treatments and caregiver interventions can delay entry into nursing homes and potentially reduce Medicaid costs. However, these cost savings are not being realized because many patients with AD are either not diagnosed or diagnosed at late stages of the disease, and have no access to Medicare-funded caregiver support programs. METHODS AND RESULTS: A Monte Carlo cost-benefit analysis, based on estimates of parameters available in the medical literature, suggests that the early identification and treatment of AD have the potential to result in large, positive net social benefits as well as positive net savings for states and the federal government. CONCLUSIONS: These findings indicate that the early diagnosis and treatment of AD are not only socially desirable in terms of increasing economic efficiency, but also fiscally attractive from both state and federal perspectives. These findings also suggest that failure to fund effective caregiver interventions may be fiscally unsound.

Xu G, McLaren DG, Ries ML, Fitzgerald ME, Bendlin BB, Rowley HA, Sager MA, Atwood C, Asthana S, Johnson SC. · Geriatric Research Education and Clinical Center, William S Middleton Memorial Veterans Hospital, Madison, WI 53705, USA. · Brain. · Pubmed #18829694 No free full text.

Abstract: First-degree family history (FH) of sporadic Alzheimer's disease and the apolipoprotein E epsilon4 allele (APOE4) are risk factors for Alzheimer's disease that may affect brain function prior to onset of clinical symptoms. In this functional MRI (fMRI) study, we used an episodic recognition task that required discrimination of previously viewed (PV) and novel (NV) faces to examine differences in blood oxygen level dependent (BOLD) signal due to risk factors in 74 middle-aged cognitively normal individuals. The group effects on this recognition task were tested with a 2 x 2 ANCOVA factorial design (+FH/-FH and +APOE4/-APOE4). There were significant APOE4 and FH effects in the left dorsal posterior cingulate cortex and precuneus, where decreased risk resulted in greater activity during recollection. Recognition performance was positively correlated with BOLD signal in the left posterior hippocampus, parahippocampal-retrosplenial gyrus and left superior frontal cortex regardless of risk factors. To examine condition-specific group effects, both the PV and NV faces were tested further in separate 2 x 2 ANCOVAs. Both models revealed an APOE effect, with the -APOE4 group showing stronger signal than the +APOE4 group in anterior cingulate cortices, while a FH effect was found in the dorsal cuneus and medial frontal cortices with the -FH group showing stronger signal than the +FH group. Finally, interactions between APOE4 and FH effects were found bilaterally in the fusiform gyrus. These results suggest that risk factors and cognitive performance each influence brain activity during recognition. The findings lend further support to the idea that functional brain changes may begin far in advance of symptomatic Alzheimer's disease.

La Rue A, Hermann B, Jones JE, Johnson S, Asthana S, Sager MA. · Wisconsin Alzheimer's Institute, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA. <> · Alzheimers Dement. · Pubmed #18631980 links to  free full text

Abstract: BACKGROUND: An exaggerated recency effect (ie, disproportionate recall of last-presented items) has been consistently observed in the word list learning of patients with Alzheimer's disease (AD). Our study sought to determine whether there were similar alterations in serial position learning among asymptomatic persons at risk for AD as a result of parental family history. METHODS: Subjects included 623 asymptomatic middle-aged children of patients with AD (median, 53 years) and 157 control participants whose parents survived to at least age 70 without AD or other memory disorders. All participants were administered the Rey Auditory Verbal Learning Test, which requires learning and recall of 15 unrelated nouns. RESULTS: There was no significant difference in total words recalled between the AD children and control groups. However, compared with controls, AD children exhibited a significantly greater tendency to recall words from the end (recency) versus beginning (primacy) of the list. Serial position effects were unrelated to apolipoprotein allele epsilon 4 or depressive symptoms. CONCLUSIONS: Asymptomatic persons at risk for AD by virtue of family history do not show a difference in total words recalled compared with controls, but they exhibit a distinctly different serial position curve, suggesting greater reliance on immediate as opposed to episodic memory. This is the same serial position pattern observed in mild AD, seen here in reduced severity. Longitudinal follow-up is planned to determine whether changes in serial position patterns are a meaningful marker for preclinical detection of AD.

Carlsson CM, Gleason CE, Hess TM, Moreland KA, Blazel HM, Koscik RL, Schreiber NT, Johnson SC, Atwood CS, Puglielli L, Hermann BP, McBride PE, Stein JH, Sager MA, Asthana S. · Department of Medicine, Section of Geriatrics and Gerontology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA. · J Alzheimers Dis. · Pubmed #18376061 No free full text.

Abstract: BACKGROUND: Statins reduce amyloid-beta (Abeta) levels in the brain and cerebrospinal fluid (CSF) in animals and may thereby favorably alter the pathobiology of AD. It is unclear if statins modify Abeta metabolism or improve cognition in asymptomatic middle-aged adults at increased risk for AD. METHODS: In a 4-month randomized, double-blind, controlled study, we evaluated the effects of simvastatin 40 mg daily vs. placebo on CSF Abeta42 levels and cognition in 57 asymptomatic middle-aged adult children of persons with AD. RESULTS: Compared to placebo, individuals randomized to simvastatin for 4 months had similar changes in CSF Abeta42 (p=0.344) and total tau levels (p=0.226), yet greater improvements in some measures of verbal fluency (p=0.024) and working memory (p=0.015). APOE4 genotype, gender, and vascular risk factors were associated with CSF biomarker levels, but did not modify treatment effects. CONCLUSION: In asymptomatic middle-aged adults at increased risk for AD, simvastatin use improved selected measures of cognitive function without significantly changing CSF Abeta42 or total tau levels. Further studies are needed to clarify the impact of higher dose and/or longer duration statin therapy on not only Abeta metabolism, but also other preclinical processes related to the development of AD.

Trivedi MA, Schmitz TW, Ries ML, Hess TM, Fitzgerald ME, Atwood CS, Rowley HA, Asthana S, Sager MA, Johnson SC. · Geriatric Research Education and Clinical Center, Wm. S. Middleton Memorial Veterans Hospital, Madison, WI 53705, USA. · Neuropsychologia. · Pubmed #18241895 links to  free full text

Abstract: In the present study, we used fMRI to examine the influence of age on two other known risk factors for Alzheimer's disease (AD), APOE genotype and parental history of AD (FH status), during episodic encoding (ENC) and metacognitive self-appraisal (SA) paradigms. These paradigms have previously been shown to evoke activity from brain regions that are implicated in AD. First we examined the effect of age across the adult lifespan (age 18-84 years) on cerebral activity in a large sample (n=231) of cognitively healthy individuals. Next we examined a subset (n=155) on whom APOE status and FH status were known. For ENC, we found that increasing age was associated with reduced activity in the ventral temporal lobes and hippocampus. Our analysis of risk factors suggested that FH and age exerted independent effects, but APOE interacted with age such that APOE e4 carriers exhibit age-related increases in activity in the hippocampus. For the metacognitive SA task, increasing age was found to be associated with reduced activity in the medial prefrontal cortex, and increased activity in the mesial temporal lobe, posterior orbital cortex and striatum. Neither AD risk factor significantly modified age-related changes in brain activity during SA. These results suggest that FH and aging are exerting independent effects in both tasks while APOE affected the relationship with age in the hippocampus in one of the two tasks given.

Johnson SC, Ries ML, Hess TM, Carlsson CM, Gleason CE, Alexander AL, Rowley HA, Asthana S, Sager MA. · Geriatric Research Education and Clinical Center, William S. Middleton Memorial Veterans Hospital, 2500 Overlook Terrace, Madison, WI 53705, USA. · Arch Gen Psychiatry. · Pubmed #17909128 links to  free full text

Abstract: CONTEXT: Asymptomatic middle-aged adult children of patients with Alzheimer disease (AD) recently were found to exhibit functional magnetic resonance imaging (fMRI) deficits in the mesial temporal lobe during an encoding task. Whether this effect will be observed on other fMRI tasks is yet unknown. This study examines the neural substrates of self-appraisal (SA) in persons at risk for AD. Accurate appraisal of deficits is a problem for many patients with AD, and prior fMRI studies of healthy young adults indicate that brain areas vulnerable to AD such as the anterior mesial temporal lobe and posterior cingulate are involved during SA tasks. OBJECTIVE: To determine whether parental family history of AD (hereafter referred to as FH) or presence of the epsilon4 allele of the apolipoprotein E gene (APOE4) exerts independent effects on brain function during SA. DESIGN: Cross-sectional factorial design in which APOE4 status (present vs absent) was one factor and FH was the other. All participants received cognitive testing, genotyping, and an fMRI task that required subjective SA decisions regarding trait adjective words in comparison with semantic decisions about the same words. SETTING: An academic medical center with a research-dedicated 3.0-T MR imaging facility. PARTICIPANTS: Cognitively normal middle-aged adults (n = 110), 51 with an FH and 59 without an FH. MAIN OUTCOME MEASURE: Blood oxygen-dependent contrast measured using T2*-weighted echo-planar imaging. RESULTS: Parental family history of AD and APOE4 status interacted in the posterior cingulate and left superior and medial frontal regions. There were main effects of FH (FH negative > FH positive) in the left hippocampus and ventral posterior cingulate. There were no main effects of APOE genotype. CONCLUSIONS: Our results suggest that FH may affect brain function during subjective SA in regions commonly affected by AD. Although the participants in this study were asymptomatic and middle-aged, the findings suggest that there may be subtle alterations in brain function attributable to AD risk factors.

Johnson SC, Schmitz TW, Trivedi MA, Ries ML, Torgerson BM, Carlsson CM, Asthana S, Hermann BP, Sager MA. · University of Wisconsin-Madison, Wisconsin 53705, USA. · J Neurosci. · Pubmed #16738250 links to  free full text

Abstract: First-degree family history of sporadic Alzheimer disease (AD) and the apolipoprotein E epsilon4 (APOE4) are risk factors for developing AD. Although the role of APOE4 in AD pathogenesis has been well studied, family history remains a rarely studied and poorly understood risk factor. Both putatively cause early brain changes before symptomatic disease, but the relative contribution of each to brain function is unknown. We examined 68 middle-aged participants with a parent diagnosed with AD [family history (+FH)] and 64 age- and education-matched controls without a first-degree family history of any dementia [no family history (-FH)]. All underwent cognitive testing, APOE genotyping, and a functional magnetic resonance imaging encoding task that required discrimination of novel items from previously learned items. A 2 x 2 factorial ANOVA (presence/absence of parental family history and presence/absence of the APOE4) was used to detect group effects. A greater response to novel items was detected in the mesial temporal lobe and fusiform gyrus bilaterally among persons without a first-degree family history of AD. In hippocampal areas, the -FH +epsilon4 group exhibited the greatest signal change, and the +FH +epsilon4 group exhibited the least. These findings indicate that FH of AD is an important predictor of hippocampal activation during encoding and that FH may modulate the effect of APOE4 in these middle-aged adults, suggesting that an as yet unspecified factor embodied in first-degree family history of AD is influencing the expression of APOE4 on brain function.

Trivedi MA, Schmitz TW, Ries ML, Torgerson BM, Sager MA, Hermann BP, Asthana S, Johnson SC. · Geriatric Research Education and Clinical Center, William S. Middleton Veteran's Affairs Hospital, Madison, WI, USA. · BMC Med. · Pubmed #16412236 links to  free full text

Abstract: BACKGROUND: The presence of the apolipoprotein E (APOE) epsilon4 allele is a major risk factor for the development of Alzheimer's disease (AD), and has been associated with metabolic brain changes several years before the onset of typical AD symptoms. Functional MRI (fMRI) is a brain imaging technique that has been used to demonstrate hippocampal activation during measurement of episodic encoding, but the effect of the epsilon4 allele on hippocampal activation has not been firmly established. METHODS: The present study examined the effects of APOE genotype on brain activation patterns in the medial temporal lobe (MTL) during an episodic encoding task using a well-characterized novel item versus familiar item contrast in cognitively normal, middle-aged (mean = 54 years) individuals who had at least one parent with AD. RESULTS: We found that epsilon3/4 heterozygotes displayed reduced activation in the hippocampus and MTL compared to epsilon3/3 homozygotes. There were no significant differences between the groups in age, education or neuropsychological functioning, suggesting that the altered brain activation seen in epsilon3/4 heterozygotes was not associated with impaired cognitive function. We also found that participants' ability to encode information on a neuropsychological measure of learning was associated with greater activation in the anterior MTL in the epsilon3/3 homozygotes, but not in the epsilon3/4 heterozygotes. CONCLUSION: Together with previous studies reporting reduced glucose metabolism and AD-related neuropathology, this study provides convergent validity for the idea that the MTL exhibits functional decline associated with the APOE epsilon4 allele. Importantly, these changes were detected in the absence of meaningful neuropsychological differences between the groups. A focus of ongoing work in this laboratory is to determine if these findings are predictive of subsequent cognitive decline.

Sager MA, Hermann B, La Rue A. · Wisconsin Alzheimer's Institute, Department of Medicine, University of Wisconsin-Madison, 53719, USA. · J Geriatr Psychiatry Neurol. · Pubmed #16306248 No free full text.

Abstract: Adult children of persons with Alzheimer's disease are at increased risk of developing Alzheimer's disease because of hereditary, environmental, and health risk factors shared with affected parents. The Wisconsin Registry for Alzheimer's Prevention (WRAP) has completed baseline assessments on 452 middle-aged persons (mean = 53 years) who have at least 1 parent with AD. Forty-five percent had 1 or more apolipoprotein (APOE) epsilon4 alleles. There were few significant differences between epsilon4 carriers and noncarriers in demographics, health, and lifestyle measures or in neuropsychological performance. The high percentage of WRAP participants who are carriers of APOE epsilon4 underscores their increased risk for developing Alzheimer's disease, but the absence of differences related to APOE status and high mean scores on cognitive tests suggests that the APOE epsilon4 gene has yet to have a clinical impact on cognitive functioning. The WRAP cohort may be a valuable group to follow prospectively to characterize the nature of cognitive change in relation to risk factors and to identify underlying preclinical neurobiological changes.