Alzheimer Disease: Johnson SC

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.

Baxter LC, Caselli RJ, Johnson SC, Reiman E, Osborne D. · Neuropsychology Neuroimaging Laboratory, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, 222 W. Thomas Rd., Suite 310, Phoenix, AZ 85013, USA. · Neurobiol Aging. · Pubmed #12928055 No free full text.

Abstract: The Apolipoprotein E (APOE) epsilon 4 allele is an important risk factor for Alzheimer's disease (AD). Given the interest in early identification of at-risk individuals, we examined memory decline as a function of APOE status and age in cognitively intact participants aged 48-77 years old (yo). Participants were grouped by age (<60 versus > or =60) and APOE (epsilon4+/-). Longitudinal analysis of several components of memory over a 2-year interval showed a significant Age-by-APOE interaction reflecting a decline in new learning for the > or =60 epsilon4+ group only. Among epsilon4+, 76% of the > or =60 participants showed a decline versus 32% of the <60, but the amount of decline in new learning over the 2-year interval within the > or =60 group was not further influenced by age. That is, the size of the 2-year change was the same for 60 and 70 year old participants. This suggests that longitudinal study of new learning is a sensitive measure for detecting early cognitive changes in at-risk individuals that precede the symptomatic onset of mild cognitive impairment and AD.

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.

Sparks DL, Lemieux SK, Haut MW, Baxter LC, Johnson SC, Sparks LM, Sampath H, Lopez JE, Sabbagh MH, Connor DJ. · Roberts Laboratory for Neurodegenerative Disease Research, Sun Health Research Institute, Sun City, AZ, USA. · Cleve Clin J Med. · Pubmed #18540154 links to  free full text

Abstract: Numerous clinical studies suggest a link between elevated cholesterol and increased risk of Alzheimer disease (AD), and the preponderance of data suggests that statin therapy may reduce the risk of AD later in life. The first clinical investigation of statin therapy in patients with AD, the AD Cholesterol-Lowering Treatment (ADCLT) trial, found that atorvastatin 80 mg/day was associated with improvements relative to placebo on some, but not all, cognitive measures after 6 months and 1 year of therapy. We report here findings from a pilot ADCLT substudy showing a nonsignificant reduction in total hippocampal volume with 1 year of atorvastatin therapy compared with placebo, driven by a highly significant reduction in right hippocampal volume with atorvastatin therapy.

Haasl RJ, Ahmadi MR, Meethal SV, Gleason CE, Johnson SC, Asthana S, Bowen RL, Atwood CS. · Section of Geriatrics and Gerontology, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA. · BMC Med Genet. · Pubmed #18439297 links to  free full text

Abstract: ABSTRACT: Genetic and biochemical studies support the apolipoprotein E (APOE) epsilon4 allele as a major risk factor for late-onset Alzheimer's disease (AD), though ~50% of AD patients do not carry the allele. APOE transports cholesterol for luteinizing hormone (LH)-regulated steroidogenesis, and both LH and neurosteroids have been implicated in the etiology of AD. Since polymorphisms of LH beta-subunit (LHB) and its receptor (LHCGR) have not been tested for their association with AD, we scored AD and age-matched control samples for APOE genotype and 14 polymorphisms of LHB and LHCGR. Thirteen gene-gene interactions between the loci of LHB, LHCGR, and APOE were associated with AD. The most strongly supported of these interactions was between an LHCGR intronic polymorphism (rs4073366; lhcgr2) and APOE in males, which was detected using all three interaction analyses: linkage disequilibrium, multi-dimensionality reduction, and logistic regression. While the APOE epsilon4 allele carried significant risk of AD in males [p = 0.007, odds ratio (OR) = 3.08(95%confidence interval: 1.37, 6.91)], epsilon4-positive males carrying 1 or 2 C-alleles at lhcgr2 exhibited significantly decreased risk of AD [OR = 0.06(0.01, 0.38); p = 0.003]. This suggests that the lhcgr2 C-allele or a closely linked locus greatly reduces the risk of AD in males carrying an APOE epsilon4 allele. The reversal of risk embodied in this interaction powerfully supports the importance of considering the role gene-gene interactions play in the etiology of complex biological diseases and demonstrates the importance of using multiple analytic methods to detect well-supported gene-gene interactions.

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, Asthana S, Gluck MA, Myers C. · Geriatric Research Education and Clinical Center, Wm. S. Middleton VA Hospital, Madison, WI 53705, USA. · Neuropsychol Dev Cogn B Aging Neuropsychol Cogn. · Pubmed #17851984 links to  free full text

Abstract: The ability to form associations between choice alternatives and their contingent outcomes is an important aspect of learning that may be sensitive to hippocampal dysfunction in memory disorders of aging such as amnestic mild cognitive impairment (MCIa), or early Alzheimer disease. In this preliminary study we examined brain activation using functional magnetic resonance imaging (fMRI) in 12 healthy elderly participants and nine patients with MCIa during an associative learning task. Using a high-field 3.0-Tesla MRI scanner, we examined the dynamic neural response during associative learning over trials. The slope of signal attenuation associated with learning was analyzed for differences between groups within an a priori defined hippocampal region. Results indicated dynamic signal attenuation associated with learning in the healthy elderly sample, but not in MCIa. The absence of an associative learning effect in the MCIa sample reaffirms an important link between the learning difficulties that are commonly encountered in MCIa and the mesial temporal region.

Wung JK, Perry G, Kowalski A, Harris PL, Bishop GM, Trivedi MA, Johnson SC, Smith MA, Denhardt DT, Atwood CS. · Institute of Pathology, Case Western Reserve University, Cleveland, Ohio 44106, USA. · Curr Alzheimer Res. · Pubmed #17316167 No free full text.

Abstract: Osteopontin (OPN) is a glycophosphoprotein expressed by several cell types and has pro-adhesive, chemotactic, and cytokine-like properties. OPN is involved in a number of physiologic and pathologic events including angiogenesis, apoptosis, inflammation, oxidative stress, remyelination, wound healing, bone remodeling, cell migration and tumorigenesis. Since these functions of OPN, and the events that it regulates, are involved with neurodegeneration, we examined whether OPN was differentially expressed in the hippocampus of the Alzheimer's disease (AD) compared with age-matched (59-93 years) control brain. We report for the first time the immunocytochemical localization of OPN in the cytoplasm of pyramidal neurons. In AD brains, there was a significant 41 % increase in the expression of neuron OPN compared with age-matched control brain. No staining of other neuronal cell types was observed. Additionally, there was a significant positive correlation between OPN staining intensity and both amyloid-beta load (r(2) = 0.25; P < 0.05; n = 20) and aging (r(2) = 0.32; P < 0.01; n = 20) among all control and AD subjects. Controlling for age indicated that OPN expression was significantly influenced by amyloid-beta load, but not age. While the functional consequences of this amyloid-beta associated increase in OPN expression are unclear, it is notable that OPN is primarily localized to those neurons that are known to be vulnerable to AD-related neurite loss, degeneration and death. Given that the induction of OPN expression (and amyloid-beta generation) is associated with remodeling and tumorigenesis, our results suggest that OPN may play a role in the aberrant re-entry of neurons into the cell cycle and/or neuronal remyelination in AD.

Baxter LC, Sparks DL, Johnson SC, Lenoski B, Lopez JE, Connor DJ, Sabbagh MN. · Barrow Neurological Institute, Phoenix, AZ 85013, USA. · J Alzheimers Dis. · Pubmed #16914835 No free full text.

Abstract: OBJECTIVE: To examine the relationship between commonly used screening cognitive measures with gray and white matter integrity in patients with mild to moderate AD. BACKGROUND: New neuroimaging techniques, such as voxel-based morphometry (VBM), make it possible to study the relationship between structural brain integrity and cognitive functioning in AD. METHODS: Gray and white matter integrity was evaluated using VBM in fifteen patients with mild to moderate AD. ADAS-Cog and MMSE scores were also performed as part of the baseline assessment for a larger clinical trial in the AD patients. Correlations between cognitive measures and VBM were performed. RESULTS: Both the ADAS-Cog and the MMSE showed a similar relationship with gray matter degeneration, reflecting greater cognitive impairment with decreased gray matter in the left temporal lobe. However, the MMSE score was much more reflective of underlying white matter changes than ADAS-Cog scores, particularly in frontotemporal region. These findings suggest that the ADAS-Cog and MMSE reflect different aspects of the underlying brain changes observed in AD. The ADAS-Cog was more specific to gray matter integrity whereas the MMSE reflected a more global reduction in both gray and white matter. CONCLUSIONS: These results support using neuroimaging markers of neural integrity as an important consideration when evaluating treatment efficacy. Furthermore, whole-brain analyses such as VBM help to evaluate neural systems that are not necessarily targeted by the treatment.

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.

Johnson SC, Schmitz TW, Moritz CH, Meyerand ME, Rowley HA, Alexander AL, Hansen KW, Gleason CE, Carlsson CM, Ries ML, Asthana S, Chen K, Reiman EM, Alexander GE. · Geriatric Research Education and Clinical Center, Wm. S. Middleton VA Hospital, 2500 Overlook Terrace (11G), GRECC, Madison, WI 53705, USA. · Neurobiol Aging. · Pubmed #16226349 links to  free full text

Abstract: This study examined the functionality of the medial temporal lobe (MTL) and posterior cingulate (PC) in mild cognitive impairment amnestic type (MCI), a syndrome that puts patients at greater risk for developing Alzheimer disease (AD). Functional MRI (fMRI) was used to identify regions normally active during encoding of novel items and recognition of previously learned items in a reference group of 77 healthy young and middle-aged adults. The pattern of activation in this group guided further comparisons between 14 MCI subjects and 14 age-matched controls. The MCI patients exhibited less activity in the PC during recognition of previously learned items, and in the right hippocampus during encoding of novel items, despite comparable task performance to the controls. Reduced fMRI signal change in the MTL supports prior studies implicating the hippocampus for encoding new information. Reduced signal change in the PC converges with recent research on its role in recognition in normal adults as well as metabolic decline in people with genetic or cognitive risk for AD. Our results suggest that a change in function in the PC may account, in part, for memory recollection failure in AD.

Johnson SC, Saykin AJ, Baxter LC, Flashman LA, Santulli RB, McAllister TW, Mamourian AC. · Department of Psychiatry, New Hampshire Hospital, Lebanon, New Hampshire, 03756, USA. · Neuroimage. · Pubmed #10694460 No free full text.

Abstract: Functional MRI has recently been used to examine activation associated with aging and dementia, yet little is known regarding the effect of cerebral atrophy on fMRI signal. The purpose of this study was to examine the relationship between measures of global and regionally specific atrophy and fMRI activation in normal aging and in Alzheimer disease (AD). Two groups of subjects were studied with echoplanar imaging and quantitative structural volumetry: healthy controls spanning a broad age and atrophy range (n = 16) and patients with mild AD (n = 8). Results from a semantic task previously found to activate left inferior frontal (LIFG) and left superior temporal (LSTG) gyri were analyzed. The correlations between clusters of activation in the LIFG and LSTG and measures of local atrophy in the LIFG and LSTG regions were evaluated. For control subjects, there was no significant correlation between activation and regional or total brain atrophy (for LIFG r = -0.03, NS; for LSTG r = 0.20, NS). In contrast, for AD patients, there was a significant positive correlation between atrophy and activation in LIFG (r = 0.70, P = 0.05) but not LSTG (r = 0.00, NS). These results suggest that activation of language regions and atrophy within those regions may be independent among healthy adults spanning a broad age and atrophy range. However, in AD, a relationship exists in the LIFG that may reflect compensatory recruitment of cortical units or disease-specific changes in the hemodynamic response.

Saykin AJ, Flashman LA, Frutiger SA, Johnson SC, Mamourian AC, Moritz CH, O'Jile JR, Riordan HJ, Santulli RB, Smith CA, Weaver JB. · Department of Psychiatry, Dartmouth Medical School, Lebanon, NH 03756, USA. · J Int Neuropsychol Soc. · Pubmed #10439584 No free full text.

Abstract: Impairment in semantic processing occurs early in Alzheimer's disease (AD) and differential impact on subtypes of semantic relations have been reported, yet there is little data on the neuroanatomic basis of these deficits. Patients with mild AD and healthy controls underwent 3 functional MRI auditory stimulation tasks requiring semantic or phonological decisions (match-mismatch) about word pairs (category-exemplar, category-function, pseudoword). Patients showed a significant performance deficit only on the exemplar task. On voxel-based fMRI activation analyses, controls showed a clear activation focus in the left superior temporal gyrus for the phonological task; patients showed additional foci in the left dorsolateral prefrontal and bilateral cingulate areas. On the semantic tasks, predominant activation foci were seen in the inferior and middle frontal gyrus (left greater than right) in both groups but patients showed additional activation suggesting compensatory recruitment of locally expanded foci and remote regions, for example, right frontal activation during the exemplar task. Covariance analyses indicated that exemplar task performance was strongly related to signal increase in bilateral medial prefrontal cortex. The authors conclude that fMRI can reveal similarities and differences in functional neuroanatomical processing of semantic and phonological information in mild AD compared to healthy elderly, and can help to bridge cognitive and neural investigations of the integrity of semantic networks in AD.