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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
 
J Int Neuropsychol Soc. Author manuscript; available in PMC 2006 October 23.
Published in final edited form as:
PMCID: PMC1621044
NIHMSID: NIHMS12570

Neuropsychological and neuroimaging changes in preclinical Alzheimer's disease

Abstract

Alzheimer's disease (AD) is a common, devastating form of dementia. With the advent of promising symptomatic treatment, the importance of recognizing AD at its very earliest stages has increased. We review the extant neuropsychological and neuroimaging literature on preclinical AD, focusing on longitudinal studies of initially nondemented individuals and cross-sectional investigations comparing at-risk with normal individuals. We systematically reviewed 91 studies of neuropsychological functioning, structural neuroimaging, or functional neuroimaging in preclinical AD. The neuropsychological studies indicated that preclinical AD might be characterized by subtle deficits in a broad range of neuropsychological domains, particularly in attention, learning and memory, executive functioning, processing speed, and language. Recent findings from neuroimaging research suggest that volume loss and cerebral blood flow or metabolic changes, particularly in the temporal lobe, may be detected before the onset of dementia. There exist several markers of a preclinical period of AD, in which specific cognitive and biochemical changes precede the clinical manifestations. The preclinical indicators of AD reflect early compromise of generalized brain integrity and temporal lobe functioning in particular.

Keywords: Dementia, Neuropsychology, Magnetic resonance imaging, Positron emission tomography, Cognition disorders, Memory disorders

INTRODUCTION

The neuropathologic changes of Alzheimer's disease (AD) begin well before the disease becomes clinically apparent. The brain may compensate for such changes until cognitive decline becomes obvious and disrupts daily functioning, and the clinical diagnosis of AD can be made. However, cognitive signs and brain changes are subtly present prior to clinical diagnosis, thus denoting a “preclinical” stage of AD in which affected individuals exhibit only very mild changes in cognition despite an ongoing disease process. This stage gradually progresses to mild cognitive impairment (MCI; Petersen et al., 2001), characterized by mild but detectable cognitive impairment, and then to the more severe and clinically apparent stages of AD.

Much research into new AD treatments has focused on slowing or halting the disease process, rather than reversing its neuropathology. Many patients with MCI already exhibit substantial neuropathologic signs of AD (Price & Morris, 1999), illustrating the need to identify the preclinical stages of AD so that treatment can begin promptly. Identifying preclinical disease markers would improve characterization of predisposing factors for AD, promote our understanding of disease course, and improve our ability to assess treatment response without waiting for evidence of significant cognitive or functional declines.

Better recognition of preclinical markers of AD could have profound social and financial effects. Early detection could help reduce the cost of Alzheimer's care ($100 billion per year in the United States; DeKosky & Orgogozo, 2001); an intervention delaying AD onset by two years would result in nearly two million fewer cases 50 years from now (Brookmeyer et al., 1998). Additionally, early and accurate diagnosis will aid patients and families in healthcare decision-making.

We reviewed the current literature on neuropsychological and neuroimaging changes that may reflect preclinical AD. In doing so, we distinguished between “preclinical AD” and “MCI,” typically defined as mild memory impairment without other cognitive or functional deficits (Petersen et al., 2001). In contrast, preclinical AD is conceptualized as a stage featuring subtle cognitive declines (not necessarily impairments, however, and not necessarily in the domain of memory) and no perceptible declines in daily functioning. Another distinction exists on autopsy, at which those with MCI may exhibit substantial AD pathology, whereas preclinical AD patients may exhibit only minor changes (Price & Morris, 1999). Detecting AD in its preclinical stage, before the development of MCI, is crucial, particularly given that the conversion rate from MCI to AD within two years is up to 30% (Petersen et al., 2001). In a recent meta-analysis, Bäckman et al. (2005) found that neuropsychological tests of global cognition, delayed recall, perceptual speed, and executive functioning best discriminated subjects who developed AD from those who remained well. However, of the 47 studies included in their meta-analysis, 27 investigated cognition in MCI, cognitively impaired, or memory clinic samples, thereby making memory measures the most likely to emerge as predictors of future AD. The current review excluded studies of subjects with MCI or memory complaints in favor of a more pure focus on preclinical AD. We present a model of accelerated, nonlinear cognitive decline in the preclinical period and provide evidence that helps reconcile the heterogeneity in AD presentation.

As a backdrop to our focus on preclinical AD, we first review briefly the neuropathology of AD and the diagnostic criteria for the disease. Study designs and the rationale for using at-risk samples in this research are outlined. A comprehensive review of the current neuropsychological and neuroimaging research follows. Finally, the empirical evidence is put into a clinical context, gaps in our understanding are presented, and the potential impact of research on preclinical AD is discussed.

Neuropathologic and Diagnostic Criteria for AD

AD is a progressive degenerative disease characterized by neocortical atrophy, neuron and synapse loss, neuritic plaques, and neurofibrillary tangles (Alzheimer, 1907; Terry et al., 1991). These neuropathologic changes occur primarily in the hippocampus and entorhinal cortex, with later changes occurring in frontal, temporal, and parietal association cortices (Braak & Braak, 1991; Hyman et al., 1984). Eventually, the limbic regions and neocortex are affected (Bobinski et al., 1999; Xu et al., 2000). Additionally, subcortical neuron loss in the nucleus basalis of Meynert and locus coeruleus results in decreased levels of cholinergic and noradrenergic markers, respectively (Bondareff et al., 1982).

Clinically, AD is characterized by profound global dementia, with severe amnesia and additional deficits in other cognitive domains, such as language, executive functions, attention, and visuospatial/constructional abilities (American Psychiatric Association, 1994; Salmon & Bondi, 1999). The current DSM-IV criteria (American Psychiatric Association, 1994) include: (a) Memory impairment and at least one additional cognitive impairment; (b) Impaired functioning and functional decline; (c) Gradual onset and continuing cognitive decline; (d) Cognitive deficits not due to other causes. The criteria for AD suggest that cognitive deficits, structural volume loss, or functional brain changes appear gradually and thus might be identified before the neural degeneration produces clinically diagnosable dementia.

Study Designs

The prototypic longitudinal case-control research design used to identify potential preclinical markers of AD involves a baseline assessment of a large cohort of normal older adults and periodic follow-up evaluations (Collie & Maruff, 2000). Then, individuals who later develop AD are compared with those who remain nondemented on the presence and magnitude of cognitive declines, structural changes, and/or functional imaging changes. Retrospective studies of nondemented individuals who came to autopsy have also been published, comparing neuropsychological profiles of individuals with and without AD pathology.

Studying individuals at high risk for AD has been a common approach to research on preclinical indicators of the disease. Early studies recruited individuals at risk for AD due to family history (e.g., Hom et al., 1994), whereas more recent studies have focused on older adults with genetic susceptibilities such as the presence of an apolipoprotein E (APOE) ε4 allele (Corder et al., 1993). Such studies have used both cross-sectional designs and longitudinal evaluations to examine cognitive decline or neuroimaging changes. To provide a backdrop for our review of longitudinal and cross-sectional studies of preclinical AD, we briefly discuss the established risk factors for AD next.

Risk Factors for AD

Advancing age is the single most important risk factor for AD (Kawas & Katzman, 1999), with exponential increases in AD prevalence in individuals between 65 and 85. Epidemiologic studies of people over age 85, the fastest growing segment of our population (U.S. Census Bureau, 2004), show that the incidence of AD does not plateau, as was previously speculated, but continues to rise in this advanced age group, with 25–50% of this cohort developing the disease (Kawas & Katzman, 1999; Rocca et al., 1998).

In addition to age, certain genetic mutations have been implicated in the pathogenesis of AD. Early-onset AD is associated with defects on chromosome 21, particularly a mutation of the amyloid precursor protein (APP) gene, chromosome 1, and chromosome 14, both due to mutations in the presenilin-2 and presenilin-1 genes (Kawas & Katzman, 1999). Together, these known genetic mutations account for only about 2% of all cases of early-onset AD (Pericak-Vance et al., 2000).

The vast majority of people who develop AD do so after age 65, and the APOE gene on chromosome 19 has been identified as a susceptibility gene for both familial and sporadic late-onset AD (Corder et al., 1993). APOE is a protein influencing cholesterol transport in the blood and appears to be related to the deposition of amyloid and0or the formation of neurofibrillary tangles in the brain. The three different alleles (ε2, ε3, and ε4) yield different disease risks, with the ε4 allele conferring the greatest risk. APOE ε4 is present in up to 50% to 60% of AD patients, compared to only 16% of nondemented individuals. The risk of developing AD is three to four times higher for individuals with one copy of the ε4 allele, and approximately ten-fold in those with two copies of ε4 (Corder et al., 1993). Although APOE genotyping cannot be used alone as a diagnostic test for AD, it significantly improves diagnostic specificity when used in combination with clinical criteria (Mayeux et al., 1998). In a recent meta-analysis, Small et al. (2004) found significant differences between nondemented APOE ε4 carriers and noncarriers in global cognition, episodic memory, and executive functioning.

Numerous environmental, medical, and social factors have also been suggested as putative risk factors for AD, including head injury, hypertension, hypotension, toxin exposure, and low education. Some of these risk factors may interact with each other, and some may contribute to an individual's “cognitive reserve” or brain reserve capacity that buffers one against the cognitive effects of neurodegeneration (Kawas & Katzman, 1999).

METHOD

The literature providing a basis for this review was obtained by searching the Medline and PsycInfo databases for English-language articles containing the key terms “preclinical” and “Alzheimer.” Other terms entered into the search included “neuropsychologic,” “neuropsychological,” and “neuroimaging.” All articles up to April 2005 were included. Relevant papers from the reference lists of identified articles were also reviewed. Only studies that promoted knowledge on how to screen and diagnose AD using noninvasive, in vivo methods were included. Given our focus on ante mortem indicators, we excluded retrospective autopsy studies aimed at identifying biomarkers of AD after death. Family pedigree studies were only included if subjects were compared to normal control groups or genetically unaffected relatives. Given our specific focus on identifying AD before the manifestation of any clinical symptoms, we included only cross-sectional or prospective studies of nondemented, cognitively normal individuals; whereas studies of age-associated memory impairment (AAMI), MCI, questionable AD, or memory clinic populations were excluded. We also excluded investigations that focused solely on evoked potentials, event-related potentials, or olfactory testing, due to the relative paucity of research in these areas. Seventy-three neuropsychological studies, eleven structural neuroimaging studies, and seven functional neuroimaging studies were included in the present review. Comprehensive tables of relevant research were constructed (see the Appendices). When articles presented both neuropsychological and neuroimaging results, they were listed in both tables; cross-sectional and longitudinal results from the same study were listed in those respective sections of the tables. We then summarized the results across studies in Table 1.

Table 1
Summary of neuropsychological and neuroimaging results across studies

RESULTS

Neuropsychological Changes in Preclinical AD

Compared with older adults who remain nondemented, those who later develop AD perform more poorly across a broad range of neuropsychological measures. Appendix 1, presents summaries of 73 studies of neuropsychological changes in the preclinical period. There were 30 longitudinal case-control studies (Appendix 1, part A); 16 longitudinal studies examining decline in APOE ε4+ and ε4− subjects (Appendix 1, part B); 26 cross-sectional studies comparing neuropsychological performance in subjects with and without the APOE ε4 allele (Appendix 1, part C); 3 retrospective studies using autopsy data (Appendix 1, part D); and 4 studies comparing neuropsychological performance in subjects with and without a family history of AD (Appendix 1, part E).

The domains most consistently associated with preclinical AD were attention (71% of studies in which it was assessed), verbal learning and memory (57% and 50%, respectively), executive functioning (44%), processing speed (43%), and language (33%), with studies showing either early declines in these abilities or significant differences between at-risk subjects and control subjects (see Table 1). Global measures of cognition (e.g., the Mini-Mental State Examination) were less consistently associated with preclinical AD (38% of studies). Although not the focus of the current review, there was one study (Schiffman et al., 2002) that included olfactory processing as part of a comprehensive neuropsychological battery; this and other studies (e.g., Murphy et al., 1998) have shown that olfactory impairment may be an important preclinical indicator.

The current review revealed that attention, although not as commonly assessed as learning and memory in studies of preclinical AD, is even more consistently associated with the later development of AD. Only 10% of the longitudinal case-control studies measured attention, but of those, 100% found that attention performance discriminated cases from controls. Furthermore, verbal learning was a somewhat more consistent indicator of preclinical AD than was verbal delayed recall; these findings suggest that the deficits in verbal delayed recall in preclinical AD may partly reflect poor attention and encoding.

Episodic memory decline is one of the earliest and most prominent features of preclinical AD (Bondi et al., 1995, 1999; Linn et al., 1995). Subtle declines in episodic memory often occur several years before the emergence of the obvious cognitive and behavioral changes required for a clinical diagnosis of AD (Albert et al., 2001; Bäckman et al., 2001; Bondi et al., 1994, 1999; Chen et al., 2000, 2001; Fox et al., 1998; Grober & Kawas, 1997; Howieson et al., 1997; Jacobs et al., 1995; Lange et al., 2002; Masur et al., 1994). It is thought that episodic memory tasks are strong predictors of future AD, because the brain structures subserving episodic memory, such as the medial temporal lobes and the hippocampal formation (Squire, 1992), are among the first affected.

Some studies suggest that, compared to those who remain nondemented, individuals who later develop AD exhibit lower baseline levels of cognitive functioning. Fox and colleagues (1998), for example, tested asymptomatic at-risk members of early-onset familial AD pedigrees over a six-year period. Those who developed AD had demonstrated normal, but significantly lower verbal memory and performance IQ scores at their initial assessment (when they were ostensibly unaffected) compared to the group that remained nondemented. Similarly, Elias and colleagues (2000), in a 22-year prospective study of the Framingham cohort, found that only abstract reasoning (Similarities) and verbal retention performance predicted AD in subjects who were dementia-free for at least ten years after baseline neuropsychological assessment.

Lower baseline functioning among APOE ε4 carriers could represent either a preclinical stage of AD or simply a genetic phenotype for poorer cognition. One study suggested that the ε4 allele is associated with low normal cognitive performance (Berr et al., 1996). However, a later study found that ε4 and non-ε4 subjects' CVLT profiles did not differ once incident AD cases were excluded from the analyses (Bondi et al., 1999). Thus, it seems unlikely that allelic group differences represent evidence for a cognitive phenotype of the APOE gene (Reed et al., 1994). Instead, it appears that more ε4 individuals were demonstrating subtle memory decrements indicative of preclinical AD (see also Small et al., 1998 and Smith et al., 1998).

Although few studies have systematically examined the course of episodic memory changes during the preclinical phase (Bäckman et al., 2001; Chen et al., 2001; Lange et al., 2002; Rubin et al., 1998), summarizing and combining their findings may have important implications for detecting AD preclinically and projecting the course of decline. In two studies that have examined memory changes over time, Small et al. (2000a) and Bäckman et al. (2001) measured changes in episodic memory in individuals who eventually developed probable AD. Both studies found that the subjects who had mild episodic memory declines six years prior to diagnosis showed little memory change in the following three years, but exhibited precipitous declines just prior to the development of AD. Similarly, Chen et al. (2001) found a significant decline in episodic memory and executive functioning in individuals with preclinical AD during the 3.5 to 1.5 years before diagnosis, and Lange et al. (2002) found abrupt declines in episodic memory one to two years before AD onset.

The APOE ε4 genotype may hasten the decline in episodic memory that occurs prior to the emergence of diagnosable AD (Bondi et al., 1995, 1999; Reed et al., 1994). In the studies we reviewed, those comparing APOE genotype groups found that the ε4 allele is associated with both verbal and visual learning and memory. Caselli and colleagues (1999) compared performances of ε4 homozygotes, ε4 heterozygotes (all ε3/ε4), and non-ε4 carriers on various neuropsychological measures and found that older subjects in the ε4 homozygote group performed worse on immediate and delayed recall tasks. Baxter et al. (2003) also found that verbal learning ability declined over two years in a group of cognitively normal individuals who had the ε4 allele, but only in those who were 60 years of age or older. Thus, age-related memory decline seems to occur earlier in cognitively normal ε4 homozygotes than in ε4 heterozygotes and noncarriers, and precedes clinically detectable AD.

Neuroimaging Changes in Preclinical AD

Although no routine diagnostic test confirms the presence of AD, imaging techniques are an adjunctive screening measure for undetected pathology (Knopman et al., 2001) and represent an important expanding field in biological neuropsychiatry. Structural imaging techniques can detect early volumetric changes predictive of dementia, and functional imaging can detect preclinical changes in cerebral blood flow, metabolic activity, and neurotransmitter and receptor function. Appendix 2 presents summaries of 18 studies of neuroimaging changes in the preclinical period. There were three longitudinal case-control studies (Appendix 2, part A); one longitudinal magnetic resonance imaging (MRI) study that examined decline in APOE ε4+ and ε4− subjects (Appendix 2, part B); one longitudinal PET study that examined decline in APOE ε4+ and ε4− subjects (Appendix 2, part C); seven cross-sectional studies comparing structural MRI data in subjects with and without the APOE ε4 allele (Appendix 2, part D); and six studies comparing functional imaging data in at-risk versus not-at-risk subjects (Appendix 2, part E).

Of the eleven structural imaging studies and seven functional imaging studies we reviewed (see Appendix 2), most hypothesized that, given the histopathology of AD and the cognitive hallmark of AD (rapid forgetting), changes in temporal and hippocampal functioning would be among the earliest indicators of AD. Indeed, temporal lobe changes were the most common finding in preclinical AD, with 64% of studies measuring temporal lobe changes finding significant differences; changes in the parietal lobe (45% of studies), frontal lobe (40% of studies), hippocampus (39% of studies), and posterior cingulate (36% of studies) were also identified (see Table 1). Global brain changes were not as consistently associated with preclinical AD (27% of studies). We review these studies further in the two following sections on structural and functional brain imaging.

Structural Brain Imaging

Autopsy studies reveal that neurofibrillary changes in incident AD cases occur initially in the transentorhinal and entorhinal cortex, then in the hippocampal formation, and later in the neocortical structures (Braak & Braak, 1995). Amyloid plaque deposition may occur early in other cortical structures (e.g., anterior cortical regions; Morris et al., 1996). MRI can measure volumes of specific brain structures and can thereby distinguish normally aging subjects from potential AD patients even in the earliest stages of the disease. MRI studies reveal that portions of the medial temporal lobe (MTL), particularly the entorhinal cortex and hippocampus, are initially affected in AD.

Studies of the relationship between morphological and cognitive measures of AD have demonstrated that atrophy of the MTL region, especially the hippocampus, correlates with episodic memory impairment in AD (de Leon et al., 1997). Other cognitive abilities are affected as the neuropathologic changes of AD spread from limbic structures to neocortical association areas (Braak et al., 1998). The longitudinal MRI studies reviewed in Appendix 2, part A, uniformly found that MTL volume loss was detectable in preclinical AD cases and that the rate of volume loss also predicted future AD. A similar pattern implicating hippocampal volume loss emerged when APOE status was investigated longitudinally (Cohen et al., 2001).

Controversy exists as to whether greater MTL volume reduction among APOE ε4 carriers reflects preclinical AD or a structural phenotype. Some studies have shown an ε4 effect on MTL volumes (den Heijer et al., 2002; Plassman et al., 1997; Tohgi et al., 1997), but others have not (Jernigan et al., 2001; Schmidt et al., 1996). Cohen et al. (2001), however, showed that ε4 carriers demonstrated greater hippocampal volume loss over time than did noncarriers, suggesting that the cross-sectional differences between groups may reflect a preclinical AD state.

Functional Brain Imaging

Positron emission tomography

Positron emission tomography (PET) studies of AD patients reveal hypometabolism in the neocortical structures, mainly the parietal, frontal, and posterior temporal association cortices, the same areas where neuronal and synaptic degeneration appear most severe in post-mortem AD brains. Later, more advanced stages of AD are denoted by functional brain changes across the neocortex, with relative preservation of the sensorimotor and visual cortices.

Many of the PET studies in this area have compared APOE ε4 carriers with noncarriers. In the first PET study of this kind, Kennedy and colleagues (1995) found that ε4 carriers had lower global and temporoparietal glucose metabolism than did noncarriers. Reiman and colleagues (1996), who compared cognitively normal, middle-aged ε4 homozygotes and matched non-ε4 control participants, found that the ε4 homozygotes had reduced glucose metabolism in the posterior cingulate, parietal, temporal, and prefrontal regions, all of which were regions demonstrating specific metabolic reductions in mild AD. In a later study, Reiman et al. (2004) found that these same abnormalities existed in even younger (20–39 years old) ε4 carriers.

Functional magnetic resonance imaging

Functional MRI (fMRI) studies have generally shown decreased hippocampal activation in elderly subjects with memory decline relative to normal control groups. In one of the first studies to use fMRI to explore preclinical brain changes, Smith and colleagues (1999) examined cortical activation in two groups of cognitively normal middle-aged women who differed only in terms of their AD risk (i.e., family history of AD and APOE status). The groups performed equally well on visual naming and letter fluency tasks during scanning, but their activation patterns during both tasks differed, with the high-risk group demonstrating lower activations in the bilateral mid- and posterior inferotemporal regions.

Other researchers, however, have found increased activation associated with incipient AD. Bookheimer and colleagues (2000) found that during a word recall task, nondemented ε4 carriers had greater activation than did noncarriers in the left prefrontal region and bilateral orbitofrontal, superior temporal, and inferior and superior parietal regions. These abnormal patterns of activation may represent a compensatory functional response, that is, the use of additional brain resources to perform the task. The increased activations in the ε4 carriers were specific to episodic encoding, and were not seen in attentional tasks studied by the same group (Burggren et al., 2002).

Such studies suggest that compensatory mechanisms in brain activity exist in preclinical AD, before the manifestation of frank cognitive and functional impairments (Becker et al., 1996). Several functional neuroimaging studies have shown that the brain activity associated with performance on memory tasks is more diffuse in patients with early AD than in normal older individuals, probably because of the need to recruit additional brain resources to maintain performance. It may be that after an initial decline in memory following damage to MTL structures, patients in the preclinical stage of AD are able to recruit enough compensatory brain resources to slow further memory decline for a period of time. As the disease progresses, however, these additional resources become compromised and rapid episodic memory decline ensues (Lange et al., 2002).

It could be argued that functional neuroimaging methods will be more sensitive to early MTL dysfunction than will structural MRI (Haxby et al., 1986). However, PET studies of at-risk older adults or patients with early AD have not typically demonstrated MTL metabolic changes (Reiman et al., 1996; Small et al., 1995), findings that differ from those derived from structural neuroimaging and neuropathologic studies that demonstrate that the earliest changes in AD occur in MTL regions (Braak & Braak, 1991). Furthermore, studies of brain changes using PET have not unequivocally demonstrated the characteristic temporal-parietal hypoperfusion or hypometabolism in all cases of early AD (Azari et al., 1993).

DISCUSSION

This literature review reveals that a preclinical phase of detectable cognitive decline and structural and functional brain changes precedes the clinical diagnosis of AD by several years or more. Declines in attention, episodic memory, atrophy in medial temporal lobe structures, and/or hypoperfusion in temporoparietal areas appear to be the most common markers of preclinical AD. In contrast to other reviews focusing solely or partially on MCI subjects (Bäckman et al., 2005; Wolf et al., 2003), we found relatively greater evidence for deficits in attention and more evidence for early differences in parietal and posterior cingulate volumes. Bäckman and colleagues' (2005) review found the largest effect for global cognitive measures [e.g., the Mini-Mental State Examination (MMSE) or the Dementia Rating Scale (DRS)], also reported that the effect size confidence intervals overlapped for the domains of episodic memory, executive functioning, and perceptual speed, and found moderate effect sizes for attention tests. Also consistent with our review, Greenwood et al. (2005a, 2005b) demonstrated deleterious effects of the APOE ε4 allele on experimental tests of visuospatial attention, and Jacobson and colleagues (2005a) have shown that performance discrepancies between auditory and spatial attention are associated with presence of the APOE ε4 allele in older adults. Together with this emerging literature, our review suggests that episodic memory is certainly not the only marker of preclinical AD. Using novel measures from cognitive neuroscience or comparing standardized neuropsychological measures in novel ways (e.g., cognitive asymmetry calculations) will be important new directions (Houston et al., 2005; Jacobson et al., 2005b).

Neuroimaging studies have predominantly focused on the temporal lobe, but newer methods examining, for example, the whole brain (e.g., voxel-based morphometry), amyloid imaging (Wu et al., 2005), or diffusion imaging (Medina et al., 2005), are suggesting other areas of interest in preclinical AD. Although neurofibrillary tangle pathology spreads from medial temporal to association cortices (Braak & Braak, 1991), the amyloid plaque burden is more widely dispersed (Arnold et al., 1991), variable in progression, and may also mediate the association of genetic risk to cognition (Bennett et al., 2005). Consistent with this early heterogeneity, AD may initially present with cognitive (Jacobson et al., 2002) or metabolic (Haxby et al., 1985) asymmetries. Recent MR morphometric studies also show that changes sensitive to progression to AD appear asynchronous across brain regions and are more pronounced with global indices, such as whole brain atrophy and ventricular enlargement rates, than with MTL structures (Gunter et al., 2003; Jack et al., 2005; Kaye et al., 2005). Thus, it may be that many possible brain regions are susceptible, and earlier than previously thought, in preclinical AD. The neuropsychological and neuroimaging studies to date argue for comprehensive measurement of cognitive domains and brain regions in future studies.

The cognitive and neuroimaging changes of incipient AD appear to remain relatively stable until a few years before clinical diagnosis, when there is a more notable decline. The mild course of decline in the early preclinical period may reflect the initial invocation of compensatory brain mechanisms, whereas the more rapid decline of the clinical period may reflect the inability of these brain resources to overcome the accrual of plaques, tangles, and neuron and synapse losses. A growing body of fMRI evidence among at-risk persons supports this notion (Bookheimer et al., 2000; Bondi et al., 2005; Dickerson et al., 2005; Han et al., 2006; Johnson et al., 2004), and a similar compensatory response in brain-derived neurotrophic factors (Durany et al., 2000; Egan et al., 2003) or cholinergic activity (DeKosky et al., 2002) may also occur. Given these converging lines of evidence for brain compensation, we propose a nonlinear model of episodic memory decline and neuroimaging changes to characterize this preclinical period of accruing AD pathology (see Figure 1). Consistent with this model, Martins et al. (2005) have demonstrated that APOE ε4 possession is associated with earlier and faster cognitive decline in patients with AD, whereas the ε2 allele is related to slower decline, and that a nonlinear model best predicts these differential rates of decline.

Fig. 1
Proposed model of nonlinear pattern of episodic memory decline during the preclinical period of Alzheimer's disease (based on data of Bäckman et al., 2001; Bunce et al., 2004; Chen et al., 2001; Lange et al., 2002).

We believe this review contributes to the field in four major ways. First, it provides the only comprehensive review of both neuropsychological and neuroimaging indicators of preclinical AD. Second, it addresses a significant flaw of previous studies or review articles by excluding studies of subjects with MCI, AAMI, or memory complaints. In doing so, it concludes that if one is looking for preclinical AD, one needs to look beyond memory and the temporal lobe. Third, from the extant literature we present a model of cognitive decline showing that there appears to be an accelerated and nonlinear decline in the period immediately preceding AD diagnosis. Fourth, we provide both evidence for the often conflicting presentation of AD changes in brain and cognition during the preclinical period, as well as possible explanations for these wide-ranging findings across the literature.

Our methodology for the present review has limitations. Although memory deficits are the hallmark of AD, we did not assume that memory declines would be the foremost marker of preclinical AD, and wanted to avoid “stacking the deck” in favor of memory. Thus, we excluded articles on MCI, AAMI, and memory clinic populations to focus specifically on normal older adults or younger people at risk for AD. However, some studies recruited participants via advertisements rather than population sampling, and some of the participants in the studies we reviewed may have met criteria for MCI or AAMI or may have had memory complaints. A second and related limitation is that by excluding research on memory-impaired populations, the present review may over-represent certain groups (e.g., APOE ε4 carriers) whose cognitive profiles may not characterize those of the general population. For this reason, we separated the APOE studies from the others in our review. We focused on neuropsychological and neuroimaging tests, excluding other potentially promising methodologies without substantial published literature (e.g., olfactory testing, Murphy et al., 1998). Finally, although a formal meta-analysis that would have weighted each study based on the number of participants, we chose to use a “box score” approach to examining the findings of the included studies, due to considerable heterogeneity in study methodologies and measures.

Although there have been many exciting developments in this growing area of research, conclusions about the nature and course of preclinical AD remain limited by contradictory findings in at-risk groups and/or studies that rely on retrospective or cross-sectional designs or small datasets. To improve detection of preclinical markers, the neuropsychological functioning, brain structure, and brain functioning of at-risk individuals who develop AD should ultimately be tested against that of persons who remain dementia-free over the same follow-up period. Furthermore, they might be compared to individuals with other conditions (e.g., depression, other dementias) and validated by autopsy-confirmed diagnosis.

In addition to documenting the cognitive deficits in preclinical AD, the longitudinal course of these deficits is also important. There has been a lack of consensus regarding when the preclinical period begins and how early preclinical changes may be detected. Most investigations have used relatively short test-retest intervals (e.g., two to three years after initial assessment), but other studies have used longer intervals (decades or more). With longer test-retest intervals, cognitive changes are more likely to be detected, but it is more difficult to determine when decline began. With some groups finding differences between AD cases and controls five to six decades before the onset of AD (see Snow-don et al., 1996 and Whalley et al., 2000), future research should address the question of the age range in which it is possible to detect a preclinical AD state and whether such states can be distinguished from lower levels of cognitive reserve.

With respect to fMRI studies of at-risk groups, contradictory findings across studies [e.g., decreased vs. increased blood oxygen level dependent (BOLD) responses] may reflect different mechanisms linking the hemodynamic response to its underlying neuroanatomy and neurophysiology. One concern is that differences in the “resting state” will influence the amplitude of the BOLD response (Cohen et al., 2002). If the AD brain is in a lower resting state, as suggested by Reiman et al. (1996), it should show an increased hemodynamic response compared with a non-AD brain in the context of equal stimulation. The BOLD signal must be calibrated to the resting state to prevent over-interpretation of greater BOLD responses as signifying heightened compensatory responses. Recent research using APP23 transgenic mice has demonstrated that amyloid plaques have a direct effect on the hemodynamic response, due partly to compromised cerebrovascular reactivity (Mueggler et al., 2002). Human studies also demonstrate that the hemodynamic response itself changes with age (D'Esposito et al., 1999). Thus, future efforts should incorporate other MR-based techniques such as perfusion imaging and structural morphometry to help delineate the contributions of the neuroanatomic and neurophysiologic underpinnings of the BOLD signal.

It remains that there is still no single marker of AD. Combined cognitive, imaging, and genetic assessments may ultimately be needed to achieve accurate and reliable identification of preclinical AD (Albert, 1996; Small et al., 1996). Detecting preclinical AD will probably be best accomplished by examining decline longitudinally with sensitive cognitive tests and structural or functional markers of brain integrity. Early detection may be enhanced if risk factors such as advancing age or the presence of the APOE ε4 allele (Mayeux et al., 1998) are also considered.

The ability to detect AD in its earliest, preclinical phase will continue to be an important topic of neuropsychological and neuroimaging research. The rapid development of neuroprotective agents designed to impede the progression of the disease is a testament to the recognized importance of early identification and treatment of AD (DeLaGarza, 2003). Moreover, preserving cognitive status and functional independence with more effective interventions will have far-reaching implications for maintaining patients' quality of life and decreasing caregivers' financial and emotional burden (Brookmeyer et al., 1998).

ACKNOWLEDGMENTS

This work was supported by NIMH grants K23 MH066011, T32 MH019934, and NIA grants R01 AG012674 and P50 AG005131.

APPENDIX 1

Neuropsychological Studies

Part A. Prospective longitudinal studies of initially nondemented subjects, comparing cases (subjects who developed AD) and controls (subjects who remained nondemented)
AuthorsNumber and
Type of
Subjects;
Methodological
Comments
Age (A = mean
years unless
otherwise indicated)
Gender
(G = percent male)
Education Level
(E = mean years)
Tests UsedResults
Bäckman and Small (1998) 24 cases
134 controls

3-year study
Cases
A = 84
G = 4% male
E = 8

Controls
A = 83
G = 18% male
E = 9
MMSE
Immediate memory tasks involving:
1. Free recall of slowly and rapidly
  presented unrelated words
2. Free and cued recall of related
  words
At baseline, cases performed worse on:
MMSE
Free and cued recall (regardless of speed
of presentation or relatedness of words)

Bäckman et al. (2001) 15 cases
105 controls

6-year study
Cases
A = 84
G = 7% male
E = 9

Controls
A = 82
G = 20% male
E = 10
MMSE
Free recall and recognition of
slowly presented unrelated words
WAIS-R Digit Span
At baseline and 3-year follow-up,
cases performed worse on:
MMSE
Free recall and recognition

These results held after controlling for
age, education, and gender

Cases and controls had similar slopes
of decline

Bondi et al. (1994)5 cases
51 controls
28/56 subjects
were FH+

3-year study

Subjects also
were compared
to 25 patients
with probable
AD at baseline

Cross-sectional
results from
baseline testing
reported below
FH+:
A = 70
G = 36% male
E = 16

FH−:
A = 71
G = 36% male
E = 15

AD at follow-up:
A = 74
G = 40% male
E = 15
AD at baseline:
A = 71
G = 56% male
E = 14
CVLT
MMSE
DRS
Number Information Test
(general knowledge)
Letter and category fluency
BNT
WAIS-R (Digit Span, Vocabulary,
Arithmetic, Similarities,
Digit Symbol)
WISC-R Block Design
Trail Making Test, Parts A and B
Clock Drawing Test
Clock Setting Test
Grooved Pegboard Test
Modified WCST
WMS-R (Visual Memory Span,
Logical Memory)
SRT
Cases performed worse than
controls but better than AD patients on:
CVLT learning and delayed recall
measures
MMSE
DRS Total
Category Fluency
WAIS-R Digit Symbol
Logical Memory I
SRT Total
Cases performed worse than controls
and comparably to AD patients on:
CVLT learning and delayed recall
measures
DRS Conceptualization
Letter Fluency
WAIS-R Similarities
Logical Memory II
SRT Recall

Bondi et al. (1999)7 cases
79 controls

23 ε4+
63 ε4−

Mean length of
follow-up wa
3 years

Sample included
52 subjects from
Bondi et al. (1995)

Cross-sectional
results from baseline
testing reported below
ε4+
A = 68
G = 47% male
E = 15

ε4−
A = 70
G = 43% male
E = 15
MMSE
DRS
CVLT
WMS Visual Reproduction
WAIS-R (Digit Span,
Digit Symbol,
Vocabulary)
WISC Block Design
BNT
Letter fluency
Trail Making Test,
Parts A and B
Modified WCST
Cases performed worse on:
CVLT List A Total

Analyses controlled for age and
education

Bunce et al. (2004)162 cases
373 controls

161 ε4+
374 ε4−

6-year study
ε4+
A = 80
G = 16% male
E = 8

ε4−
A = 80
G = 25% male
E = 9
MMSECases at 3-year follow-up and at 6-year
follow-up exhibited greater declines
on MMSE
Decline was most marked in the 3 years
prior to diagnosis
E4 status did not predict rate of decline
or AD diagnosis over time

Chen et al. (2000)120 cases
483 controls

10-year study
Cases
A = 78
G = 43% male
E = 50% less than high school

Controls
A = 75
G = 38% male
E = 32% less than high school
CERAD word list learning and
memory test
WMS Logical Memory
Trail Making Test, Parts A and B
Letter and category fluency
CERAD version of BNT
CERAD Praxis
Clock Drawing
MMSE
Cases performed worse on:
Word List Delayed Recall
Word List learning measures
Trail Making Test, Part B
MMSE

Chen et al. (2001)68 cases
483 controls

10-year study
Same sample as
above, examined change
between assessments
3.5 and 1.5 years before
AD diagnosis
Cases
A = 77
G = 43% male
E = 47% less than high school

Controls
A = 73
G = 38% male
E = 32% less than high school
CERAD word list learning and
memory test
WMS Logical Memory
Trail Making Test, Parts A and B
Letter and category fluency
CERAD version of BNT
CERAD Praxis
Clock Drawing
MMSE Orientation
Cases declined most on:
Trail Making Test, Part A
Trail Making Test, Part B
Word List Delayed Recall and
Recognition measures
Word List learning measures
CERAD Praxis
Clock Drawing
CERAD Boston Naming Test
MMSE Orientation

Dartigues et al. (1997)59 cases
2667 controls

3-year study
A = 75
G = 40% male
E = mostly grade
school
MMSE
BVRT
Isaaks Set Test (category fluency)
Cases performed worse on:
MMSE
BVRT
Isaaks Set Test
All three tests were independent
predictors of conversion to AD even
after adjusting for age and education

Elias et al. (2000)109 cases
967 controls

22-year study
controlling for
age, education,
occupation level,
and gender
Cases
G = 21% male

Controls
G = 39% male

A: 65–94
E: Majority of
subjects had ≥HS
WMS (Logical Memory, Paired
Associate Learning, Visual
Reproduction)
COWAT
WAIS (Similarities, Digit Span)
MMSE
Cases performed worse on:
Logical Memory (% retained)
Similarities
Paired Associate Learning
WMS Learning and Immediate Recall
Among an older (age 75–94),
but not a younger (age 65–74) cohort,
lower COWAT scores were associated
with later AD diagnosis

Fabrigoule et al. (1998)16 cases
1143 controls

2-year study
A = 73
G = 44% male
E = 56% grade
school educated,
remainder secondary
or university
education
MMSE
BVRT
WMS Paired Associates Test
Isaacs Set Test (category fluency)
Zazzo's Cancellation Task
(processing speed)
WAIS (Digit Symbol, Similarities)
Cases performed worse on:
BVRT
WAIS Digit Symbol
Isaacs Set Test
Zazzo's Cancellation Task
Wechsler Paired Associates Test
WAIS Similarities
MMSE

Fox et al. (1998)10 cases
53 controls

All subjects at risk
for autosomal
dominant familial
AD

6-year study
A = 45
G = 42% male
E = NR
MMSE
WAIS-R (Vocabulary, Arithmetic,
Digit Span, Similarities, Block Design,
Picture Completion, Picture Arrangement)
Recognition Memory Test
(words and faces)
Graded Naming Test
Visual Object and Spatial Perception Test
Psychomotor Speed Tests
Graded Difficulty Arithmetic Test
Graded Difficulty Spelling Test
NART
Cases performed worse on:
Recognition Memory Test (words)
WAIS-R Block Design, Picture
Completion, and Picture Arrangement

Grober and Kawas (1997)20 cases
60 controls

3-year study
Cases
A = 79
G = 45% male
E = 17

Controls
A = 79
G = 48% male
E = 17
SRTCases performed worse on:
SRT learning measures

Hall et al. (2000)35 cases
293 controls

15-year study
Cases
A = 80
G = NR
E = NR

Controls
A = 80
G = NR
E = NR
SRT learningCases performed worse on:
SRT learning

Howieson et al. (1997)16 cases
31 controls

Mean length of
follow-up was
2.8 years
Cases
A = 90
G = 44% male
E = 15

Controls
A = 85
G = 42% male
E = 14
CERAD version of BNT
WAIS-R (Vocabulary, Picture
Completion, Block Design)
CERAD Word List Memory Test
WMS-R Logical Memory and
Visual Reproduction
Cases performed worse on:
Boston Naming Test
Logical Memory I and II
Block Design
CERAD Word List Delayed Recall
Picture Completion
Visual Reproduction I

Jacobs et al. (1995)41 cases
402 controls

4-year study
Cases
A = 79
G = 22% male
E = 8

Controls
A = 73
G = 27% male
E = 11
SRT
BVRT
MMSE Orientation items
WAIS-R Similarities subtest
DRS Identities and Oddities
BNT (15 item version)
Letter and category fluency
BDAE Complex Ideational Material
Rosen Drawing Test
(visuoconstruction)
Visual matching test
(visuoperception)
Cases performed worse on:
Boston Naming Test
SRT Immediate Recall
WAIS-R Similarities

Analyses controlled for age, education,
sex, and language of test administration

Katzman et al. (1989)32 cases
402 controls

5-year study
Cases
A = 81
G = 16% male
E = modal 7–9

Entire sample
A = 79
G = 36% male
E = modal 7–9
Blessed Information-Memory-
Concentration Test
Cases performed worse on:
Blessed Information-Memory-
Concentration Test
Those with 0–2 errors developed AD at
a rate less than 0.6% per year, whereas
those with 5–8 errors developed AD at
a rate of over 12% per year

Klages et al. (2003)27 cases
182 controls

5-year study
A = 77
G = 38% male
E = 10
SRTCases performed worse on:
SRT (delayed free recall)

Laukka et al. (2004)43 cases
149 controls

6-year study
A = 84
G = 16% male
E = 9
WAIS-R Digit Span
Episodic Memory (Random Recall, Organized Recall,
Word Recognition, Face Recognition)
Visuospatial Ability (WAIS-R Block
Design, Clock Reading,
Clock Setting)
Letter and category fluency
Cases performed worse on:
All episodic memory measures
Fluency measures
WAIS-R Block Design
Clock Setting

Lindeboom et al. (2002)24 cases
204 controls

3-year study
Cases
A = 79
G = 25% male
E = completed
primary education

Controls
A = 73
G = 45% male
E = completed
primary education
MMSECases performed worse on:
MMSE

Lindsay et al. (2002)194 cases
3894 controls

5-year study
Cases
A = 81
G = 32% male
E = 10

Controls
A = 73
G = 42% male
E = 11
3MS ExaminationCases performed worse on:
3MS

Linn et al. (1995)55 cases
990 controls

13-year study
Cases
A = 76
G = 29% male

Controls
A = 72
G = 38% male

E = Majority of
subjects had ≥HS
WMS (Logical Memory,
Visual Reproduction,
Paired Associate Learning,
Digit Span)
COWAT
WAIS Similarities
Cases performed worse on:
Logical Memory I and II
and percent retained
Visual Reproduction I
Paired Associate Learning
Controlled Oral Word Association
Similarities
Analyses controlled for age and education

Masur et al. (1994)64 cases
253 controls

Minimum length of
follow-up was 4 years
Cases
A = 80
G = 41% male
E = modal 7–9

Controls
A = 79
G = 39% male
E = modal 7–x9
WAIS (Information, Vocabulary,
Similarities, Digit Span, Block Design,
Object Assembly, Digit Symbol)
Fuld Object Memory Evaluation
SRT
Category fluency
Raven's Colored Matrices
Purdue Pegboard Test
Cases performed worse on:
SRT delayed recall
Fuld Object Memory recall
Category Fluency
WAIS Digit Symbol

Nielsen et al. (1999)102 cases
2350 controls

2-year study
A = 65–84
G = NR
E = NR
CAMCOG:
Orientation
Comprehension
Naming
Category fluency
Definitions
Memory
Recognized pictures
General knowledge
Attention
Copying
Ideomotor praxis
Abstraction
Visual perception
Cases performed worse on:
Category fluency
Memory
General knowledge
Attention

Rapp and Reischies (2005)15 cases
172 controls

4-year study
A = 80
G = 50% male
E = 11
MMSE
Trail Making Test, Part B
Digit Letter Test (processing speed)
WAIS Digit Symbol
WMS Paired Associate Learning
Identical Pictures (attention)
Memory for Text (learning)
Activity Recall (recall of tests given)
Cases performed worse on:
Trail Making Test, Part B
Digit Letter Test
Digit Symbol Substitution Test
Identical Pictures
Paired Associates Test
Memory for Text
Activity Recall

After controlling for age differences
between groups, cases performed
worse on:
Identical Pictures
Trail Making Test, Part B

Saxton et al. (2004)72 cases
621 controls

Study combined data
from 3 separate
prospective studies
with 8 years of
follow-up
A = 73
G = 44% male
E = 13
WMS-R Orientation
WMS-R Immediate Memory
(Verbal, Visual, General)
WMS-R Delayed Memory
Speed/Attention (WMS-R Attention/
Concentration, WAIS-R Digit Symbol,
Trail Making Test, Parts A and B)
Verbal Productivity/Vocabulary
(WAIS-R Vocabulary, Letter and
category fluency)
BNT
WAIS-R Block Design
For 1.5–3.4 year follow-up, cases
performed worse on:
WMS-R Verbal
WMS-R Visual
WMS-R General
WMS-R Delayed
WMS-R Attention/Concentration
Trail Making Test, Parts A and B
Category Fluency
Boston Naming Test

For 3.5–5 year follow-up,
cases performed worse on:
WMS-R General
WMS-R Delayed
Trail Making Test, Part B
Category Fluency

For 5.1–8 year follow-up, cases
performed worse on:
WMS-R Verbal
WMS-R Delayed

Small et al. (1997b)32 cases
189 controls

3-year study
A = 84
G = 19% male
E = 9
MMSECases performed worse on:
MMSE (particularly delayed recall
and orientation to time)

Small et al. (1997a)26 cases
179 controls

3-year study
Cases
A = 85
G = 12% male
E = 9

Controls
A = 83
G = 21% male
E = 9
MMSE
Face Recognition Task
Free Recall and Recognition of
Random and Organizable Words
Letter and category fluency
Poppelreuter's Figures
(visual perception)
Clock Test
WAIS-R (Block Design, Digit Span)
Cases performed worse on:
MMSE
Face Recognition Task
Free Recall and Recognition of
Random and Organizable Words
Letter and Category Fluency
Poppelreuter's Figures
Clock Test
WAIS-R Block Design

Small et al. (2000a)73 cases
459 controls

6-year study
Cases
A = 82
G = 21% male
E = 8
MMSECases performed worse on:
MMSE delayed memory item
Cases were those
diagnosed with AD
at 6-year, but not
3-year, follow-up
Controls
A = 79
G = 23% male
E = 9

Yoshitake et al. (1995)42 cases
784 controls

7-year study
A = 74
G = 40% male
E = 26% had ε6
Hasegawa Dementia Scale
(11-item mental status exam including
orientation, memory, common
knowledge, and calculation)
Cases performed worse on:
Hasegawa Dementia Scale

Zonderman et al. (1995)7 cases
364 controls

Longitudinal study
since 1960 with
testing every 6–8 years
A = 72
G = 68% male
E = mostly HS
or college educated
BVRTCases performed worse on:
BVRT learning
Cases declined more rapidly on the
BVRT in the 6 years before diagnosis
of AD

Part B. Prospective longitudinal studies examining differential cognitive decline in ε4+ and ε4− subjects

AuthorsNumber and
Type of
Subjects; Methodological
Comments
Age (A = mean
years unless
otherwise indicated)
Gender
(G = percent male)
Education Level
(E = mean years)
Tests UsedResults

Baxter et al. (2003)54 ε4+
59 ε4−

2-year study
ε4+
A = 58
G = 33% male
E = 16
RAVLT
COWAT
ε4+ subjects over age 60 declined in
their novel word learning ability
ε4−
A = 59
G = 37% male
E = 16

Bretsky et al. (2003)227 ε4+
738 ε4−

7-year study
A = 74
G = 44% male
E = NR
Overall cognitive performance:
4 items from WAIS-R Similarities
Delayed spatial recognition
BNT (18-item version)
Spatial ability
Memory:
Delayed verbal and visual memory
Story recall
At 3-year follow-up, ε4+ subjects
declined in naming and spatial ability

At 7-year follow-up, ε4+ subjects
declined in overall cognitive
performance, naming, spatial ability,
abstraction, and verbal and visual
memory

Cohen et al. (2001)16 ε4+
9 ε4−

2-year study

Groups also compared
on structural MRI (see
findings reported below)
ε4+
A = 55
G = 0% male
E = NR

ε4−
A = 61
G = 0% male
E = NR
SRT free recall
Letter and category fluency
Rey CFT
WMS-R
WAIS-R Block Design
No significant group differences

Dik et al. (2000)213 ε4+
653 ε4−

Mean length of
follow-up was
3.1 years
A = 72
G = 51% male
E = 9
MMSE (baseline only)
Alternate forms of an abbreviated
(3-trial) RAVLT
At baseline, ε4+ and ε4− subjects did not
differ on the MMSE

At follow-up, ε4+ subjects over 75 per-
formed better on RAVLT immediate recall

Ercoli et al. (2003)23 ε4+
31 ε4−

2-year study
ε4+
A = 65
G = 39% male
E = 15

ε4−
A = 66
G = 42% male
E = 15
MMSE
MMSE subset items
(delayed 3-item recall;
serial 7s; intersecting pentagons;
time and place orientation)
No significant group differences

For ε4+ subjects, lower baseline scores
on the MMSE subset items predicted
decline in visual construction and naming

Helkala et al. (1996)192 ε4+
(including ε2/ε4)
378 ε3/ε3
62 ε2+

3-year study
A = 73
G = 35% male
E = 7
MMSE
SRT (total score)
Visual Reproduction test
(immediate, delay, copy)
Letter and category fluency
Trail Making Test,
Parts A and B
At follow-up, ε2+ subjects performed
better than ε4+ and ε3/ε3 subjects on:
SRT
Letter fluency

Hofer et al. (2002)94 ε4+
340 ε4−

7-year study
A = 76
G = 49% male
E = 12
Verbal ability (Vocabulary,
Similarities, NART items)
Memory (word recognition test,
3 word recall with 2 minute delay,
address recall with 2 minute delay)
Speed (symbol-letter modalities test)
ε4+ subjects declined on:
Memory

Jonker et al. (1998)25 ε4+
292 ε4−

3-year study
A = 75
G = 43% male
E = 8
CAMCOG (total score, memory
and nonmemory subscales)
ε4+ subjects declined on:
CAMCOG total score
memory subscale
nonmemory subscale

Mayeux et al. (2001)80 ε4+
483 ε4−

7-year study
A = 76
G = 31% male
E = 10
Visuospatial/Cognitive factor
(Rosen Drawing Test, BVRT,
DRS Identities and Oddities)
Language factor (BNT, COWAT,
WAIS-R Similarities)
Memory factor (seven subtests
of the SRT)
ε4+ subjects declined faster on:
Memory

Pendleton et al. (2002)201 ε4+
566 ε4−

15-year study
A = modal 60–69
G = 30% male
E = NR
Heim AH4 part 1
(fluid general intelligence)
No significant group differences

Reiman et al. (2001)10 ε4+
15 ε4−
All subjects had
a family history
of AD

2-year study

Groups also
compared on PET
(see findings
reported below)
ε4+
A = 56
G = 30% male
E = 15

ε4−
A = 57
G = 33% male
E = 16
MMSE
RAVLT
CFT
BNT
WAIS-R (Information, Digit Span,
Block Design, Arithmetic, Similarities)
COWAT
No significant group differences

Riley et al. (2000)34 ε4+
207 ε4−
All subjects were nuns

4-year study
A = 81
G = 0% male
E = 17
CERAD:
MMSE
Delayed word recall
Verbal fluency
BNT
Constructional praxis
ε4+ subjects declined on:
MMSE
Delayed word recall

Small et al. (1998)20 ε4+
54 ε4−

3-year study

Cross-sectional results
from baseline testing
reported below
ε4+
A = 80
G = 25% male
E = 10

E4−
A = 82
G = 30% male
E = 10
MMSE
Face Recognition Task
Free Recall and Recognition of
Random and Organizable Words
Letter and category fluency
Poppelreuter 's Figures
Clock Test
WAIS-R (Block Design, Digit Span)
ε4+ subjects declined on:
Recognition memory for faces and words

Wilson et al. (2002)161 ε4+
450 ε4−

6-year follow-up

Cross-sectional results
from baseline testing
reported below
A = 76
G = 38% male
E = 18
Episodic memory (CERAD Word
List Memory, Recall, and Recognition,
Immediate and Delayed Story Memory,
WMS-R Logical Memory Story A)
Semantic memory (BNT, Verbal Fluency,
Extended Range Vocabulary, NART)
Working memory (WMS-R Digit Span,
Digit Ordering, Alpha Span)
Perceptual speed (Symbol Digit
Modalities Test, Number Comparison)
Visuospatial ability (Judgment of Line
Orientation, Raven's Standard
Progressive Matrices)
ε4+ subjects declined on all cognitive
domains, with the most decline on
episodic memory

Winnock et al. (2002)130 ε4+
470 ε4−

7-year study

Cross-sectional results
from baseline testing
reported below
A = 74
G = 76% male
E = mostly
primary education
or above
MMSENo significant group differences
in decline

Yaffe et al. (before 1997)271 ε4+
1479 ε4−

6-year study

Cross-sectional results
from baseline testing
reported below
A = 71
G = 0% male
E = 12
MMSE
Trail Making Test, Part B
WAIS-R Digit Symbol
ε4+ subjects declined on all cognitive
tests

Part C. Cross-sectional studies comparing neuropsychological profiles of healthy, nondemented ε4+ and ε4− subjects

AuthorsNumber and
Type of
Subjects;
Methodological
Comments
Age (A = mean
years unless
otherwise indicated)
Gender
(G = percent male)
Education Level
(E = mean years)
Tests UsedResults

Albert et al. (1995)60 ε4+
158 ε4−
A = 74
G = 26% male
E = 8
SRT (total recall and delayed recall)No significant group differences

Berr et al. (1996)270 ε4+
904 ε4−
A = 65
G = 42% male
E = 11
MMSE
Trail Making Test, Part B
RAVLT
Benton Face Recognition Test
WAIS-R Digit Symbol
Finger Tapping Test
BVRT
Raven's Progressive Matrices
PASAT
Word Fluency Test
After adjusting for age, education,
and gender, the number of ε4 alleles was
associated with worse performance on:
MMSE
Trail Making Test, Part B
Finger Tapping Test

Bondi et al. (1999)43 ε4+
90 ε4−

Sample included
52 subjects from
Bondi et al. (1995)

Longitudinal
results reported
above
ε4+
A = 68
G = 47% male
E = 15

ε4−
A = 70
G = 43% male
E = 15
MMSE
DRS
CVLT
WMS Visual Reproduction
WAIS-R (Digit Span, Digit
Symbol, Vocabulary)
WISC Block Design
BNT
Letter fluency
Trail Making Test, Parts A and B
Modified WCST
ε4+ subjects performed worse on:
WCST nonperseverative errors
CVLT learning and memory measures

Caselli et al. (1999)25 ε4/ε4
25 ε4 heterozygotes
50 ε4−

All subjects were
first-degree
relatives of
AD patients
ε4/ε4
A = 56
G = 28% male
E = 16

ε4 heterozygotes
A = 56
G = 28% male
E = 15
COWAT
WAIS-R (Arithmetic, Digit Span,
Similarities, Block Design,
Information)
WMS-R Orientation
RAVLT
BNT
CFT
BVRT
No significant group differences,
whether all three groups were compared
or whether ε4+ subjects were compared
with ε4− subjects
ε4−
A = 57
G = 28% male
E = 15

Caselli et al. (2001)20 ε4/ε4
20 ε4 heterozygotes
40 ε4−

All subjects were
first-degree
relatives of
AD patients
ε4/ε4
A = 57
G = 40% male
E = 16

ε4 heterozygotes
A = 56
G = 40% male
E = 16
COWAT
WAIS-R (Arithmetic, Digit Span,
Similarities, Block Design,
Information)
WMS-R Orientation
RAVLT
BNT
CFT
BVRT
ε4 heterozygotes performed worse than
did ε4− subjects on:
Complex Figure Test Recall
ε4−
A = 56
G = 40% male
E = 16

Caselli et al. (2002)42 ε4/ε4
38 ε4−

ε4/ε4 subjects were
matched to ε4−
subjects on age,
gender, education,
family history of
dementia
A = 55
G = 31% male
E = 16
MMSE
RAVLT
BVRT
Rey-Osterrieth CFT
WAIS-R (Information, Digit Span,
Arithmetic, Similarities,
Block Design)
Letter fluency
BNT
ε4/ε4 subjects performed worse than
did ε4− subjects on:
RAVLT learning
Similarities

Chen et al. (2002)72 ε4+
81 ε4−
A = 67
G = 50% male
E = 16
MMSE
CVLT
No significant group differences

Deary et al. (2004)120 ε4+
342 ε4−

All subjects born
in 1921
A = 79
G = 41% male
E = NR
MMSE
WMS-R Logical Memory
Raven's Progressive Matrices
Letter fluency
ε4+ subjects performed worse on:
Logical Memory I and II

Fillenbaum et al. (2001)548 ε4+
1343 ε4−

Longitudinal study
with applicable
cross-sectional
data at baseline
A = 77
G = 33% male
E = 10
Short Portable Mental Status
Questionnaire
ε4+ subjects performed worse on:
Short Portable Mental Status
Questionnaire

Flory et al. (2000)61 ε4+
159 ε4−
A = 46
G = 51% male
E = 16
Verbal associative learning
Verbal associative learning delayed recall
Verbal associative learning recognition
CFT delayed recall
WAIS-R (Digit Symbol immediate recall,
Digit Span)
ε4+ subjects performed worse on:
CFT delayed recall
Verbal associative learning

Greenwood et al., (2000)38 ε4+
48 ε3/ε3
11 ε2+
A = 59
G = 39% male
E = 17
Cued letter discrimination task
Cued visual search task
Vigilance task
No significant group differences in
accuracy or reaction time on any task
ε4+ subjects had slower reaction
times to invalid cues than did other
groups on the cued letter discrimina-
tion task and had reduced spatial
scaling of attention on the cued
visual search task

Greenwood et al. (2005)64 ε4+
113 ε4−

Cross-sectional
study examining
ε4 “dose”
A = 59
G = 42% male
E = 17
Spatial cued letter discrimination task
Spatial working memory task
ε4 dose was associated with impair-
ment in: Redirecting visuospatial
attention to unexpected locations
Retaining locations in working
memory
Using attentional scaling to enhance
spatial working memory

Kim et al. (2002)74 ε4+
392 ε4−
A = 70
G = 27%
E = 6
Korean version of CERAD:
MMSE
Verbal fluency test
Modified BNT
Word list memory test
Word list recall test
Word list recognition test
Constructional praxis test
Constructional recall test
No significant group differences

Levy et al. (2004)61 ε4+
115 ε4−
A = 59
G = 36% male
E = 17
Prose Recall (WMS-R Logical
Memory I and II, percent retained)
Word Recall (SRT, WMS-R Verbal
Paired Associates I and II)
Design Recall (WMS-R Visual
Reproduction I and II, percent retained,
CFT 3 minute recall)
Visuospatial Ability (CFT copy,
WAIS-R Block Design, Digit Symbol)
Language (Letter and category fluency,
BNT)
ε4+ subjects performed worse on:
Logical Memory II
Logical Memory percent retained

Reed et al. (1994)40 dizygotic twins
(20 pairs) discordant
for presence of the
ε4 allele
Cross-sectional study
comparing education-
adjusted scores on
neuropsychological
tests in twins
discordant for ε4
A = 63
G = 100% male
E = NR
BVRT
COWAT
MMSE
WAIS-R Digit Symbol
Modified version of the Telephone
Interview for Cognitive Status
ε4+ twins performed worse than
their ε4− co-twins on:
BVRT

Rosen et al. (2002)21 ε4+
21 ε4−
A = 62
G = 43% male
E = 17
Operation Span Task (working memory)
SRT
ε4+ subjects performed worse on:
Operation Span Task

Salo et al. (2001)12 ε4+
34 ε4−
A = 89
G = 48% male
E = 4
MMSE
Fuld Object Memory Evaluation
Letter and category fluency
WAIS-R Similarities
No significant group differences

Schmidt et al. (1996)39 ε4+
175 ε4−

Groups also
compared on
structural MRI
(see findings
reported below)
ε4+
A = 59
G = about 50% male
E = 11

ε4−
A = 61
G = about 50% male
E = 12
German verbal and visual learning and memory test
German cancellation (attention and speed) test
German complex reaction time test
WCST
Trail Making Test, Part B
WAIS-R Digit Span
Purdue Pegboard Test
ε4+ subjects performed worse on:
Verbal and visual memory

Small et al. (1998)20 ε4+
54 ε4−

Longitudinal results
reported above
ε4+
A = 80
G = 25% male
E = 10

ε4−
A = 82
G = 30% male
E = 10
MMSE
Face Recognition Task
Free Recall and Recognition of Random
and Organizable Words
Letter and category fluency
Poppelreuter's Figures
Clock Test
WAIS-R (Block Design, Digit Span)
No significant group differences

Small et al. (2000b)91 ε4+
322 ε4−
A = 73
G = 49% male
E = 14
3MS
Spot-the-Word (premorbid IQ test)
Hopkins Verbal Learning Test
Word stem Completion Task (implicit memory)
Trail Making Test, Parts A and B
Stroop Test
No significant group differences

Smith et al. (1998)90 ε4+
251 ε4−
ε4+
A = 80
G = 30% male
E = 14

ε4−
A = 80
G = 31% male
E = 13
Verbal Comprehension (WAIS-R Vocabulary,
Information) Perceptual Organization
(WAIS-R Block Design, Picture Arrangement,
Picture Completion; WMS-R Visual Reproduction I)
Attention/Concentration (WMS-R Digit
Span, Mental Control; WAIS-R Arithmetic)
Learning (RAVLT acquisition; WMS-R Verbal
and Visual Paired Associates I)
Retention (percent retention for RAVLT,
WMS-R Logical Memory, and WMS-R
Visual Reproduction)
BNT
RAVLT delayed recall
No significant group differences

Staehelin et al (1999)72 ε4+
198 ε3/ε3
62 ε2+
(including 11 ε2/ε4)
A = 76
G = 68% male
E = NR
Reaction Time
Delayed free recall
WAIS-R Vocabulary (German version)
ε3/ε3 and ε4+ subjects performed
worse than did ε2 subjects on:
Reaction Time

ε4+ subjects performed worse
than did ε3/ε3 on:
WAIS-R Vocabulary

Tohgi et al. (1997)14 ε4+
40 ε4−

Groups also
compared
on structural MRI
(see findings
reported below)
A = 59
G = 52% male
E = 12
MMSENo significant group differences

Wilson et al. (2002)161 ε4+
450 ε4−

Longitudinal
results
reported above
A = 76
G = 38% male
E = 18
Episodic memory (CERAD Word List Memory,
Recall, and Recognition, Immediate and Delayed
Story Memory, WMS-R Logical Memory Story A)
Semantic memory (BNT, Verbal Fluency,
Extended Range Vocabulary, NART)
Working memory (WMS-R Digit Span,
Digit Ordering, Alpha Span)
Perceptual speed (Symbol Digit Modalities
Test, Number Comparison)
Visuospatial ability (Judgment of Line Orientation,
Raven's Standard Progressive Matrices)
ε4+ subjects performed worse on:
Episodic memory
Visuospatial ability

Winnock et al. (2002)130 ε4+
470 ε4−

Longitudinal results
reported above
A = 74
G = 76% male
E = mostly primary
education or above
MMSEε4+ subjects performed worse on:
MMSE (but not after controlling
for education)

Yaffe et al. (1997)271 ε4+
1479 ε4−

Longitudinal results
reported above
A = 71
G = 0% male
E = 12
MMSE
Trail Making Test, Part B
WAIS-R Digit Symbol
ε4/ε4 subjects performed worse on:
Trail Making Test, Part B

Part D. Cross-sectional studies comparing neuropsychological profiles of nondemented subjects with AD-like and normal brains at autopsy

AuthorsNumber and
Type of
Subjects;
Methodological
Comments
Age (A = mean
years unless
otherwise indicated)
Gender
(G = percent male)
Education Level
(E = mean years)
Tests UsedResults

Goldman et al. (2001)5 preclinical AD
brains with neuritic
and diffuse plaques
11 normal brains
Preclinical AD
brain
A = 80
G = 40% male
E = 14

Normal brain
A = 83
G = 78% male
E = 14
WMS (Mental Control, Logical Memory,
Digit Span, Paired Associate Learning)
BVRT
WAIS (Information, Block Design,
Digit Symbol)
Trail Making Test, Part A
Crossing-off (processing speed)
BNT
Letter fluency
No significant group differences

Hulette et al. (1998)4 “possible AD”
brains per CERAD
autopsy criteria
8 normal brains
Possible AD brain
A = 83
G = 50% male
E = 15

Normal brain
A = 82
G = 50% male
E = 17
MMSE
Letter and category fluency
Naming test
Constructional Praxis
Symbol-Digit Modalities Test
Trail Making Test, Parts A and B
CERAD Word List Memory
WMS Logical Memory
BVRT
Subjects with possible AD at autopsy
performed worse on:
Memory percent retained
Trail Making Test, Parts A and B
Category fluency
(trends only; sample size too small
to permit inferential tests)

Schmitt et al. (2000)7AD-like brains
52 normal brains
A = 84
G = 46% male
E = 16
MMSE
Blessed Information-Memory-Concentration Test
Temporal Orientation Test
WMS (Mental Control, Logical Memory)
BVRT
Alzheimer's Disease Assessment Scale
(word list learning/recognition and
design reproduction)
COWAT
Animal naming
BNT
WAIS-R (Vocabulary, Digit Symbol)
Trail Making Test, Parts A and B
Subjects with AD-like brains performed
worse at the evaluation before death on:
Logical Memory I
Word list delayed recall

Part E. Cross-sectional studies comparing neuropsychological profiles of healthy, nondemented, FH+ and FH− subjects

AuthorsNumber and
Type of
Subjects;
Methodological
Comments
Age (A = mean
years unless
otherwise indicated)
Gender
(G = percent male)
Education Level
(E = mean years)
Tests UsedResults

Bondi et al. (1994)5 cases
51 controls
28/56 subjects
were FH+
Longitudinal results
reported above
FH+:
A = 70
G = 36% male
E = 16

FH−:
A = 71
G = 36% male
E = 15
CVLT
MMSE
DRS
Number Information Test (general knowledge)
Letter and category fluency
BNT
WAIS-R (Digit Span, Vocabulary, Arithmetic,
Similarities, Digit Symbol)
WISC-R Block Design
Trail Making Test, Parts A and B
Clock Drawing Test
Clock Setting Test
Grooved Pegboard Test
Modified WCST
WMS-R (Visual Memory Span, Logical Memory)
SRT
FH+ subjects performed worse on:
CVLT learning and delayed recall
measures

Diaz-Olavarrieta et al. (1997)14 FH+ (from
FAD families)
14 FH−

Cognitive test
scores were
averaged over
two evaluations in
a one-year period
FH+
A = 39
G = 30% male
E = 11

FH−
A = 38
G = 71% male
E = 11
MMSE
Digit Span
Corsi cubes
WMS (Orientation, Mental Control)
Immediate verbal memory
Paired word association
Verbal learning curve
Rey-Osterreith CFT
(immediate and delayed recall)
Block Design
BNT
Letter and category fluency
No significant group differences

Hom et al. (1994)20 FH+
(first-degree
relatives of AD
probands)
20 FH−
FH+
A = 55
G = 15% male
E = 14

FH−
A = 56
G = 15% male
E = 12
WAIS
WMS-R (Logical Memory, Visual Reproduction)
Halstead Category Test
Tactual Performance Test
Seashore Rhythm Test
Speech-Sounds Perception Test
Reitan-Indiana Aphasia Screening Examination
FH+ subjects performed worse on:
WAIS Verbal IQ
Seashore Rhythm Test
Logical Memory I
WAIS Information
Halstead Impairment Index

Schiffman et al. (2002)33 FH+
32 FH−
A = 61
G = 54% male
E = 15
MMSE
CERAD battery
WMS-R Logical Memory
BVRT
COWAT
Trail Making Test, Parts A and B
Symbol Digit Modalities Test
Taste Detection Threshold, Memory,
Recognition, Identification
Smell Detection Threshold, Memory,
Recognition, Identification
FH+ subjects performed worse on:
Logical Memory I
Trail Making Test Part A
Smell Detection Threshold
Smell Memory
Taste Memory

Abbreviations Used:

3MS = Modified Mini-Mental State Exam

AD = Alzheimer's disease

BDAE = Benton Diagnostic Aphasia Examination

BNT = Boston Naming Test

BVRT = Benton Visual Retention Test

CAMCOG = Cambridge Mental Disorders of the Elderly Examination—Cognitive Section

CERAD = Consortium to Establish a Registry for Alzheimer's Disease

CFT = Complex Figure Test

COWAT = Controlled Oral Word Association Test

CVLT = California Verbal Learning Test

DRS = Dementia Rating Scale

ε4 = APOE ε4 allele

ε3 = APOE ε3 allele

ε2 = APOE ε2 allele

FAD = Familial Alzheimer's disease

FH = Family history of AD

HS = High School

MMSE = Mini-Mental State Examination

MRI = Magnetic resonance imaging

NART = National Adult Reading Test

NR = Not reported

PASAT = Paced Auditory Serial Addition Test

PET = Positron emission tomography

RAVLT = Rey Auditory Verbal Learning Test

SRT = Selective Reminding Test

WAIS = Wechsler Adult Intelligence Scale

WAIS-R = Wechsler Adult Intelligence Scale-Revised

WCST = Wisconsin Card Sorting Test

WISC = Wechsler Intelligence Scale for Children

WISC-R = Wechsler Intelligence Scale for Children–Revised

WMS = Wechsler Memory Scale

WMS-R = Wechsler Memory Scale-Revised

APPENDIX 2

Neuroimaging Studies of Preclinical Alzheimer's Disease

Part A. Longitudinal structural MRI studies examining development of Alzheimer's disease
AuthorsNumber and
Type of
Subjects;
Methodological
Comments
Age (A = mean
years unless
otherwise indicated)
Gender
(G = percent male)
Education Level
(E = mean years)
Regions ExaminedResults
Fox et al. (1996)3FH+ cases
4FH+ controls
(All 7 from a
familial AD
pedigree) 38
normal controls

3-year study
FH+
A = 45
G = 86% male
E = NR

Normal controls
A = 48
G = 50% male
E = NR
Hippocampal formation volumeIn the 3 subjects who developed AD, significant,
asymmetric hippocampal atrophy was detectable
before the development of symptoms
The 4 FH+ subjects who remained well did
not differ from NCs on hippocampal volume

Fox et al. (2001)4 FH+ cases
(All 4 from a
familial AD
pedigree) 20
normal controls

8-year study
FH+
A = median 43
G = NR
E = NR

Normal controls
A = median 51
G = NR
E = NR
Whole brainFH+ subjects had higher annual rates of
global volume loss, particularly in the medial
temporal lobe, inferolateral temporal lobe,
parietal lobe, and posterior cingulate

Kaye et al. (1997)12 cases
18 controls

Mean length
of follow-up
was 3.5 years
Cases
A = 90
G = 42% male
E = 15

Controls
A = 87
G = 44% male
E = 14
Supratentorial intracranial cavity
volume;
Temporal lobe tissue volume;
Parahippocampal gyrus volume;
Hippocampal volume
Subjects who developed AD had smaller hippo-
campal and temporal lobe tissue volumes at
baseline and showed greater temporal lobe
atrophy over time.
Hippocampal and temporal lobe tissue volumes
at baseline and rate of temporal lobe volume loss
were significant predictors of group status.

Part B. Longitudinal structural MRI study comparing nondemented ε4+ and ε4− subjects

Cohen et al. (2001)16 ε4+
9 ε4−

2-year study

Groups also compared
on neuropsychological
performance (see find-
ings reported above)
ε4+
A = 55
G = 0% male
E = NR

ε4−
A = 61
G = 0% male
E = NR
Hippocampal volumeCompared with ε4− subjects, ε4+ subjects
demonstrated greater hippocampal volume
loss

Part C. Longitudinal functional imaging study comparing nondemand ε4+ ε4− subjects

AuthorsNumber and
Type of
Subjects;
Methodological
Comments
Age (A = mean
years unless
otherwise indicated)
Gender (G = percent male)
Education Level
(E = mean years)
Tasks UsedResults

Reiman et al. (2001)10 ε4+
15 ε4−

All subjects were FH+
2-year study

Groups also compared
on neuropsychological
performance (see find-
ings reported above)
ε4+
A = 56
G = 30% male
E = 15
ε4−
A = 57
G = 33% male
E = 16
Resting PET examining regional
rates of glucose metabolism
ε4+ subjects had significantly greater
glucose metabolism declines over 2 years
in temporal, posterior cingulate, prefrontal
cortex, basal forebrain, parahippocampal
gyrus, and thalamus

Part D. Cross-sectional structural MRI studies comparing nondemented ε4+ and ε4− subjects

AuthorsNumber and
Type of
Subjects;
Methodological
Comments
Age (A = mean
years unless
otherwise indicated)
Gender
(G = percent male)
Education Level
(E = mean years)
Regions ExaminedResults

den Heijer et al. (2002)117 ε4+
259 ε3/ε3
52 ε2+
A = 72
G = 48% male
E = NR
Hippocampal and amygdalar
volume
ε4+ subjects had smaller hippocampal and
amygdalar volumes bilaterally
No significant differences between ε2+ subjects
and ε3/ε3 subjects

Jack et al. (1998)30 ε4+
95 ε4−
ε4+
A = 80
E = 13

ε4−
A = 79
E = 13

G = 26% male
Hippocampal volumeTrend toward smaller hippocampi in the
ε4+ group

Jernigan et al. (2001)21 ε4+
22 ε4−
A = NR
G = NR
E = NR
Whole brainε4+ subjects had lower subcortical gray matter volumes
than did ε4− subjects; the difference was due to lower
lenticular nucleus volumes in the ε4+ subjects

Plassman et al. (1997)3 ε4+ twin pairs
7ε4− twin pairs
ε4+
A = 65
G = 33% male
E = 15

ε4−
A = 62
G = 29% male
E = 13
Hippocampal volumeControlling for education, the ε4+ group had
smaller hippocampi than did the ε4− group;
there were no group differences in hippocampal
volume asymmetry.

Reiman et al. (1998)11 ε4/ε4
22 ε4−

All subjects were FH+
ε4+
A = 55
G = 27% male
E = 17

ε4−
A = 56
G = 27% male
E = 16
Hippocampal volumeε4 homozygotes had 8% smaller left and right
hippocampal volumes, but the difference was not
statistically significant

Schmidt et al. (1996)39 ε4+
175 ε4−

Groups also compared
on neuropsychological
performance (see find-
ings reported above)
ε4+
A = 59
G = about 50% male
E = 11

ε4−
A = 61
G = about 50% male
E = 12
Whole brainNo differences in presence of infarcts, white
matter hyperintensities, sulcal widening,
ventricular enlargement, or hippocampal/
parahippocampal volumes

Tohgi et al. (1997)14 ε4+
40 ε4−

Groups also compared
on neuropsychological
performance (see find-
ings reported above)
A = 59
G = 52% male
E = 12
Hippocampal volumeCompared to ε4− subjects, ε4+ subjects had
smaller right hippocampal volumes

Part E. Cross-sectional functional imaging studies comparing at-risk subjects (ε4+ or FH+) to non-at-risk subjects (ε4− or FH−)

AuthorsNumber and
Type of
Subjects;
Methodological
Comments
Age (A = mean
years unless
otherwise indicated)
Gender
(G = percent male)
Education Level
(E = mean years)
Tasks UsedResults

Bookheimer et al. (2000)16 ε4+
14 ε4−

fMRI
ε4+
A = 63
G = 44% male
E = 15

ε4−
A = 62
G = 50% male
E = 15
Word pair learning and recall task
compared with resting condition
ε4+ subjects exhibited greater magnitude and
extent of activation in left hippocampal, parietal,
and prefrontal regions than did ε4− subjects

Burggren et al. (2002)13 ε4+
12 ε4−

fMRI
ε4+
A = 65
G = 38% male
E = 16

ε4−
A = 66
G = 42% male
E = 16
Digit span forward task (1–8 digits)No significant group differences in activation,
even as task difficulty increased

Kennedy et al. (1995)24 FH+ subjects
from a familial
AD pedigree
16 age-matched
control subjects

PET
FH+
A = 45
G = NR
E = NR

Controls:
A = 50
G = NR
E = NR
Resting PET examining global and
regional rates of glucose metabolism
Compared to controls, the at-risk subjects had
lower global and temporoparietal glucose
metabolism

Reiman et al. (1996)11 ε4/ε4
22 ε4−

All subjects
were FH+

PET
ε4+
A = 55
G = 27% male
E = 17

ε4−
A = 56
G = 27% male
E = 16
Resting PET examining regional rates
of glucose metabolism
ε4 homozygotes had significantly lower glucose
metabolism in posterior cingulate and bilateral
parietal, temporal, and prefrontal regions

Reiman et al. (2004)12 ε4+ (all
heterozygotes)
15 ε4−

PET
ε4+
A = 31
G = 25% male
E = 16

ε4−
A = 31
G = 20% male
E = 16
Resting PET examining regional rates
of glucose metabolism
ε4+ subjects had significantly lower glucose
metabolism bilaterally in posterior cingulate,
parietal, temporal, and prefrontal regions

Smith et al. (1999)14 ε4+, FH+
12 ε4−, FH−

fMRI
ε4+, FH+
A = 52
G = 0% male
E = 15
ε4−, FH−
A = 53
G = 0% male
E = 15
Visual naming
Letter fluency
ε4+, FH+ subjects had lower activation in the
bilateral mid- and posterior inferotemporal
regions during both tasks

Abbreviations Used:

AD = Alzheimer's disease

ε4 = APOE ε4 allele

ε3 = APOE ε3 allele

ε2 = APOE ε2 allele

fMRI = Functional magnetic resonance imaging

FH = Family history of AD

MMSE = Mini-Mental State Examination

MRI = Magnetic resonance imaging

NC = Normal control

NR = Not reported

PET = Positron emission tomography

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