Alzheimer's Disease Patients' Cognitive Status and Course Years Prior to Symptom Recognition

This is a prospective examination of the cognitive performance and cognitive course of persons in an asymptomatic “preclinical” phase who eventually developed Alzheimer's disease (AD). We compared performances on the Mayo Cognitive Factor Scales (MCFS) of 20 persons in a neurologically normal cohort who subsequently developed AD to the performances of 60 persons who remained free of dementia symptoms. For the AD patients, exams occurred prior to the appearance of dementia symptoms (an average of 4.2 and 1.5 years prior to symptom onset). Results reveal strong group differences on learning and retention, with eventual AD patients scoring lower than controls years prior to reporting symptoms of the disease. There was no significant interaction effect (group × testing session) for memory retention, suggesting that memory decline in this preclinical period may be too slow to be a useful indicator of future AD. A significant interaction (but no group effect) was seen for verbal comprehension.     

Neuropsychological indicators of preclinical Alzheimer’s disease among depressed older adults

Older adults with major depressive disorder (MDD) may also have preclinical Alzheimer’s disease (AD). Differential diagnosis is quite challenging due to the overlapping symptoms of MDD and AD. In the current study, we predicted that impaired long-term memory (an area most affected in early AD), but not executive function (an area affected in MDD and AD), would distinguish older depressed patients who developed AD from those who did not. Patients (N = 120) assessed as having MDD but not dementia at baseline were administered tests of cognitive function and followed longitudinally for subsequent diagnosis of AD. Using structural equation modeling we found a latent construct of long-term memory to be associated with AD to a greater extent than executive functioning. Additional analyses to enhance clinical utility of findings indicated that individual tests of episodic memory were most predictive of AD status. Tests of long-term memory can be utilized by the clinician when assessing for preclinical AD among depressed elderly.     

Neuropsychological function and apolipoprotein E genotype in the preclinical detection of Alzheimer's disease.

Nondemented older adults genotyped for the Apolipoprotein E (ApoE) epsilon4 allele (n = 43) were neuropsychologically compared to participants without a copy of the epsilon4 allele (n = 90). At baseline, the groups did not differ on age, education, gender, or global cognitive status. ApoE-epsilon4 participants demonstrated significantly poorer mean performances on delayed recall, but no significant group differences emerged on attention, language, constructional skills, psychomotor speed, or executive function. Significantly more ApoE-epsilon4 participants developed probable or questionable Alzheimer's disease (AD) compared with non-epsilon4 participants, suggesting that the group differences resulted from a preponderance of preclinical AD cases within the epsilon4 group and not from a direct influence of ApoE genotype on cognition. Cox proportional hazards analysis, adjusting for age, years of education, and global cognitive status, revealed that ApoE-epsilon4 allele status and measures of recall performance were significant and independent predictors of conversion to AD. Results support the importance of specific episodic memory changes and possession of the ApoE-epsilon4 allele in the preclinical detection of AD.     

Use of Functional Magnetic Resonance Imaging in the Early Identification of Alzheimer's Disease

A growing body of evidence suggests that a preclinical phase of Alzheimer's disease (AD) exists several years or more prior to the overt manifestation of clinical symptoms and is characterized by subtle neuropsychological and brain changes. Identification of individuals prior to the development of significant clinical symptoms is imperative in order to have the greatest treatment impact by maintaining cognitive abilities and preserving quality of life. Functional magnetic resonance imaging (fMRI) offers considerable promise as a non-invasive tool for detecting early functional brain changes in asymptomatic adults. In fact, evidence to date indicates that functional brain decline precedes structural decline in preclinical samples. Therefore, fMRI may offer the unique ability to capture the dynamic state of change in the degenerating brain. This review examines the clinical utility of blood oxygen level dependent (BOLD) fMRI in those at risk for AD as well as in early AD. We provide an overview of fMRI findings in at-risk groups by virtue of genetic susceptibility or mild cognitive decline followed by an appraisal of the methodological issues concerning the diagnostic usefulness of fMRI in early AD. We conclude with a discussion of future directions and propose that BOLD-fMRI in combination with cerebral blood flow or diffusion techniques will provide a more complete accounting of the neurovascular changes that occur in preclinical AD and thus improve our ability to reliably detect early brain changes prior to disease onset.     

Predictors of cognitive change from preclinical to clinical Alzheimer's disease

We examined individual-difference variables in relation to the rate of change in global cognitive performance, measured by the MMSE, from 3 years prior to diagnosis of Alzheimer's disease (AD) to the time of diagnosis. The population-based sample consisted of 230 incident AD persons who were followed over a 3-year interval. The average annual decline in MMSE was 1.81 points. Being older and acquiring additional diseases during the 3 years preceding diagnosis predicted a faster rate of decline in global cognitive functioning. However, other individual difference variables such as sex, education, depression, vitamin levels (vitamin B12 and folic acid), apolipoprotein status, and social network did not precipitate the rate of decline in the preclinical phase of AD.     

Detectable Neuropsychological Differences in Early Preclinical Alzheimer’s Disease: A Meta-Analysis

The development of methods for in vivo detection of cerebral beta amyloid retention and tau accumulation have been increasingly useful in characterizing preclinical Alzheimer’s disease (AD). While the association between these biomarkers and eventual AD has been demonstrated among cognitively intact older adults, the link between biomarkers and neurocognitive ability remains unclear. We conducted a meta-analysis to test the hypothesis that cognitively intact older adults would show statistically discernable differences in neuropsychological performance by amyloid status (amyloid negative = A-, amyloid positive = A+). We secondarily hypothesized a third group characterized by either CSF tau pathology or neurodegeneration, in addition to amyloidosis (A+/N+ or Stage 2), would show lower neuropsychology scores than the amyloid positive group (A+/N- or Stage 1) when compared to the amyloid negative group. Pubmed, PsychINFO, and other sources were searched for relevant articles, yielding 775 total sources. After review for inclusion/exclusion criteria, duplicates, and risk of bias, 61 studies were utilized in the final meta-analysis. Results showed A+ was associated with poorer performance in the domains of global cognitive function, memory, language, visuospatial ability, processing speed, and attention/working memory/executive functions when compared to A-. A+/N+ showed lower performances on memory measures when compared to A+/N- in secondary analyses based on a smaller subset of studies. Results support the notion that neuropsychological measures are sensitive to different stages of preclinical AD among cognitively intact older adults. Further research is needed to determine what constitutes meaningful differences in neuropsychological performance among cognitively intact older adults.     

The relation between APOE status and neuropsychological memory test performance: an analysis of the Canadian Study of Health and Aging

This study examined the relationship between two risk factors for dementia, the apolipoprotein (APOE) epsilon4 allele and poor memory test performance. Participants were from the Canadian Study of Health and Aging, a 4-year longitudinal population-based study. Persons with no cognitive impairment who had an epsilon4 allele but whose memory was average or better were not at increased risk of developing dementia after five years. Risk was increased for those with below average memory and no epsilon4 allele, but was particularly increased for those with below average memory and an epsilon4 allele. While the APOE epsilon4 allele was associated with slightly lower memory test performance for persons without cognitive impairment at baseline, it only increased their risk of developing dementia if their memory was below average.     

Heterogeneity in verbal memory: a marker of preclinical Alzheimer's disease?

Demonstrations of memory changes in those at risk for Alzheimer's disease by the presence of the APOE e4 allele have been inconsistent to date. The present study went beyond traditional analyses of central tendency (i.e., group differences on mean test scores) and also conducted distribution analyses to search for subtle cognitive differences in subgroups of normal-functioning elderly persons with the APOE e4 genotype. The results of the study revealed that (a) the e4 and non-e4 groups failed to differ in terms of their mean scores on tests of memory and verbal skills; and (b) relative to the non-e4 group, the e4 subjects had significantly greater heterogeneity of variance on the memory measures but not on fundamental verbal skills. Logistic regression analyses indicated that the discrepancy in scores on the memory measures was a significant predictor of genotype group membership (82% correct classification rate). Implications of these findings for the detection of a preclinical phase of AD are discussed.     

Tower of London test: a comparison between conventional statistic approach and modelling based on artificial neural network in differentiating fronto-temporal dementia from Alzheimer's disease

The early differentiation of Alzheimer's disease (AD) from frontotemporal dementia (FTD) may be difficult. The Tower of London (ToL), thought to assess executive functions such as planning and visuo-spatial working memory, could help in this purpose. Twentytwo Dementia Centers consecutively recruited patients with early FTD or AD. ToL performances of these groups were analyzed using both the conventional statistical approaches and the Artificial Neural Networks (ANNs) modelling. Ninety-four non aphasic FTD and 160 AD patients were recruited. ToL Accuracy Score (AS) significantly (p < 0.05) differentiated FTD from AD patients. However, the discriminant validity of AS checked by ROC curve analysis, yielded no significant results in terms of sensitivity and specificity (AUC 0.63). The performances of the 12 Success Subscores (SS) together with age, gender and schooling years were entered into advanced ANNs developed by Semeion Institute. The best ANNs were selected and submitted to ROC curves. The non-linear model was able to discriminate FTD from AD with an average AUC for 7 independent trials of 0.82. The use of hidden information contained in the different items of ToL and the non linear processing of the data through ANNs allows a high discrimination between FTD and AD in individual patients.     

Atrophy of the parietal lobe in preclinical dementia

Cortical grey matter atrophy patterns have been reported in healthy ageing and Alzheimer disease (AD), but less consistently in the parietal regions of the brain. We investigated cortical grey matter volume patterns in parietal areas. The grey matter of the somatosensory cortex, superior and inferior parietal lobule was measured in 75 older adults (38 cognitively stable and 37 individuals with cognitive decline after 3 years). Dementia screening 6 years after scanning resulted in nine AD cases from the cognitively stable (n=3) and cognitive decline group (n=6), who were assigned to a third group, the preclinical AD group. When regional differences in cortical volume in the parietal lobe areas were compared between groups, significant differences were found between either the cognitive decline or stable group on the one hand and preclinical AD individuals on the other hand in the inferior parietal lobule. Group membership was best predicted by the grey matter volume of the inferior parietal lobule, compared to the other parietal lobe areas. The parietal lobe was characterised by a differential atrophy pattern based on cognitive status, which is in agreement with the 'last-developed-first-atrophied' principle. Future studies should investigate the surplus value of the inferior parietal lobe as a potential marker for the diagnosis of AD compared to other brain regions, such as the medial temporal lobe and the prefrontal lobe.     

Short- and long-term implicit memory in aging and Alzheimer's disease

Implicit memory processes were investigated via picture naming in healthy young and older adults and in persons with mild Alzheimer's disease (AD). Repetition priming in picture-naming was intact in all groups over the course of a short retention interval (seconds), and only the AD group revealed a deficit over a longer interval (72 hours). In addition, the AD group showed impaired procedural memory, with no benefit of practice on picture-naming. Impaired long-term priming was related to severity of AD. Both theoretical and methodological implications are discussed.     

Can cognitive and behavioural disorders differentiate frontal variant-frontotemporal dementia from Alzheimer's disease at early stages?

Frontal variant-Frontotemporal dementia (fvFTD) and Alzheimer's disease (AD) patients matched for severity of dementia at the Clinical Dementia Rating (CDR) received neuropsychological testing in order to explore if the dysexecutive disorder might characterise fvFTD at early stage, when AD is dominated by the episodic memory defect. We also determined if the behavioural syndrome was more severe in fvFTD than AD, and if specific patterns of behavioural symptoms could differentiate the two types of dementia, using the Neuropsychiatry Inventory (NPI). AD patients performed worse than fvFTD not only in memory but also in executive tasks. Apathy and eating disorders proved to be more severe or frequent in fvFTD even if the two groups did not differ in the total NPI score. CDR score significantly correlated with the NPI score in fvFTD and with the MMSE in AD. Our data confirm that the memory disorders may differentiate the two types of dementia; however, the dysexecutive syndrome is as severe, and even more severe in AD. The severity of the behavioural syndrome is comparable in the two groups but the nature of the behavioural disorders may vary to some extent. We conclude that AD dementia at early stage is a behavioural-cognitive syndrome, while in fvFTD the behavioural disorders appear when the cognitive deficit is still relatively mild.     

Diagnostic Accuracy of Memory Measures in Alzheimer’s Dementia and Mild Cognitive Impairment: a Systematic Review and Meta-Analysis

With an increasing focus on biomarkers in dementia research, illustrating the role of neuropsychological assessment in detecting mild cognitive impairment (MCI) and Alzheimer’s dementia (AD) is important. This systematic review and meta-analysis, conducted in accordance with PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses) standards, summarizes the sensitivity and specificity of memory measures in individuals with MCI and AD. Both meta-analytic and qualitative examination of AD versus healthy control (HC) studies (n = 47) revealed generally high sensitivity and specificity (≥ 80% for AD comparisons) for measures of immediate (sensitivity = 87%, specificity = 88%) and delayed memory (sensitivity = 89%, specificity = 89%), especially those involving word-list recall. Examination of MCI versus HC studies (n = 38) revealed generally lower diagnostic accuracy for both immediate (sensitivity = 72%, specificity = 81%) and delayed memory (sensitivity = 75%, specificity = 81%). Measures that differentiated AD from other conditions (n = 10 studies) yielded mixed results, with generally high sensitivity in the context of low or variable specificity. Results confirm that memory measures have high diagnostic accuracy for identification of AD, are promising but require further refinement for identification of MCI, and provide support for ongoing investigation of neuropsychological assessment as a cognitive biomarker of preclinical AD. Emphasizing diagnostic test accuracy statistics over null hypothesis testing in future studies will promote the ongoing use of neuropsychological tests as Alzheimer’s disease research and clinical criteria increasingly rely upon cerebrospinal fluid (CSF) and neuroimaging biomarkers.     

Short- and Long-Term Implicit Memory in Aging and Alzheimer's Disease

ABSTRACT

Implicit memory processes were investigated via picture naming in healthy young and older adults and in persons with mild Alzheimer's disease (AD). Repetition priming in picture-naming was intact in all groups over the course of a short retention interval (seconds), and only the AD group revealed a deficit over a longer interval (72 hours). In addition, the AD group showed impaired procedural memory, with no benefit of practice on picture-naming. Impaired long-term priming was related to severity of AD. Both theoretical and methodological implications are discussed.     

Heterogeneity in Verbal Memory: A Marker of Preclinical Alzheimer's Disease?

ABSTRACT

Demonstrations of memory changes in those at risk for Alzheimer's disease by the presence of the APOE e4 allele have been inconsistent to date. The present study went beyond traditional analyses of central tendency (i.e., group differences on mean test scores) and also conducted distribution analyses to search for subtle cognitive differences in subgroups of normal-functioning elderly persons with the APOE e4 genotype. The results of the study revealed that (a) the e4 and non-e4 groups failed to differ in terms of their mean scores on tests of memory and verbal skills; and (b) relative to the non-e4 group, the e4 subjects had significantly greater heterogeneity of variance on the memory measures but not on fundamental verbal skills. Logistic regression analyses indicated that the discrepancy in scores on the memory measures was a significant predictor of genotype group membership (82% correct classification rate). Implications of these findings for the detection of a preclinical phase of AD are discussed.     

Linguistic and nonlinguistic impairments in writing: a comparison of patients with focal and multifocal CNS disorders

The hypothesis that the language disorder in Alzheimer's disease (AD) depends on degenerative brain changes in classical left-hemisphere language zones was tested by comparing the written language performances of a group of AD patients with mild-moderate dementia and left-hemisphere stroke patients with equally severe naming and auditory comprehension deficits who were in varying stages of recovery from Wernicke's aphasia. The results indicated significant qualitative group differences in performances between tasks and in errors within tasks. The findings are consistent with hypothesized disruption of more diffusely organized neurolinguistic systems in AD. The hypothesis that the language disorder in AD represents an exaggeration of the pattern of language change in normal aging was also examined by comparing the performances of AD patients to the changes that occur with very advanced normal aging. The data indicate convergence between AD and very elderly healthy subjects in some aspects of written language production.     

The Effects of Estrogen Replacement Therapy on Neuropsychological Functioning in Postmenopausal Women With and Without Dementia: A Critical and Theoretical Review

We review 42 studies examining the effects of estrogen replacement therapy (ERT) on memory and cognition in nondemented postmenopausal women. Although there are an appreciable number of nonsignificant findings, the number of significant findings favoring ERT users considerably outnumbers the rare findings of better performance in controls. Experimental studies demonstrate a consistent beneficial effect on verbal memory, but these are short-term studies of the more acute effects of ERT. The observational studies suggest that there may be a long-lasting effect of continued ERT on cognitive functioning, but these studies need to be interpreted with caution because of the lack of random assignment and a possible healthy user bias. We also summarize findings from studies on the effects of ERT on Alzheimer's disease (AD). ERT is associated with a decreased risk for dementia, but there is little evidence for a positive effect on cognition in women with AD. Definitive answers to questions about the long-term effects of ERT on cognitive aging and risk of developing AD should be provided by 3 ongoing clinical trials.     

Influences of preclinical dementia and impending death on the magnitude of age-related cognitive deficits

The authors examined the influence of preclinical dementia and impending death on the cross-sectional relationship between age and performance in tasks assessing episodic memory, visuospatial skill, and verbal fluency. Increasing age was associated with a general decrease in cognitive performance. In addition, those who were to be diagnosed with dementia or had died by a 3-year follow-up, were older, and performed at a lower level than the remaining sample across all cognitive tasks at baseline. Nevertheless, removal of the preclinical dementia and impending death groups from the original sample affected the cross-sectional age-cognition relations relatively little. This pattern of findings suggests that the biological aging process exerts negative influences on cognitive functioning beyond those resulting from disease and mortality.     

Apolipoprotein epsilon4 is associated with more rapid decline in odor identification than in odor threshold or Dementia Rating Scale scores

Individuals with the apolipoprotein E epsilon4 genetic risk factor for Alzheimer's disease (AD) show deficits in olfactory function. The purpose of the present study was to examine longitudinally odor identification (odor ID), odor threshold, picture identification, and global cognitive status in allele positive (epsilon4+) and negative (epsilon4-) persons. Participants were initially given the San Diego Odor Identification test, an odor threshold test, and the Dementia Rating Scale (DRS). Participants were re-tested approximately four years later. The results indicate: (1) odor ID declined more rapidly in epsilon4+ than in epsilon4- normal elderly adults; (2) neither group exhibited a significant decline in odor threshold, picture identification or DRS scores. These results suggest that declines in odor identification occur before declines in other measures of dementia in persons at risk for AD because of their APOE allele genetic status.     

Cognitive Functioning in Aging and Dementia: The Kungsholmen Project

The Kungsholmen Project (KP) is a community-based longitudinal study of aging and dementia targeting the 75+ population. In this article, we review empirical studies with a cognitive focus from the KP. The main findings indicate that (a) there is an age-related decline for some cognitive domains (e.g., episodic memory, verbal fluency, visuoconstructive skill, psychomotor speed), but not for others (e.g., primary memory, visuoperceptive skill, motor-hand coordination), (b) multiple individual-difference variables within demographic (e.g., sex, education) life-style (e.g., activity levels), genetic (e.g., apolipoprotein E genotype), and health-related (e.g., vitamin B deficiency, depression, diabetes) domains are related to late-life cognitive functioning, (c) a potential for improving cognitive performance – a reserve capacity – is present also among very old adults, (d) the 2 most common dementia diseases, Alzheimer’s disease (AD) and vascular dementia (VaD), affect cognition in a strikingly similar manner, (e) the role of individual-difference variables in cognitive functioning is markedly reduced in dementia – the pathogenesis itself may overshadow the influence of other variables, and (f) there is a long preclinical period in dementia during which cognitive deficits are detectable. As is true with the other projects represented in this issue, the KP portrays a rather diversified picture of cognitive aging, although systematic patterns are evident with regard to the variability of late-life cognitive functioning.