Lindy E. Harrell

ApoE-4 and Age at Onset of Alzheimer's Disease The NIMH Genetics Initiative

Objective: To explore the impact of apoE-4 on Alzheimers disease (AD) and its age at onset. Design: A genetic linkage study using affected relative pairs, predominantly siblings. Setting: Three academic medical centers ascertained subjects from memory disorder clinics, nursing homes, and the local community. Subjects: 310 families including 679 subjects with AD by NINCDS/ADRDA and/or Khachaturian criteria and 231 unaffected subjects. Outcome measure: ApoE genotype. Analytic methods: Association, affected pedigree member, sibling pair, and lod score analyses. Results: ApoE-4 was strongly associated with AD in this sample (allele frequency = 0.46 vs. 0.14 in controls, p < 0.000001). Results of lod score, affected pedigree member analysis, and sib-pair analysis also supported apoE-4 as a risk factor for AD. When the sample was stratified on family mean age at onset, the risk conferred by apoE-4 was most marked in the 61 to 65 age group. Individuals with two copies of apoE-4 had a significantly lower age at onset than those with one or no copies (66.4 vs. 72.0, p < 0.001), but individuals with one copy did not differ from those with none. Within families, the individual with the earliest age at onset had, on average, significantly more apoE-4 alleles (p < 0.0001) than the individual with the latest onset. Discussion: This work supports previous reports of an association between apoE-4 and the development of AD and demonstrates that apoE-4 exerts its maximal effect before age 70. These findings have important implications for the potential use of apoE genotyping for diagnosis and prediction of disease. They also underscore the need to identify additional genetic factors involved in AD with onset beyond age 70 years. NEUROLOGY 1997;48: 139-147

Psychological, social, and health impact of caregiving: A comparison of Black and White dementia family caregivers and noncaregivers.

Psychological, social, and health variables were compared in 175 Black and White family caregivers of patients with dementia and 175 Black and White noncaregivers. Caregivers and noncaregivers did not differ within race on demographic variables. Caregiving was associated with increased depression and decreased life satisfaction only in White families. However, caregiving appears to have similar social consequences for Black and White families, including restriction of social activity and increased visits and support by family from outside of the home. Race, but not caregiving, was associated with physical health variables. Methodological issues in comparing well-being in Black and White caregivers, in particular the importance of including noncaregiving comparison subjects are discussed.

Impaired financial abilities in mild cognitive impairment A direct assessment approach

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Consistency of Physician Judgments of Capacity to Consent in Mild Alzheimer's Disease

OBJECTIVE: To investigate the agreement of physician judgments of capacity to consent to treatment for normal and demented older adults.

Competency to consent to medical treatment in cognitively impaired patients with Parkinson’s disease

Objectives: To investigate capacity to consent to medical treatment (competency) in cognitively impaired patients with PD. Background: Although competency has been studied empirically in patients with cortical dementia (AD), no empirical studies have examined competency in patients with PD or other subcortical neurodegenerative disorders. Methods: Patients with PD with cognitive impairment (n = 20) and older controls (n = 20) were compared using a standardized competency measure (Capacity to Consent to Treatment Instrument [CCTI]) and neuropsychological test measures. The CCTI tests competency performance and assigns outcomes (capable, marginally capable, incapable) under four different legal standards (LS). Results: Patients with PD performed below controls on the four LS: capacity to evidence a treatment choice (LS1) (p < 0.03), capacity to appreciate consequences of a treatment choice (LS3) (p < 0.03), capacity to provide rational reasons for a treatment choice (LS4) (p < 0.0001), and capacity to understand the treatment situation and choices (LS5) (p < 0.0001). With respect to competency outcomes, patients with PD demonstrated increasing compromise (marginally capable or incapable outcomes) across the four standards: LS1 (25%), LS3 (45%), LS4 (55%), and LS5 (80%). In the PD group, simple measures of executive function (the Executive Interview) and to a lesser extent memory/orientation (Dementia Rating Scale, Memory subscale) were key predictors of competency performance and outcome on the LS. Conclusions: Cognitively impaired patients with PD are likely to have impaired consent capacity, and are at risk of losing competency over the course of their neurodegenerative illness. Patients with PD have parti-cular difficulty meeting more stringent, clinically relevant competency standards that tap reasoning skills and comprehension of treatment information. Executive dysfunction appears to be a primary neurocognitive mechanism for competency loss in PD.

Association of a haplotype for tumor necrosis factor in siblings with late-onset Alzheimer disease: The NIMH Alzheimer disease genetics initiative

Tumor necrosis factor (TNF), a proinflammatory cytokine, may be involved in the pathogenesis of Alzheimer disease (AD) based on observations that senile plaques have been found to upregulate proinflammatory cytokines. Additionally, nonsteroidal anti-inflammatory drugs have been found to delay and prevent the onset of AD. A collaborative genome-wide scan for AD genes in 266 late-onset families implicated a 20 centimorgan region at chromosome 6p21.3 that includes the TNF gene. Three TNF polymorphisms, a -308 TNF promoter polymorphism, whose TNF2 allele is associated with autoimmune inflammatory diseases and strong transcriptional activity, the -238 TNF promoter polymorphism, and the microsatellite TNFa, whose 2 allele is associated with a high TNF secretion, were typed in 145 families consisting of 562 affected and unaffected siblings. These polymorphisms formed a haplotype, 2-1-2, respectively, that was significantly associated with AD (P = 0.005) using the sibling disequilibrium test. Singly, the TNFa2 allele was also significantly associated (P = 0.04) with AD in these 145 families. This TNF association with AD lends further support for an inflammatory process in the pathogenesis of AD. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:823-830, 2000.

Cholinergic activity and amyloid precursor protein metabolism.

With more than 4 million Alzheimers victims nationwide, there is intense research to elucidate the relationship among the hallmarks of the disease, amyloid plaques, neurofibrillary tangles, and degeneration of the basal forebrain cholinergic neurons. There has been much debate about which of these is the primary lesion, and which develops secondarily. The correlation between plaques and tangles and dementia is not absolute, but a consistent feature of Alzheimers disease is loss of cortical and hippocampal cholinergic function as a result of basal forebrain compromise. Additionally, factors associated with the cholinergic system have been shown to influence the processing and metabolism of the amyloid precursor, a protein that contains the amyloidogenic sequence found in plaques. In this paper, the relationship between cholinergic compromise and amyloid deposition, as well as the cholinergic system-associated factors which appear to participate in amyloid precursor protein processing, are discussed.

Medical decision-making capacity in patients with mild cognitive impairment

Objectives: To empirically assess the capacity of patients with amnestic mild cognitive impairment (MCI) to consent to medical treatment under different consent standards (Ss). Methods: Participants were 56 healthy controls, 60 patients with MCI, and 31 patients with mild Alzheimer disease (AD). Each participant was administered the Capacity to Consent to Treatment Instrument (CCTI) and a comprehensive neuropsychological battery. Group differences in performance on the CCTI and neuropsychological variables were examined. In addition, the capacity status (capable, marginally capable, or incapable) of each MCI participant on each CCTI standard was examined using cut scores derived from control performance. Results: Patients with MCI performed comparably to controls on minimal consent standards requiring merely expressing a treatment choice (S1) or making the reasonable treatment choice [S2], but significantly below controls on the three clinically relevant standards of appreciation (S3), reasoning (S4), and understanding (S5). In turn, the MCI group performed significantly better than the mild AD group on [S2], S4, and S5. Regarding capacity status, patients with MCI showed a progressive pattern of capacity compromise (marginally capable and incapable outcomes) related to stringency of consent standard. Conclusions: Patients with amnestic mild cognitive impairment (MCI) demonstrate significant impairments on clinically relevant abilities associated with capacity to consent to treatment. In obtaining informed consent, clinicians and researchers working with patients with MCI must consider the likelihood that many of these patients may have impairments in consent capacity related to their amnestic disorder and related cognitive impairments. GLOSSARY: AD = Alzheimer disease; ADRC = Alzheimers Disease Research Center; CCTI = Capacity to Consent to Treatment Instrument; CVLT-II = California Verbal Learning Test, second edition; DRS-2 = Dementia Rating Scale, 2nd edition; GDS = Geriatric Depression Scale; MCI = mild cognitive impairment; MDC = medical decision-making capacity; MMSE = Mini-Mental State Examination; Ss = consent standards; WAIS-III = Wechsler Adult Intelligence Scale, third edition; WMS-III = Wechsler Memory Scale, third edition; WMS-R = Wechsler Memory Scale, revised edition; WRAT-3 = Wide Range Achievement Test, third edition.

Consistency of physicians' legal standard and personal judgments of competency in patients with Alzheimer's disease

OBJECTIVES: To investigate the consistency of physician judgments of treatment consent capacity (competency) for patients with Alzheimers disease (AD) when specific legal standards (LS) for competency are used, and to identify the LS most clinically relevant to experienced physicians.

Declining financial capacity in mild cognitive impairment A 1-year longitudinal study

Objective: To investigate 1-year change in financial capacity in relation to conversion from amnestic mild cognitive impairment (MCI) to dementia. Methods: Seventy-six cognitively healthy older controls, 25 patients with amnestic MCI who converted to Alzheimer-type dementia during the study period (MCI converters), and 62 patients with MCI who did not convert to dementia (MCI nonconverters) were administered the Financial Capacity Instrument (FCI) at baseline and 1-year follow-up. Performance on the FCI domain and global scores was compared within and between groups using multivariate repeated-measures analyses. Results: At baseline, controls performed better than MCI converters and nonconverters on almost all FCI domains and on both FCI total scores. MCI converters performed below nonconverters on domains of financial concepts, cash transactions, bank statement management, and bill payment and on both FCI total scores. At 1-year follow-up, MCI converters showed significantly greater decline than controls and MCI nonconverters for the domain of checkbook management and for both FCI total scores. The domain of bank statement management showed a strong trend. For both the checkbook and bank statement domains, MCI converters showed declines in procedural skills, such as calculating the correct balance in a checkbook register, but not in conceptual understanding of a checkbook or a bank statement. Conclusions: Declining financial skills are detectable in patients with mild cognitive impairment (MCI) in the year before their conversion to Alzheimer disease. Clinicians should proactively monitor patients with MCI for declining financial skills and advise patients and families about appropriate interventions.