Effect of Alzheimer's disease risk genes on trajectories of cognitive function in the Cardiovascular Health Study.

OBJECTIVE: The trajectory of cognitive decline in patients with late-onset Alzheimer's disease varies widely. Genetic variations in CLU, PICALM, and CR1 are associated with Alzheimer's disease, but it is unknown whether they exert their effects by altering cognitive trajectory in elderly individuals at risk for the disease. METHOD: The authors developed a Bayesian model to fit cognitive trajectories in a cohort of elderly subjects and test for genetic effects. They first validated the model's ability to detect the previously established effects of APOE ε4 alleles on age at cognitive decline and of psychosis on the rate of cognitive decline in 802 subjects from the Cardiovascular Health Cognition Study who did not have dementia at study entry and developed incident dementia during follow-up. The authors then evaluated the effects of CLU, PICALM, and CR1 on age and rate of decline in 1,831 subjects who did not have dementia at study entry and then did or did not develop incident dementia by study's end. RESULTS: The model generated robust fits to the observed cognitive trajectory data, and validation analysis supported the model's utility. CLU and CR1 were associated with more rapid cognitive decline. PICALM was associated with an earlier age at midpoint of cognitive decline. Associations remained after accounting for the effects of APOE and demographic factors. CONCLUSIONS: Evaluation of cognitive trajectories provides a powerful approach to dissecting genetic effects on the processes leading to cognitive deterioration and Alzheimer's disease.

Trajectory of cognitive decline as a predictor of psychosis in early Alzheimer disease in the cardiovascular health study.

OBJECTIVE: To compare the trajectories of cognitive decline between groups with, and without, the later development of psychotic symptoms during Alzheimer disease (AD) or mild cognitive impairment (MCI). DESIGN: : The authors examined cognitive function in a new analysis of an existing data set, the Cardiovascular Health Study, an epidemiologic, longitudinal follow-up study. Our analyses examined 9 years of follow-up data. SETTING: Community. PARTICIPANTS: The authors examined subjects who were without dementia at study entry, received a diagnosis of AD or MCI during follow-up, and had been rated on the Neuropsychiatric Inventory for the presence of psychosis; 362 participants for the modified Mini-Mental State Examination (3MS) analysis and 350 participants for the digit symbol substitution test (DSST) analysis had sufficient follow-up data and apolipoprotein-∊ (APOE) genotyping. MEASUREMENTS: The 3MS and DSST were administered annually and analyzed using mixed-effects models including APOE4 status. RESULTS: : Mean 3MS and DSST scores did not differ between AD with psychosis (AD + P) and without psychosis groups at baseline. The 3MS and DSST scores decreased more rapidly in subjects who ultimately developed psychosis. CONCLUSIONS: Individuals who ultimately develop psychosis have more rapid cognitive deterioration during the earliest phases of AD than individuals with AD not developing psychosis. The genetic and other neurobiologic factors leading to the expression of AD + P may exert their effects by acceleration of the neurodegenerative process.

No association of psychosis in Alzheimer disease with neurodegenerative pathway genes.

Psychotic symptoms occur in approximately 40% of subjects with Alzheimer disease (AD with psychosis; AD + P) and identify a subgroup with more rapid cognitive decline. We evaluated in 867 AD subjects the association of AD + P with genes which may modify the pathological process via effects on the accumulation of amyloid beta (Aß) protein and/or hyperphosphorylated microtubule-associated protein tau (MAPT): amyloid precursor protein (APP), beta-site amyloid precursor protein cleaving enzyme (BACE1), sortilin-related receptor (SORL1), and MAPT. Each gene was thoroughly interrogated with tag single-nucleotide polymorphisms (SNPs), and gene-based tests were used to enhance power. We found no association of these genes with AD + P.

The relationship of excess cognitive impairment in MCI and early Alzheimer's disease to the subsequent emergence of psychosis.

BACKGROUND: Psychotic symptoms in Alzheimer disease (AD + P) identify a heritable phenotype associated with greater cognitive impairment. Knowing when the cognitive course of AD + P subjects diverges from that of subjects without psychosis would enhance understanding of how genetic variation results in AD + P and its associated cognitive burden. This study seeks to determine whether the degree of cognitive impairment and cognitive decline in early AD predicts subsequent AD + P onset. METHODS: 361 subjects with possible or probable AD or mild cognitive impairment (MCI) without psychosis were evaluated every 6 months until psychosis onset. RESULTS: Severity of cognitive dysfunction was a strong predictor of AD + P up to two years prior to psychosis onset. Cognition did not decline more rapidly prior to onset of AD + P. CONCLUSIONS: Individuals who will develop AD + P already demonstrate excess cognitive impairment during the mild stages of disease. Genetic variation and brain pathophysiology may lead to a cognitive risk phenotype which is present prior to dementia onset.

Complementary and alternative medicine in the treatment of bipolar disorder--a review of the evidence.

A growing number of patients with mood disorders are using complementary and alternative medicine (CAM) interventions. In this paper, we review the published scientific evidence on the benefits and risks of CAM for the treatment of patients with bipolar disorder. Since very few studies of CAM have involved patients with bipolar disorder, most available evidence is derived from trials conducted in patients with major depressive disorder. The use of omega-3 fatty acids has been studied in two controlled studies in bipolar disorder while St. John's wort (Hypericum perforatum), S-adenosyl-l-methionine (SAMe), and acupuncture have been studied in a series of randomized controlled trials in patients with major depression. Overall, the best evidence supports the use of St. John's wort for the treatment of mild to moderate depression. SAMe may also be effective for depression. However, both of these products have the potential to induce mania; the extent of this risk needs to be quantified. St. John's wort can also interact with a variety of medications. Evidence regarding the benefits of omega-3 fatty acids or acupuncture is inconsistent. Data regarding other CAM interventions (e.g., aromatherapy massage, massage therapy, yoga) are almost entirely lacking. In conclusion, better studies are needed before CAM interventions can be recommended to patients with bipolar disorder. In the meantime, patients need to be informed about the possible risks associated with the use of these interventions.