Aging and Dementia Division
Alzheimer's disease and mild cognitive impairment
Rates of mild cognitive impairment (MCI) vary widely. Using the cohort in Washington Heights, we developed diagnostic criteria for MCI to examine its frequency in our ethnically and linguistically diverse elders of northern Manhattan. The frequency of amnestic MCI, the form thought to represent early Alzheimer's disease, was 5.0 percent. MCI was frequent among older individuals and those with nine years of schooling or less. As in Alzheimer's disease, the APOE-e4 allele was also more frequent among those with amnestic MCI. In a related clinical study from the Memory Disorders Center, we found that APOE-e4 was one of the most consistent predictors of conversion to Alzheimer's disease in older outpatients.
We also studied several risk factors for cognitive decline among nondemented elderly. For example, we found that smoking among elderly below the age of 75 years was related to poor performance on cognitive tests and to a decline in memory over time. However, contrary to other studies, we observed that elevated plasma triglycerides or low-density lipoprotein were not associated with decline in cognitive performance over time and that the use of lipid-lowering agents, such as Lipitor, did not improve cognitive performance.
Our studies of risk factors related to Alzheimer's disease focused primarily on cardio-vascular and cerebrovascular risk factors. Diabetes and current smoking were the strongest risk factors, but clusters including hypertension and heart disease also increased the risk of this disease. We also led a large multicenter study examining the association between cerebrovascular disease and the pathologic manifestations of Alzheimer's disease using data from the United States National Alzheimer's Coordinating Center database. We studied data from 1,054 individuals and found that neuritic plaques and neurofibrillary tangles were associated with amyloid angiopathy. The most surprising finding was that the presence of large-vessel cerebrovascular disease, or atherosclerosis, was strongly associated with an increased frequency of neuritic plaques, which are a hallmark of the illness.
Genetics of Alzheimer's Disease in the Dominican Republic and Puerto Rico
Over the last two decades, variant alleles in four genes have been firmly implicated in the cause of this disease. These genes appear to be involved in the production, processing, or clearance of amyloid, a beta pleated sheet polypeptide. These genes: amyloid precuror protein (APP), presenilin 1 (PS1) and presenilin 2 (PS2), are found in families with an autosomal dominant pattern of disease inheritance beginning as early as the third decade of life, but have also been observed in families without a distinct Mendelian pattern of inheritance. Studies of mutant genes from early-onset families indicate that many lead to enhanced generation or aggregation of amyloid ß peptide that is subsequently deposited in brain in the form of neuritic plaques, implicating this peptide as a critical factor in the cause of this disease.
APOE has been called a "susceptibility" gene because possession of the ε4 allele does not always lead to Alzheimer's disease. One APOE-ε4 allele is associated with a two- to three-fold increased risk, while having two copies is associated with a five-fold increase and each APOE-ε4 allele lowers the age-at-onset in a dose dependent fashion. Approximately 20% of all late-onset or more typical Alzheimer's disease can be attributed to this variant form of APOE.
Continued studies of families with Alzheimer's disease, here and elsewhere, have shown at least four additional loci with possible association to the disease on chromosomes 9q, 10q, 12p, 20q, and 18q. However, though several putative loci have been linked to familial Alzheimer's disease, no specific variation in a gene has yet been reported, but the linkages has been confirmed.
The elderly Hispanic population is expected to increase 11-fold by 2050, especially in the northeast, where a majority of the Hispanic population is from the Caribbean Islands. Thus, the Hispanic elderly will face many of the diseases associated with advanced age, such as Alzheimer's disease, but there are few investigations of age-related diseases in this population.
Within the Taub Institute and Sergievsky Center at Columbia University Irving Medical Center, our efforts focus on the Caribbean Hispanic population in the Dominican Republic, Puerto Rico, and New York City for several scientific and practical reasons: 1) the effect of APOE-ε4 on disease risk is less than that observed in whites of European descent; 2) the cumulative risk of disease is 3 times higher for Hispanics than Caucasians suggesting additional genetic or environmental factors; 3) Caribbean Hispanics generally had larger surviving families than either whites or African-American elderly; 4) family members of Caribbean Hispanic patients tend to be either in our community or in the Dominican Republic; 5) and several of our medical and research staff are from the Dominican Republic which has facilitated work in that country.
We have already identified, examined, and collected blood samples from more than 6,050 individuals from 864 families of Caribbean Hispanic origin with familial Alzheimer's disease, as well as 2,900 unrelated controls and 1,790 unrelated cases. We have completed numerous genome-wide scans consisting of microsatellite markers and have conducted fine mapping of major regions in the genome that we believe harbor variant genes that increase the susceptibility to Alzheimer's disease. The ultimate goal of this project is to realize a more complete molecular picture of Alzheimer's disease by identifying proteins or enzymes that are altered by variant genes. In doing so, we will uncover new targets for the development of therapeutic agents that we hope will some day cure or prevent this disease.
*This study has been supported by NIH and was recently designated as a MERIT Award (R37 AG15473).