The apolipoprotein-epsilon 4 allele increases the risk of Alzheimer's disease (AD), but cerebral deposition of beta-amyloid with age, a genetic mutation, or head injury may contribute to the pathogenesis of this disease. We examined the risks of AD associated with traumatic head injury and apolipoprotein-epsilon 4 in 236 community-dwelling elderly persons. A 10-fold increase in the risk of AD was associated with both apolipoprotein-epsilon 4 and a history of traumatic head injury, compared with a two-fold increase in risk with apolipoprotein-epsilon 4 alone. Head injury in the absence of an apolipoprotein-epsilon 4 allele did not increase risk. These data imply that the biological effects of head injury may increase the risk of AD, but only through a synergistic relationship with apolipoprotein-epsilon 4.

Objective-To evaluate a history of remote head injury as a risk factor for subsequent dementia due to Alzheimer's disease. Methods-271 participants of a community based longitudinal study of aging in north Manhattan without evidence of significant cognitive impairment were interrogated for a history ofhead injury on two occasions at entry into the study. The exminng physician sought a history of head injury with loss of conciousness. Independently, a risk factor interviewer inquired about a history of head injury with loss of consiousness or amnesia, the duration of any loss of consiousness, and the date of the head injury. Patients were followed up with standardised annual evaluations for up to five years to determine the first occurrence of dementia.

The presence of the apolipoprotein epsilon 4 (apo epsilon 4) allele significantly increases the risk of Alzheimer's disease. Whether this is due to biological effects of the apo epsilon 4 protein or reflects linkage disequilibrium with an as yet unidentified Alzheimer's disease susceptibility gene is of critical importance. In a community study in northern Manhattan we found a fivefold increase in the risk of Alzheimer's disease among African-Americans, Hispanics, and whites homozygous for apo epsilon 4. Overall, the risk between Alzheimer's disease and apo epsilon 4 heterozygosity was also increased by twofold, but the association was somewhat weaker for African-Americans than for Hispanics and whites. In contrast, the apo epsilon 2/epsilon 3 genotype was associated with an eightfold increased risk of Alzheimer's disease in African-Americans but it was associated with reduced risk in whites. Variability in the strength and type of association between Alzheimer's disease and the apo E polymorphisms in the three ethnic groups could not be fully explained by age differences. The allelic frequency of apo epsilon *4 was significantly higher in patients than control subjects in all ethnic groups at age 70 or younger, reflecting the higher proportion of apo epsilon 4 homozygotes, but this difference diminished with increasing age. The allelic frequency of apo epsilon *2 for African-Americans and Hispanics, but not whites, was significantly higher in patients than control subjects, but only after age 70.(ABSTRACT TRUNCATED AT 250 WORDS)

We evaluated the frequency of depression and psychosis in 46 patients with AD and 135 control subjects with the apolipoprotein (APO) E3/3 or E3/4 genotype. Patients with AD and the APOE3/4 genotype had a more than threefold increase in the signs of depression and psychosis when compared with either patients with the APOE3/3 genotype or to control subjects. Our preliminary study suggests that the phenotype of AD associated with the epsilon 4 allele is more likely to include psychiatric manifestations.

Extrapyramidal signs frequently accompany Alzheimer's disease (AD), but the pathological substrate remains unknown. Clinical and postmortem information from patients with AD, Parkinson's disease, or progressive supranuclear palsy and control subjects seen at a large tertiary medical center between 1989 and 1994 was examined. AD patients who had taken neuroleptics and AD brains that also contained Lewy bodies were excluded. The presence of extrapyramidal signs was determined using the Unified Parkinson's Disease Rating Scale. Sections of basal ganglia, subthalamic nucleus, and substantia nigra were examined for neurofibrillary tangles and neuropil threads and the nigra for neuronal numbers. Patients with AD (with or without extrapyramidal signs) did not show neuronal loss in the nigra compared to control subjects, while both Parkinson's disease and progressive supranuclear palsy brains showed marked depletion. The number of neurofibrillary tangles and neuropil threads was increased in AD (with or without extrapyramidal signs) nigra compared to control tissue, and also in progressive supranuclear palsy nigra, but not Parkinson's disease nigra. The numbers of nigral neurofibrillary tangles and neuropil threads were positively related to extrapyramidal signs in AD. There were no correlations between tangles and threads in the basal ganglia or subthalamic nucleus and extrapyramidal signs in AD. Thus, extrapyramidal signs in AD correlate best with tangle pathology in the nigra and do not require the concomitant presence of Lewy bodies.