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Current evidence from genetic and epidemiological studies supports the view that Alzheimer's disease (AD) is a heterogeneous disorder. While the disease is pathologically defined by the presence of specified lesions in form of amyloid plaques and neurofibrillary tangles within the parenchyma, other features of pathology are often either neglected or considered coincidental. Our studies suggest that cerebrovascular pathology is inherently part of the disorder, which could be an important factor in a cause or effect manner. We have recently identified subjects having died with severe amyloid beta (A beta) protein cerebral amyloid angiopathy (CAA) in the absence of a profound Alzheimer pathology. These subjects, diagnosed with dementia had a late onset disease and were found at autopsy to exhibit severe CAA but paucity of typical AD changes. Immunocytochemical studies showed numerous microvascular abnormalities as well as characteristic degeneration of the vascular smooth muscle in both surface and intracortical vessels. The pathology was also characterized by occasional intracerebral hemorrhages and multiple infarcts. Further assessment of the abnormalities and amyloid infiltrated cerebral vessels with antibodies to the carboxyl terminus of A beta indicated that the longer, more pathogenic form of A beta(1-42) was found to be highly associated with intracerebral hemorrhages. Our observations suggest that these mild AD cases with a predominantly vascular pathology are variants of AD and bear resemblance to the familial Dutch and Flemish versions of cerebral amyloidosis. We propose that AD is a group of diseases with a variable pathology analogous to the prion diseases, in which a vascular variant also exists.

There is little knowledge of the existence of Alzheimer disease (AD) or Alzheimer type of dementia in indigenous populations of developing countries. In an effort to evaluate this, we assessed the deposition of amyloid beta (A beta) protein and other lesions associated with AD in brains of elderly East Africans. Brain tissues were examined from 32 subjects, aged 45 to 83 years with no apparent neurological disease, who came to autopsy at two medical Institutions in Nairobi and Dar es Salaam. An age-matched sample from subjects who had died from similar causes in Cleveland was assessed in parallel. Of the 20 samples from Nairobi, 3 (15%) brains exhibited neocortical A beta deposits that varied from numerous diffuse to highly localized compact or neuritic plaques, many of which were also thioflavin S positive. Two of the cases had profound A beta deposition in the prefrontal and temporal cortices and one of these also exhibited moderate to severe cerebral amyloid angiopathy. Similarly, 2 of the 12 samples from Dar es Salaam exhibited diffuse and compact A beta deposits that were also predominantly reactive for the longer A beta 42 species compared to A beta 40. We also noted that A beta plaques were variably immunoreactive for amyloid associated proteins, apolipoprotein E, serum amyloid P and complement C3. Tau protein reactive neurofibrillary tangles (NFT) were also evident in the hippocampus of 4 subjects. By comparison, 4 (20%) of the 20 samples from randomly selected autopsies performed in Cleveland showed A beta deposits within diffuse and compact parenchymal plaques and the vasculature. These observations suggest A beta deposition and some NFT in brains of non-demented East Africans are qualitatively and quantitatively similar to that in age-matched elderly controls from Cleveland. While our small scale study does not document similar prevalence rates of preclinical AD, it suggests that elderly East Africans are unlikely to escape AD as it is known in developed countries.

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The presence of apolipoprotein E (ApoE)-E4 allele has been implicated as a risk factor for Alzheimer's disease (AD). We examined the occurrence of ApoE 4 alleles in AD associated with cerebral amyloid angiopathy and other vascular lesions. We found significantly high frequency of the ApoE 4 allele in AD with moderate to severe CAA. The frequency of the allele was also high in AD cases with other vascular lesions such as multiple infarcts and lacunes. As previously reported, we confirm a greater frequency of the ApoE 4 allele in the diffuse Lewy body variant of AD. Our results suggest ApoE 4 allele to be a significant factor in the development of CAA in AD. While this may be related to increased brain amyloid load as a consequence of ApoE genotype, the possibility exists that ApoE may be a specific factor in vascular abnormalities associated with AD.