Fig. 23.24 ). APP also can be cleaved by α-secretase and γ-secretase, liberating a different peptide that is nonpathogenic. Mutations in APP or in components of γ-secretase (encoded by the presenilin-1 or presenilin-2 gene) lead to familial AD by increasing the rate at which Aβ, particularly its most aggregation-prone form, is generated. The APP gene is located on chromosome 21, and the risk for AD also is higher in those with an extra copy of the APP gene, such as patients with trisomy 21 (Down syndrome) and individuals with small interstitial duplications of APP, presumably because this too leads to greater Aβ generation. Once generated, Aβ is highly prone to aggregation; it first forms small oligomers, and these eventually propagate into large aggregates and fibrils. It is these aggregates that deposit in the brain and are visible as plaques. There is evidence that these oligomers decrease the number of synapses present and alter the function of those that remain so that the cellular processes felt to underlie learning and memory are disrupted.
Role of tau. Because neurofibrillary tangles contain the tau protein, there has been much interest in the role of this protein in AD. Tau is a microtubule-associated protein present in axons in association with the microtubular network. With the development of tangles in AD, tau shifts to a somatic-dendritic distribution, becomes hyperphosphorylated, and loses the ability to bind to microtubules. The formation of tangles is an important component of AD, but the mechanism of tangle injury to neurons remains poorly understood. Two pathways have been suggested; 1) aggregates of tau protein elicit a stress response, which persists and eventually leads to cell death; and 2), the microtubule stabilizing function of tau protein is lost, leading to neuronal toxicity and death. It has been shown that tau aggregates can be passed across synapses from one neuron to the next; this may underlie some of the spread of lesions across the brain.
Other genetic risk factors. The genetic locus on chromosome 19 that encodes apolipoprotein E (ApoE) has a strong influence on the risk for developing AD. Three alleles have been identified (ε2, ε3, and ε4) based on two amino acid polymorphisms. The dosage of the ε4 allele increases the risk for AD. This ApoE isoform promotes Aβ generation and deposition, although the mechanisms have not been established. Overall, this locus has been estimated to convey about one fourth of the risk for development of late-onset AD. Genome-wide association studies have identified multiple other loci that contribute to the risk for AD, but the roles of the encoded proteins in disease pathogenesis are not established.
Role of inflammation. Both genetic and histologic studies have indicated that the innate immune system responds to Aβ and tau. Deposits of Aβ elicit an inflammatory response from microglia and astrocytes. This response probably assists in the clearance of the aggregated peptide, but also may stimulate the secretion of mediators that cause neuronal injury over time.
Basis for cognitive impairment. Deposits of Aβ and tangles begin to appear in the brain well in advance of cognitive impairment. While there remains disagreement regarding the best correlate of dementia in individuals with AD, the presence of a large burden of plaques and tangles is strongly associated with severe cognitive dysfunction. The number of neurofibrillary tangles correlates better with the degree of dementia than does the number of neuritic plaques. Biochemical markers that have been correlated with the degree of dementia include amyloid burden.