An 86-year-old man has become progressively unable to live independently for the past 10 years, and he now requires assistance with bathing, dressing, toileting, feeding, and transfers in and out of chairs and bed. On physical examination, he has no motor or sensory deficits. He cannot give the current date or state where he is. Six months later, he suddenly becomes comatose and dies. At autopsy, there is a large superficial left parietal lobe hemorrhage. Histologic examination of the brain shows numerous neocortical neuritic plaques and neurofibrillary tangles. The peripheral cerebral arteries and the core of each plaque stain positively with Congo red. Which of the following mechanisms is most likely responsible for his disease?

Alzheimer's disease (AD) can be complicated by cerebral amyloid angiopathy and terminal hemorrhagic stroke. Formation and aggregation of the Ap peptide are now considered central to the pathogenesis of AD. Ap peptide is derived from the abnormal processing of amyloid precursor protein (APP). When APP, a transmembrane protein, is cleaved by a-secretase within the Ap sequence, followed by g-secretases, a soluble nontoxic fragment is formed. Cleavage of the Ap sequence by b-secretase and then g-secretase gives rise to Ap peptides that aggregate and form the amyloid cores that elicit a microglial and astrocytic response to form neuritic plaques. Conformational change in prion protein leads to Creutzfeldt-Jakob disease, rapidly progressive dementia with spongiform encephalopathy but not neuritic plaques or amyloid deposition. Loss of dopaminergic neurons with a deficiency of dopamine is central to the pathogenesis of Parkinson's disease. Expansion of polyglutamine repeats owing to CAG trinucleotide repeat-expansion underlies Huntington disease. Although abnormally phosphorylated forms of tau protein are found in neurofibrillary tangles seen in AD, there is no mutation of the tau gene, and the tangles are not considered primary in the pathogenesis of AD. Mutation of the tau gene can be found in frontotemporal lobe dementias.