many human diseases, environmental effects and genetic modifiers result in incomplete penetrance. for example, certain nigerian populations do not show the relationship between dose of apoeε4 and incidence or age-of-onset for alzheimer's disease seen in other human populations. alleles in the trem2 gene have been associated with a 3 to 5 times higher risk of developing alzheimer's disease. a japanese pedigree of familial alzheimer's disease was found to be associated with a deletion mutation of codon 693 of app. this mutation and its association with alzheimer's disease was first reported in 2008, and is known as the osaka mutation. only homozygotes with this mutation have an increased risk of developing alzheimer's disease. this mutation accelerates aβ oligomerization but the proteins do not form the amyloid fibrils that aggregate into amyloid plaques, suggesting that it is the aβ oligomerization rather than the fibrils that may be the cause of this disease. mice expressing this mutation have all the usual pathologies of alzheimer's disease. other hypotheses in alzheimer's disease, changes in tau protein lead to the disintegration of microtubules in brain cells. the tau hypothesis proposes that tau protein abnormalities initiate the disease cascade. in this model, hyperphosphorylated tau begins to pair with other threads of tau as paired helical filaments. eventually, they form neurofibrillary tangles inside nerve cell bodies. when this occurs, the microtubules disintegrate, destroying the structure of the cell's cytoskeleton which collapses the neuron's transport system. a number of studies connect the misfolded amyloid beta and tau proteins associated with the pathology of alzheimer's disease, as bringing about oxidative stress that leads to chronic inflammation. sustained inflammation (neuroinflammation) is also a feature of other neurodegenerative diseases including parkinson's disease, and als. spirochete infections have also been linked to dementia. dna damages accumulate in ad brains; reactive oxygen species may be the major source of this dna damage. sleep disturbances are seen as a possible risk factor for inflammation in alzheimer's disease. sleep problems have been seen as a consequence of alzheimer's disease but studies suggest that they may instead be a causal factor. sleep disturbances are thought to be linked to persistent inflammation. the cellular homeostasis of biometals such as ionic copper, iron, and zinc is disrupted in alzheimer's disease, though it remains unclear whether this is produced by or causes the changes in proteins. smoking is a significant alzheimer's disease risk factor. systemic markers of the innate immune system are risk factors for late-onset alzheimer's disease. exposure to air pollution may be a contributing factor to the development of alzheimer's disease. according to one theory, dysfunction of oligodendrocytes and their associated myelin during aging contributes to axon damage, which in turn generates in amyloid production and tau hyper-phosphorylation. retrogenesis is a medical hypothesis that just as the fetus goes through a process of neurodevelopment beginning with neurulation and ending with myelination, the brains of people with alzheimer's disease go through a reverse neurodegeneration process starting with demyelination and death of axons (white matter) and ending with the death of grey matter. likewise the hypothesis is, that as infants go through states of cognitive development, people with alzheimer's disease go through the reverse process of progressive cognitive impairment. the association with celiac disease is unclear, with a 2019 study finding no increase in dementia overall in those with cd, while a 2018 review found an association with several types of dementia including alzheimer's disease. pathophysiology histopathologic images of alzheimer's disease, in the ca3 area of the hippocampus, showing an amyloid plaque (top right), neurofibrillary tangles (bottom left), and granulovacuolar degeneration bodies (bottom center) neuropathology alzheimer's disease is characterised by loss of neurons and synapses in the cerebral cortex and certain subcortical regions. this loss results in gross atrophy of the affected regions, including degeneration in the temporal lobe and parietal lobe, and parts of the frontal cortex and cingulate gyrus. degeneration is also present in brainstem nuclei particularly the locus coeruleus in the pons. studies using mri and pet have documented reductions in the size of specific brain regions in people with alzheimer's disease as they progressed from mild cognitive impairment to alzheimer's disease, and in comparison with similar images from healthy older adults. both aβ plaques and neurofibrillary tangles are clearly visible by microscopy in brains of those with alzheimer's disease, especially in the hippocampus. however, alzheimer's disease may occur without neurofibrillary tangles in the neocortex. plaques are dense, mostly insoluble deposits of beta-amyloid peptide and cellular material outside and around neurons. tangles (neurofibrillary tangles) are aggregates of the microtubule-associated protein tau which has become hyperphosphorylated and accumulate inside the cells themselves. although many older individuals develop some plaques and tangles as a consequence of aging, the brains of people with alzheimer's disease have a greater number of them in specific brain regions such as the temporal lobe. lewy bodies are not rare in the brains of people with alzheimer's disease. biochemistry main article: biochemistry of alzheimer's disease enzymes act on the app (amyloid-beta precursor protein) and cut it into fragments. the beta-amyloid fragment is crucial in the formation of amyloid plaques in alzheimer's disease. alzheimer's disease has been identified as a protein misfolding disease, a proteopathy, caused by the accumulation of abnormally folded amyloid beta protein into amyloid plaques, and tau protein into neurofibrillary tangles in the brain. plaques are made up of small peptides, 39–43 amino acids in length, called amyloid beta (aβ). amyloid beta is a fragment from the larger amyloid-beta precursor protein (app) a transmembrane protein that penetrates the neuron's membrane. app is critical to neuron growth, survival, and post-injury repair. in alzheimer's disease, gamma secretase and beta secretase act together in a proteolytic process which causes app to be divided into smaller fragments. one of these fragments gives rise to fibrils of amyloid beta, which then form clumps that deposit outside neurons in dense formations known as amyloid plaques. alzheimer's disease is also considered a tauopathy due to abnormal aggregation of the tau protein. every neuron has a cytoskeleton, an internal support structure partly made up of structures called microtubules. these microtubules act like tracks, guiding nutrients and molecules from the body of the cell to the ends of the axon and back. a protein called tau stabilises the microtubules when phosphorylated, and is therefore called a microtubule-associated protein. in alzheimer's disease, tau undergoes chemical changes, becoming hyperphosphorylated; it then begins to pair with other threads, creating neurofibrillary tangles and disintegrating the neuron's transport system. pathogenic tau can also cause neuronal death through transposable element dysregulation. disease mechanism exactly how disturbances of production and aggregation of the beta-amyloid peptide give rise to the pathology of alzheimer's disease is not known. the amyloid hypothesis traditionally points to the accumulation of beta-amyloid peptides as the central event triggering neuron degeneration. accumulation of aggregated amyloid fibrils, which are believed to be the toxic form of the protein responsible for disrupting the cell's calcium ion homeostasis, induces programmed cell death (apoptosis). it is also known that aβ selectively builds up in the mitochondria in the cells of alzheimer's-affected brains, and it also inhibits certain enzyme functions and the utilisation of glucose by neurons. various inflammatory processes and cytokines may also have a role in the pathology of alzheimer's disease. inflammation is a general marker of tissue damage in any disease, and may be either secondary to tissue damage in alzheimer's disease or a marker of an immunological response. there is increasing evidence of a strong interaction between the neurons and the immunological mechanisms in the brain. obesity and systemic inflammation may interfere with immunological processes which promote disease progression. alterations in the distribution of different neurotrophic factors and in the expression of their receptors such as the brain-derived neurotrophic factor (bdnf) have been described in alzheimer's disease. diagnosis