Alzheimer Disease


A number sign (#) is used with this entry because of evidence that familial Alzheimer disease-1 (AD1) is caused by mutation in the gene encoding the amyloid precursor protein (APP; 104760) on chromosome 21q.

A homozygous mutation in the APP gene with a dominant-negative effect on amyloidogenesis was found in a patient with an early-onset progressive dementia and his affected younger sister (104760.0022).

A coding single-nucleotide polymorphism (SNP) in the APP gene (104760.0023) has been shown to have a protective effect against Alzheimer disease.

See also APP-related cerebral amyloid angiopathy (CAA; 605714), which shows overlapping clinical and neuropathologic features.


Alzheimer disease is the most common form of progressive dementia in the elderly. It is a neurodegenerative disorder characterized by the neuropathologic findings of intracellular neurofibrillary tangles (NFT) and extracellular amyloid plaques that accumulate in vulnerable brain regions (Sennvik et al., 2000). Terry and Davies (1980) pointed out that the 'presenile' form, with onset before age 65, is identical to the most common form of late-onset or 'senile' dementia, and suggested the term 'senile dementia of the Alzheimer type' (SDAT).

Haines (1991) reviewed the genetics of AD. Selkoe (1996) reviewed the pathophysiology, chromosomal loci, and pathogenetic mechanisms of Alzheimer disease. Theuns and Van Broeckhoven (2000) reviewed the transcriptional regulation of the genes involved in Alzheimer disease.

Genetic Heterogeneity of Alzheimer Disease

Alzheimer disease is a genetically heterogeneous disorder. See also AD2 (104310), associated with the APOE*4 allele (107741) on chromosome 19; AD3 (607822), caused by mutation in the presenilin-1 gene (PSEN1; 104311) on 14q; and AD4 (606889), caused by mutation in the PSEN2 gene (600759) on 1q31.

There is evidence for additional AD loci on other chromosomes; see AD5 (602096) on 12p11, AD6 (605526) on 10q24, AD7 (606187) on 10p13, AD8 (607116) on 20p, AD9 (608907), associated with variation in the ABCA7 gene (605414) on 19p13, AD10 (609636) on 7q36, AD11 (609790) on 9q22, AD12 (611073) on 8p12-q22, AD13 (611152) on 1q21, AD14 (611154) on 1q25, AD15 (611155) on 3q22-q24, AD16 (300756) on Xq21.3, AD17 (615080) on 6p21.2, and AD18 (615590), associated with variation in the ADAM10 gene (602192) on 15q21.

Evidence also suggests that mitochondrial DNA polymorphisms may be risk factors in Alzheimer disease (502500).

Finally, there have been associations between AD and various polymorphisms in other genes, including alpha-2-macroglobulin (A2M; 103950.0005), low density lipoprotein-related protein-1 (LRP1; 107770), the transferrin gene (TF; 190000), the hemochromatosis gene (HFE; 613609), the NOS3 gene (163729), the vascular endothelial growth factor gene (VEGF; 192240), the ABCA2 gene (600047), and the TNF gene (191160) (see MOLECULAR GENETICS).

Clinical Features

Alzheimer (1907) provided the first report of the disease (see HISTORY).

Schottky (1932) described a familial form of presenile dementia in 4 generations. The diagnosis was confirmed at autopsy in a patient in the fourth generation. Lowenberg and Waggoner (1934) reported a family with unusually early onset of dementia in the father and 4 of 5 children. Postmortem findings in 1 case were consistent with dementia of the Alzheimer type. McMenemey et al. (1939) described 4 affected males in 2 generations with pathologic confirmation in one.

Heston et al. (1966) described a family with 19 affected in 4 generations. Dementia was coupled with conspicuous parkinsonism and long tract signs.

Rice et al. (1980) and Ball (1980) reported a kindred in which members had clinical features of familial AD. Two patients had neuropathologic changes of spongiform encephalopathy of the Creutzfeldt-Jakob type (CJD; 123400) at autopsy, but the long clinical course was unusual for CJD. Corkin et al. (1983) found no difference in parental age of patients with AD compared to controls. Nee et al. (1983) reported an extensively affected kindred, with 51 affected persons in 8 generations. There was no increased incidence of Down syndrome (190685) or hematologic malignancy.

Heyman et al. (1983) found dementia in first-degree relatives of 17 (25%) of 68 probands with AD. These families also demonstrated an increase in the frequency of Down syndrome (3.6 per 1,000 as compared with an expected rate of 1.3 per 1,000). No excess of hematologic malignancy was found in relatives. In a study of the families of 188 Down syndrome children and 185 controls, Berr et al. (1989) found no evidence of an excess of dementia cases suggestive of AD in the families of patients with Down syndrome. In a large multicenter study of first-degree relatives of 118 AD probands and nondemented spouse controls, Silverman et al. (1994) found no association between familial AD and Down syndrome.

Stokin et al. (2005) identified axonal defects in mouse models of Alzheimer disease that preceded known disease-related pathology by more than a year; the authors observed similar axonal defects in the early stages of Alzheimer disease in humans. Axonal defects consisted of swellings that accumulated abnormal amounts of microtubule-associated and molecular motor proteins, organelles, and vesicles. Impairing axonal transport by reducing the dosage of a kinesin molecular motor protein enhanced the frequency of axonal defects and increased amyloid-beta peptide levels and amyloid deposition. Stokin et al. (2005) suggested that reductions in microtubule-dependent transport may stimulate proteolytic processing of beta-amyloid precursor protein (104760), resulting in the development of senile plaques and Alzheimer disease.

Bateman et al. (2012) performed a prospective, longitudinal study analyzing data from 128 subjects at risk for carrying a mutation for autosomal dominant AD. Subjects underwent baseline clinical and cognitive assessments, brain imaging, and cerebrospinal fluid and blood tests. Bateman et al. (2012) used the participant's age at baseline assessment and the parent's age at the onset of symptoms of AD to calculate the estimated years from expected symptom onset (age of the participant minus parent's age at symptom onset). They then conducted cross-sectional analyses of baseline data in relation to estimated years from expected symptom onset in order to determine the relative order and magnitude of pathophysiologic changes. Concentrations of amyloid-beta-42 in the CSF appeared to decline 25 years before expected symptom onset. Amyloid-beta deposition, as measured by positron-emission tomography with the use of Pittsburgh compound B, was detected 15 years before expected symptom onset. Increased concentrations of tau protein in the CSF and an increase in brain atrophy were detected 15 years before expected symptom onset. Cerebral hypometabolism and impaired episodic memory were observed 10 years before expected symptom onset. Global cognitive impairment, as measured by Mini-Mental State Examination and the Clinical Dementia Rating scale, was detected 5 years before expected symptom onset, and patients met diagnostic criteria for dementia at an average of 3 years after expected symptom onset. Bateman et al. (2012) cautioned that their results required confirmation with use of longitudinal data and may not apply to patients with sporadic Alzheimer disease.

Familial Alzheimer Disease 1

Karlinsky et al. (1992) reported a family from Toronto with autosomal dominant inheritance of Alzheimer disease. The disorder was characterized by early onset of memory deficits, decreased speed of cognitive processing, and impaired attention to complex cognitive sets. The family immigrated to Canada from the British Isles in the 18th century. Genetic analysis identified a mutation in the APP gene (V717I; 104760.0002).

Farlow et al. (1994) reviewed the clinical characteristics of the disorder in the AD family reported by Murrell et al. (1991) in which affected members had a mutation in the APP gene (V717F; 104760.0003). The mean age of onset of dementia was 43 years. The earliest cognitive functions affected were recent memory, information-processing speed, sequential tracking, and conceptual reasoning. Language and visuoperceptual skills were largely spared early in the course of the disease. Later, there were progressive cognitive deficits and inability to perform the activities of daily living. Death occurred, on average, 6 years after onset. The family was Romanian, many of its members having migrated to Indiana.

Rossi et al. (2004) reported a family in which at least 6 members spanning 3 generations had Alzheimer disease and strokes associated with a heterozygous mutation in the APP gene (A713T; 104760.0009). At age 52 years, the proband developed progressive cognitive decline with memory loss and visuospatial troubles, as well as stroke-like episodes characterized by monoparesis and language disturbances detectable for a few days. MRI showed T2-weighted signal hyperintensities in subcortical and periventricular white matter without bleeding. Neuropathologic examination showed neurofibrillary tangles and A-beta-40- and A-beta-42-immunoreactive deposits in the neuropil. The vessel walls showed only A-beta-40 deposits, consistent with amyloid angiopathy. There were also multiple white matter infarcts along the long penetrating arteries. Other affected family members had a similar clinical picture. Several unaffected family members carried the mutation, and all but 1 were under 65 years of age.

Edwards-Lee et al. (2005) reported an African American family in which multiple members spanning 3 generations had early-onset AD. The distinctive clinical features in this family were a rapidly progressive dementia starting in the fourth decade, seizures, myoclonus, parkinsonism, and spasticity. Variable features included aggressiveness, visual disturbances, and pathologic laughter. Two sibs who were tested were heterozygous for a mutation in the APP gene (T714I; 104760.0015).

Early-Onset Alzheimer Disease with Cerebral Amyloid Angiopathy

Because Alzheimer disease associated with cerebral amyloid angiopathy (CAA) is also found in Down syndrome, Rovelet-Lecrux et al. (2006) reasoned that the APP locus located on chromosome 21q21 might be affected by gene dosage alterations in a subset of demented individuals. To test this hypothesis, they analyzed APP using quantitative multiplex PCR of short fluorescent fragments, a sensitive method for detecting duplications that is based on the simultaneous amplification of multiple short genomic sequences using dye-labeled primers under quantitative conditions. This analysis was performed in 12 unrelated individuals with autosomal dominant early-onset Alzheimer disease (ADEOAD) in whom a previous mutation screen of PSEN1 (104311), PSEN2 (600759), and APP had been negative; 5 of these individuals belonged to Alzheimer disease-affected families in which the cooccurrence of CAA had been diagnosed according to neuropathologic (Vonsattel et al., 1991) or clinical criteria (intracerebral hemorrhages (ICH) in at least 1 affected individual). In the 5 index cases with the combination of early-onset Alzheimer disease and CAA, they found evidence for a duplication of the APP locus (104760.0020). In the corresponding families, the APP locus duplication was present in affected subjects but not in healthy subjects over the age of 60 years. The phenotypes of the affected subjects in the 5 families were similar. None had mental retardation before the onset of dementia. None had clinical features suggestive of Down syndrome. The most common clinical manifestation was progressive dementia of Alzheimer disease type (mean age of onset 52 +/- 4.4 years) associated, in some cases, with lobar ICH. Neuropathologic examination of the brains of 5 individuals from 3 kindreds showed abundant amyloid deposits, present both as dense-cored plaques and as diffuse deposits, in all regions analyzed. Neurofibrillary tangles were noted in a distribution consistent with the diagnosis of definite Alzheimer disease. However, the most prominent feature was severe CAA. Rovelet-Lecrux et al. (2006) estimated that in their whole cohort of 65 ADEOAD families, the frequency of the APP locus duplication was roughly 8% (5 of 65), which corresponds to half of the contribution of APP missense mutations to ADEOAD.

Other Features

In longitudinal studies using magnetic resonance spectroscopic imaging (MRSI), Adalsteinsson et al. (2000) found that 12 patients with AD had a striking decline in the neuronal marker N-acetyl aspartate, compared to 14 controls. However, there was little decline in underlying gray matter volume in these patients.

In a comparison of 59 unrelated patients with AD and over 1,000 controls, Borenstein Graves et al. (2001) found that a combination of low head circumference and presence of the APOE4 allele strongly predicted earlier onset of AD. The authors suggested that the clinical expression of AD may occur when degeneration in specific brain regions falls below a critical threshold of 'brain reserve,' beyond which normal cognitive function cannot be maintained.

In a study of 461 sibs of 371 probands diagnosed with AD, Sweet et al. (2002) found that AD plus psychosis in probands was associated with a significantly increased risk for AD plus psychosis in family members (odds ratio = 2.4), demonstrating familial aggregation of this phenotype.

In a PET study comparing brain glucose metabolism between 46 patients with sporadic AD and 40 patients with familial AD, Mosconi et al. (2003) found that both groups had reductions in the metabolic rate of glucose in similar regional areas of the brain, particularly the posterior cingulate cortex, the parahippocampal gyrus, and occipital areas, suggesting common neurophysiologic pathways of degeneration. However, patients with familial AD had a more severe reduction in glucose metabolism in all these areas, suggesting that genetic predisposition further strains the degenerative process.

Biochemical Features

Zubenko et al. (1987) described a biophysical alteration of platelet membranes in Alzheimer disease. They concluded that increased platelet membrane fluidity (see 173560) characterized a subgroup of patients with early age of symptomatic onset and rapidly progressive course. Zubenko and Ferrell (1988) described monozygotic twins concordant for probable AD and for increased platelet membrane fluid.

Abraham et al. (1988) identified one of the components of the amyloid deposits seen in AD as the serine protease inhibitor alpha-1-antichymotrypsin (AACT; 107280). Birchall and Chappell (1988) suggested that individual vulnerability of genetic factors influencing intake, transport or excretion of aluminum may be a mechanism for familial AD.

Yan et al. (1996) reported that the RAGE protein (AGER; 600214) is an important receptor for the amyloid beta peptide and that expression of this receptor is increased in AD. They noted that expression of RAGE was particularly increased in neurons close to deposits of amyloid beta peptide and to neurofibrillary tangles.

Cholinergic projection neurons of the basal forebrain nucleus basalis express nerve growth factor (NGF) receptors p75(NTR) (162010) and TrkA (191315), which promote cell survival. These same cells undergo extensive degeneration in AD. Counts et al. (2004) found an approximately 50% average reduction in TrkA levels in 4 cortical brain regions of 15 patients with AD, compared to 18 individuals with no cognitive impairment and 16 with mild/moderate cognitive impairment. By contrast, cortical p75(NTR) levels were stable across the diagnostic groups. Scores on the Mini-Mental State Examination (MMSE) correlated with TrkA levels in the anterior cingulate, superior frontal, and superior temporal cortices. Counts et al. (2004) suggested that reduced TrkA levels may be the cause or result of abnormal cholinergic function in AD.

The Framingham (Massachusetts) Study cohort has been evaluated biennially since 1948. In a sample of 1,092 subjects (mean age, 76 years) from this cohort, Seshadri et al. (2002) analyzed the relation of the plasma total homocysteine level measured at baseline and that measured 8 years earlier to the risk of newly diagnosed dementia on follow-up. They used multivariable proportional-hazards regression to adjust for age, sex, apoE genotype, vascular risk factors other than homocysteine, and plasma levels of folate and vitamins B12 and B6. Over a median follow-up period of 8 years, dementia developed in 111 subjects, including 83 given a diagnosis of Alzheimer disease. The multivariable-adjusted relative risk of dementia was 1.4 for each increase of 1 standard deviation in the log-transformed homocysteine value either at baseline or 8 years earlier. The relative risk of Alzheimer disease was 1.8 per increase of 1 SD at baseline and 1.6 per increase of 1 SD 8 years before baseline. With a plasma homocysteine level greater than 14 micromol per liter, the risk of Alzheimer disease nearly doubled. Seshadri et al. (2002) concluded that an increased plasma homocysteine level is a strong, independent risk factor for the development of dementia and Alzheimer disease.

Among 563 AD patients and 118 controls, Prince et al. (2004) found that presence of the APOE4 allele was strongly associated with reduced CSF levels of beta-amyloid-42 in both patients and controls. In a retrospective study of 443 AD patients, Evans et al. (2004) found that increased serum total cholesterol was associated with more rapid disease progression in patients who did not have the APOE4 allele. The effect was not seen in patients with the APOE4 allele and high cholesterol.

Botella-Lopez et al. (2006) found increased levels of a 180-kD reelin (RELN; 600514) fragment in CSF from 19 patients with AD compared to 11 nondemented controls. Western blot and PCR analysis confirmed increased levels of reelin protein and mRNA in tissue samples from the frontal cortex of AD patients. Reelin was not increased in plasma samples, suggesting distinct cellular origins. The reelin 180-kD fragment was also increased in CSF samples of other neurodegenerative disorders, including frontotemporal dementia (600274), progressive supranuclear palsy (PSP; 601104), and Parkinson disease (PD; 168600).

Tesseur et al. (2006) found significantly decreased levels of TGF-beta receptor type II (TGFBR2; 190182) in human AD brain compared to controls; the decrease was correlated with pathologic hallmarks of the disease. Similar decreases were not seen in brain extracts from patients with other forms of dementia. In a mouse model of AD, reduced neuronal TGFBR2 signaling resulted in accelerated age-dependent neurodegeneration and promoted beta-amyloid accumulation and dendritic loss. Reduced TGFBR2 signaling in neuroblastoma cell cultures resulted in increased levels of secreted beta-amyloid and soluble APP. The findings suggested a role for TGF-beta (TGFB1; 190180) signaling in the pathogenesis of AD.

Counts et al. (2007) found a 60% increase in CHRNA7 (118511) mRNA levels in cholinergic neurons of the nucleus basalis in patients with mild to moderate Alzheimer disease compared to those with mild cognitive impairment or normal controls. Expression levels of CHRNA7 were inversely associated with cognitive test scores. Counts et al. (2007) suggested that upregulation of CHRNA7 receptors may be a compensatory response to maintain basocortical cholinergic activity during disease progression or may act with beta-amyloid in disease pathogenesis.


In a study of the families of Alzheimer disease patients, Heston (1977) found an excess of Down syndrome and of myeloproliferative disorders, including lymphoma and leukemia. Neurons of Alzheimer patients show a neurofibrillary tangle that is made up of disordered microtubules. An identical lesion occurs in the neurons of Down syndrome, at an earlier age than in Alzheimer disease. Leukemia and accelerated aging are also features of Down syndrome. Heston (1977) and Heston and Mastri (1977) speculated a disorder of microtubules as a common pathomechanism. Heston and White (1978) further speculated defective organization of microfilaments and microtubules in AD. Using immunoprecipitation techniques, Grundke-Iqbal et al. (1979) showed that neurofibrillary tangles in AD probably originate from neurotubules. Harper et al. (1979) could not confirm a systemic microtubular defect in Alzheimer disease; cultured skin fibroblasts from AD patients showed normal tubulin networks. Nordenson et al. (1980) found an increased frequency of acentric fragments in karyotypes from AD patients, and suggested that this was consistent with defective tubulin protein leading to erratic function of the spindle mechanism.

Gajdusek (1986) suggested that the amyloid in Alzheimer disease and Down syndrome is formed from a precursor synthesized in neurons as well as in microglial cells and brain macrophages. He further suggested that the precursor synthesized in neurons produces intracellular neurofibrillary tangles, and that the precursor synthesized in microglial cells and brain macrophages is exuded from the cell, forming the extracellular amyloid plaques and vascular amyloid deposits. Dying neurons may also contribute to extracellular deposits.

Bergeron et al. (1987) found that cerebral amyloid angiopathy (605714) was present in 86% of AD patients and 40% of age-matched controls. The findings suggested that cerebral amyloid angiopathy is an integral component of AD.

Using immunocytochemistry, Wolozin et al. (1988) identified a 68-kD protein in cerebral cortical neurons from both normal human fetal and neonatal brain and brain tissue from neonates with Down syndrome. The number of reactive neurons decreased sharply after age 2 years, but reappeared in older individuals with Down syndrome and in patients with Alzheimer disease.

Carrell (1988) speculated that plaque formation in AD was a consequence of proteolysis of a precursor protein; self-aggregation of the cleaved A4 peptides explained the precipitated amyloid, while release of a trophic inhibitory domain explained the interwoven neuritic development. Using computer-enhanced imaging of immunocytochemical stains of Alzheimer disease prefrontal cortex, Majocha et al. (1988) described the distribution of amyloid protein deposits exclusive of other senile plaque components. Joachim et al. (1989) presented evidence suggesting that Alzheimer disease is not restricted to the brain but is a widespread systemic disorder with accumulation of amyloid beta protein (104760) in nonneuronal tissues.

Ellis et al. (1996) found that 83% of 117 patients with autopsy-confirmed AD had at least a mild degree of cerebral amyloid angiopathy. Thirty (25.6%) of 117 brains showed moderate to severe CAA affecting the cerebral vessels in one or more cortical regions. These brains also showed a significantly higher frequency of hemorrhages or ischemic lesions compared to those with little or no amyloid angiopathy (43.3% versus 23.0%; odds ratio = 2.6). High CAA scores also correlated with the presence of cerebral arteriosclerosis and with older age at onset of dementia.

In light of the findings of Tomita et al. (1997) concerning PSEN2 mutation and altered metabolism of APP (summarized in 600759.0001), Hardy (1997) reviewed the evidence that Alzheimer disease has many etiologies, but one pathogenesis. Mutations in all known pathogenic genes have in common the fact that they alter processing of APP, thus lending strong support to the amyloid cascade hypothesis. Heintz and Zoghbi (1997) suggested that alpha-synuclein (163890) may provide a link between Parkinson disease (see 168600) and Alzheimer disease and possibly other neurodegenerative diseases.

The neurofibrillary tangle, one of the neuropathologic hallmarks of AD, contains paired helical filaments (PHFs) composed of the microtubule-associated protein tau (MAPT; 157140). Tau is hyperphosphorylated in PHFs, and phosphorylation of tau abolishes its ability to bind microtubules and promote microtubule assembly. Lu et al. (1999) demonstrated that PIN1 (601052) binds hyperphosphorylated tau and copurifies with PHFs, resulting in depletion of soluble PIN1 in the brains of patients with AD. PIN1 can restore the ability of phosphorylated tau to bind microtubules and promote microtubule assembly in vitro. Since depletion of PIN1 induces mitotic arrest and apoptotic cell death, sequestration of PIN1 into PHFs may contribute to neuronal death.

From detailed analysis of pathologic load and spatiotemporal distribution of beta-amyloid deposits and tau pathology in sporadic AD, Delacourte et al. (2002) concluded that there is a synergistic effect of amyloid aggregation in the propagation of tau pathology.

Kayed et al. (2003) produced an antibody that specifically recognized micellar amyloid beta but not soluble, low molecular weight amyloid beta or amyloid beta fibrils. The antibody also specifically recognized soluble oligomers among all other types of amyloidogenic proteins and peptides examined, indicating that they have a common structure and may share a common pathogenic mechanism. Kayed et al. (2003) showed that all of the soluble oligomers tested displayed a common conformation-dependent structure that was unique to soluble oligomers regardless of sequence. The in vitro toxicity of soluble oligomers was inhibited by oligomer-specific antibody. Soluble oligomers have a unique distribution in human Alzheimer disease brain that is distinct from that of fibrillar amyloid. Kayed et al. (2003) concluded that different types of soluble amyloid oligomers have a common structure and suggested that they share a common mechanism of toxicity.

Revesz et al. (2003) reviewed the pathology and genetics of APP-related CAA and discussed the different neuropathologic consequences of different APP mutations. Those that result in increased beta-amyloid-40 tend to result in increased deposition of amyloid in the vessels, consistent with CAA, whereas those that result in increased beta-amyloid-42 tend to result in parenchymal deposition of amyloid and the formation of amyloid plaques. These latter changes are common in classic Alzheimer disease.

To determine whether decreased neprilysin (MME; 120520) levels contribute to the accumulation of amyloid deposits in AD or normal aging, Russo et al. (2005) analyzed MME mRNA and protein levels in cerebral cortex from 10 cognitively normal elderly individuals with amyloid plaques (NA), 10 individuals with AD, and 10 controls who were free of amyloid plaques. They found a significant decrease in MME mRNA levels in both AD and NA individuals compared to controls. Russo et al. (2005) concluded that decreased MME expression correlates with amyloid-beta deposition but not with degeneration and dementia.

Using Western blotting, immunoprecipitation assays, and surface plasmon resonance analysis, Guo et al. (2006) showed that beta-amyloid-40 and -42 formed stable complexes with soluble tau and that prior phosphorylation of MAPT inhibited complex formation. Immunostaining of brain extracts from patients with AD and controls showed that phosphorylated tau and beta-amyloid were present within the same neuron. Guo et al. (2006) postulated that an initial step in AD pathogenesis may be the intracellular binding of soluble beta-amyloid to soluble nonphosphorylated tau.

By neuropathologic examination, Wilkins et al. (2006) found no difference in the presence or degree of neurofibrillary tangles, senile plaques, Lewy bodies, or amyloid angiopathy between 10 African American and 10 white individuals with AD. The findings suggested that race is not a major influence on AD pathology.

In HEK293 cells in vitro, Ni et al. (2006) found that activation of beta-2-adrenergic receptors (ADRB2; 109690) stimulated gamma-secretase activity and beta-amyloid production. Stimulation involved the association of ADRB2 with PSEN1 and required agonist-induced endocytosis of ADRB2. Similar effects were observed after activation of the opioid receptor OPRD1 (165195). In mouse models of AD, chronic treatment with ADRB2 agonists increased cerebral amyloid plaques, and treatment with ADRB2 antagonists reduced cerebral amyloid plaques. Ni et al. (2006) postulated that abnormal activation of ADRB2 receptors may contribute to beta-amyloid accumulation in AD.

Sun et al. (2006) found that hypoxia increased BACE1 (604252) beta-secretase activity and resulted in significantly increased beta-amyloid production in both wildtype human cells and human cells that stably overexpressed an AD-related APP mutation. Studies in transgenic mice with APP mutations showed that hypoxia upregulated Bace1 mRNA and increased deposition of brain beta-A40 and A42 compared to transgenic mice not exposed to hypoxic conditions. The findings suggested that hypoxia can facilitate AD pathogenesis and provided a molecular mechanism that linked vascular factors to AD.

In studies of rodent and human cells, Li et al. (2007) found that overexpression of hyperphosphorylated tau antagonized apoptosis of neuronal cells by stabilizing beta-catenin (CTNNB1; 116806). The findings explained why NFT-bearing neurons survive proapoptotic insults and instead die chronically of degeneration.

Schilling et al. (2008) found that the N-terminal pyroglutamate (pE) formation of amyloid beta (104760) is catalyzed by glutaminyl cyclase (607065) in vivo. Glutaminyl cyclase expression was upregulated in the cortices of individuals with Alzheimer disease and correlated with the appearance of pE-modified amyloid beta. Oral application of a glutaminyl cyclase inhibitor resulted in reduced amyloid beta(3(pE)-42) burden in 2 different transgenic mouse models of Alzheimer disease and in a new Drosophila model. Treatment of mice was accompanied by reductions in amyloid beta(X-40/42), diminished plaque formation and gliosis, and improved performance in context memory and spatial learning tests. Schilling et al. (2008) suggested that their observations were consistent with the hypothesis that amyloid beta(3(pE)-42) acts as a seed for amyloid beta aggregation by self-aggregation and coaggregation with amyloid beta(1-40/42). Therefore, amyloid beta(3(pE)-40/42) peptides seem to represent amyloid beta forms with exceptional potency for disturbing neuronal function. The authors suggested that the reduction of brain pE-modified amyloid beta by inhibition of glutaminyl cyclase offers a new therapeutic option for the treatment of Alzheimer disease and provides implications for other amyloidoses.

In vascular smooth muscle cells isolated from AD patients with CAA, Bell et al. (2009) found an association between beta-amyloid deposition and increased expression of serum response factor (SRF; 600589) and myocardin (MYOCD; 606127) compared to controls. Further studies indicated the MYOCD upregulated SRF and generated a beta-amyloid nonclearing phenotype through transactivation of SREBP2 (600481), which downregulates LRP1, a key beta-amyloid clearance receptor. SRF silencing led to increased beta-amyloid clearance. Hypoxia stimulated SRF/MYOCD expression in human cerebral vascular smooth muscle cells and in animal models of AD. Bell et al. (2009) suggested that SRF and MYOCD function as a transcriptional switch, controlling beta-amyloid cerebrovascular clearance and progression of AD.

Using microarray analysis, followed by RT-PCR of human postmortem hippocampus, Qin et al. (2009) found that decreased expression of the PPARGC1A gene (604517), a regulator of gluconeogenesis, correlated with progression of moderate to severe clinical dementia in patients with AD, as well as increased density of neuritic plaques and beta-amyloid-42. Hyperglycemia was found to attenuate PPARGC1A expression and increase beta-amyloid in the medium of Tg2576 AD neurons; this phenomenon was decreased by exogenous expression of PPARGC1A. Further studies indicated that suppression of PPARGC1A in hyperglycemia resulted in activation of the FOXO3A (602681) transcription factor, which inhibits nonamyloidogenic secretase processing of APP and promotes amyloidogenic processing of APP. The findings provided a molecular mechanism for a link between glucose metabolism and AD.

Mawuenyega et al. (2010) measured amyloid-beta kinetics in the CNS of 12 AD participants and 12 cognitively intact controls. Mawuenyega et al. (2010) found no differences in the rate of production of amyloid-beta-42 or amyloid-beta-40 in AD patients versus controls. However, there was a significant difference in the rate of amyloid-beta-40 and amyloid-beta-42 clearance in the AD subjects versus controls. There was roughly 30% impairment in the clearance of both amyloid-beta-42 and amyloid-beta-40, with a P value of 0.03 and 0.01, respectively. Estimates based on a 30% decrease in amyloid-beta clearance rate suggested that brain amyloid-beta accumulates over about 10 years in AD. The authors pointed out that the limitations of this study included the relatively small number of participants and the inability to prove causality of impaired amyloid-beta clearance for AD.

Israel et al. (2012) reprogrammed primary fibroblasts from 2 patients with familial Alzheimer disease, in both caused by a duplication of the amyloid-beta precursor protein gene (APP; 104760), 2 with sporadic Alzheimer disease, and 2 nondemented control individuals into induced pluripotent stem cell (iPSC) lines. Neurons from differentiated cultures were purified with fluorescence-activated cell sorting and characterized. Purified cultures contained more than 90% neurons, clustered with fetal brain mRNA samples by microarray criteria, and could form functional synaptic contacts. Virtually all cells exhibited normal electrophysiologic activity. Relative to controls, iPSC-derived, purified neurons from the 2 patients with the duplication and 1 sporadic patient exhibited significantly higher levels of the pathologic markers of amyloid-beta(1-40), phospho-tau(thr231), and active glycogen synthase kinase-3-beta (aGSK-3-beta). Neurons from the duplication and the same sporadic patient also accumulated large RAB5 (179512)-positive early endosomes compared to controls. Treatment of purified neurons with beta-secretase inhibitors, but not gamma-secretase inhibitors, caused significant reductions in phospho-tau(thr231) and aGSK-3-beta levels. Israel et al. (2012) concluded that their results suggested a direct relationship between APP proteolytic processing, but not amyloid-beta, in GSK-3-beta activation and tau phosphorylation in human neurons. Additionally, Israel et al. (2012) observed that neurons with the genome of 1 of the sporadic patients exhibited the phenotypes seen in familial Alzheimer disease samples.

Laganowsky et al. (2012) identified a segment of the amyloid-forming protein alpha-B crystallin (123590) that forms an oligomeric complex exhibiting properties of other amyloid oligomers: beta-sheet-rich structure, cytotoxicity, and recognition by an oligomer-specific antibody. The x-ray-derived atomic structure of the oligomer revealed a cylindrical barrel formed from 6 antiparallel protein strands that Laganowsky et al. (2012) termed a cylindrin. The cylindrin structure is compatible with a sequence segment from the beta-amyloid protein of Alzheimer disease. Laganowsky et al. (2012) concluded that cylindrins offer models for the hitherto elusive structures of amyloid oligomers.

Amino-terminally truncated, pyroglutamylated (pE) forms of amyloid-beta are strongly associated with Alzheimer disease, are more toxic than amyloid-beta(1-42) and amyloid-beta(1-40), and have been proposed as initiators of Alzheimer disease pathogenesis. Nussbaum et al. (2012) reported a mechanism by which pE-amyloid-beta may trigger Alzheimer disease. Amyloid-beta-3(pE)-42 co-oligomerizes with excess amyloid-beta(1-42) to form metastable low-n oligomers (LNOs) that are structurally distinct and far more cytotoxic to cultured neurons than comparable LNOs made from amyloid-beta(1-42) alone. Tau (157140) is required for cytotoxicity, and LNOs comprising 5% amyloid-beta-3(pE)-42 plus 95% amyloid-beta(1-42) (5% pE-amyloid-beta) seed new cytotoxic LNOs through multiple serial dilutions into amyloid-beta(1-42) monomers in the absence of additional amyloid-beta-3(pE)-42. LNOs isolated from human Alzheimer disease brain contained amyloid-beta-3(pE)-42, and enhanced amyloid-beta-3(pE)-42 formation in mice triggered neuron loss and gliosis at 3 months, but not in a tau-null background. Nussbaum et al. (2012) concluded that amyloid-beta-3(pE)-42 confers tau-dependent neuronal death and causes template-induced misfolding of amyloid-beta(1-42) into structurally distinct LNOs that propagate by a prion-like mechanism. Nussbaum et al. (2012) concluded that their results raised the possibility that amyloid-beta-3(pE)-42 acts similarly at a primary step in Alzheimer disease pathogenesis.

Raj et al. (2014) performed an expression quantitative trait locus (eQTL) study of purified CD4 (186940)+ T cells and monocytes, representing adaptive and innate immunity, in a multiethnic cohort of 461 healthy individuals. Context-specific cis- and trans-eQTLs were identified, and cross-population mapping allowed, in some cases, putative functional assignment of candidate causal regulatory variants for disease-associated loci. Raj et al. (2014) noted an overrepresentation of monocyte-specific eQTLs among Alzheimer disease and Parkinson disease (168600) variants, and of T cell-specific eQTLs among susceptibility alleles for autoimmune diseases, including rheumatoid arthritis (180300) and multiple sclerosis (126200). Raj et al. (2014) concluded that this polarization implicates specific immune cell types in these diseases and points to the need to identify the cell-autonomous effects of disease susceptibility variants.

Using solid-state nuclear magnetic resonance (ssNMR) measurements on amyloid beta-40 and amyloid beta-42 fibrils prepared by seeded growth from extracts of Alzheimer disease brain cortex, Qiang et al. (2017) investigated correlations between structural variation and Alzheimer disease phenotype. The authors compared 2 atypical Alzheimer disease clinical subtypes, the rapidly progressive form (r-AD) and the posterior cortical atrophy variant (PCA-AD), with a typical prolonged-duration form (t-AD). On the basis of ssNMR data from 37 cortical tissue samples from 18 individuals, Qiang et al. (2017) found that a single amyloid beta-40 fibril structure is most abundant in samples from patients with t-AD and PCA-AD, whereas amyloid beta-40 fibrils from r-AD samples exhibit a significantly greater proportion of additional structures. Data for amyloid beta-42 fibrils indicated structural heterogeneity in most samples from all patient categories, with at least 2 prevalent structures. Qiang et al. (2017) concluded that these results demonstrated the existence of a specific predominant amyloid beta-40 fibril structure in t-AD and PCA-AD, suggested that r-AD may relate to additional fibril structures, and indicated that there is a qualitative difference between amyloid beta-40 and amyloid beta-42 aggregates in the brain tissue of patients with Alzheimer disease.

In patients with Alzheimer disease, deposition of amyloid-beta is accompanied by activation of the innate immune system and involves inflammasome-dependent formation of ASC (606838) specks in microglia. ASC specks released by microglia bind rapidly to amyloid-beta and increase the formation of amyloid-beta oligomers and aggregates, acting as an inflammation-driven cross-seed for amyloid-beta pathology. Venegas et al. (2017) showed that intrahippocampal injection of ASC specks resulted in spreading of amyloid-beta pathology in transgenic double-mutant APP(Swe)PSEN1(dE9) mice. By contrast, homogenates from brains of APP(Swe)PSEN1(dE9) mice failed to induce seeding and spreading of amyloid-beta pathology in ASC-deficient double-mutant mice. Moreover, coapplication of an anti-ASC antibody blocked the increase in amyloid-beta pathology in the double-mutant mice. Venegas et al. (2017) concluded that these findings supported the concept that inflammasome activation is connected to seeding and spreading of amyloid-beta pathology in patients with Alzheimer disease.

In mice, Da Mesquita et al. (2018) demonstrated that meningeal lymphatic vessels drain macromolecules from the CNS (cerebrospinal and interstitial fluids) into the cervical lymph nodes. Impairment of meningeal lymphatic function slowed paravascular influx of macromolecules into the brain and efflux of macromolecules from the interstitial fluid, and induced cognitive impairment in mice. Treatment of aged mice with vascular endothelial growth factor C (VEGFC; 601528) enhanced meningeal lymphatic drainage of macromolecules from the cerebrospinal fluid, improving brain perfusion and learning and memory performance. Disruption of meningeal lymphatic vessels in transgenic mouse models of Alzheimer disease promoted amyloid-beta deposition in the meninges, which resembles human meningeal pathology, and aggravated parenchymal amyloid-beta accumulation. Da Mesquita et al. (2018) suggested that meningeal lymphatic dysfunction may be an aggravating factor in Alzheimer disease pathology and in age-associated cognitive decline.


From an extensive study in Sweden, Sjogren et al. (1952) suggested that Alzheimer disease shows multifactorial inheritance. In a study of 52 families with AD, Masters et al. (1981) concluded that the disorder showed autosomal dominant inheritance without maternal effect.

In 7 of 21 families with AD, Powell and Folstein (1984) found evidence of 3-generation transmission. Breitner and Folstein (1984) suggested that most cases of Alzheimer disease are familial. Fitch et al. (1988) found a familial incidence of 43%, and detected no clinical differences between the familial and sporadic cases. In one-third of the familial cases, the disorder developed after age 70. Breitner et al. (1988) found that the cumulative incidence of AD among relatives was 49% by age 87. The risk was similar among parents and sibs, and did not differ significantly between relatives of those with early or late onset.

In a study of 70 kindreds containing 541 affected and 1,066 unaffected offspring of parents with AD parents, Farrer et al. (1990) identified 2 distinct clinical groups: early onset (less than 58 years) and late onset (greater than 58 years). At-risk offspring in early-onset families had an estimated lifetime risk for dementia of 53%, suggesting autosomal dominant inheritance. The lifetime risk in late-onset families was 86%. Farrer et al. (1990) concluded that late-onset AD may be autosomal dominant in some families.

In a complex segregation analysis on 232 nuclear families ascertained through a single proband who was referred for diagnostic evaluation of memory disorder, Farrer et al. (1991) concluded that susceptibility to AD is determined, in part, by a major autosomal dominant allele with an additional multifactorial component. The frequency of the AD susceptibility allele was estimated to be 0.038, but the major locus was thought to account for only 24% of the 'transmission variance,' indicating a substantial role for other genetic and nongenetic mechanisms.

Silverman et al. (1994) used a standardized family history assessment to study first-degree relatives of Alzheimer disease probands and nondemented spouse controls. First-degree relatives of AD probands had a significantly greater cumulative risk of AD (24.8%) than did the relatives of spouse controls (15.2%). The cumulative risk for the disorder among female relatives of probands was significantly greater than that among male relatives.

Rao et al. (1996) carried out a complex segregation analysis in 636 nuclear families of consecutively ascertained and rigorously diagnosed probands in the Multi-Institutional Research in Alzheimer Genetic Epidemiology study in order to derive models of disease transmission that account for the influences of the APOE genotype of the proband and gender. In the total group of families, models postulating sporadic occurrence, no major gene effect, random environmental transmission, and mendelian inheritance were rejected. Transmission of AD in families of probands with at least 1 APOE4 allele best fitted a dominant model. Moreover, single gene inheritance best explained clustering of the disorder in families of probands lacking APOE4, but a more complex genetic model or multiple genetic models may ultimately account for risk in this group of families. The results suggested to Rao et al. (1996) that susceptibility to AD differs between men and women regardless of the proband's APOE status. Assuming a dominant model, AD appeared to be completely penetrant in women, whereas only 62 to 65% of men with predisposing genotypes developed AD. However, parameter estimates from the arbitrary major gene model suggested that AD is expressed dominantly in women and additively in men. These observations, taken together with epidemiologic data, were considered consistent with the hypothesis of an interaction between genes and other biologic factors affecting disease susceptibility.

In a study of 290 patients with Alzheimer disease in the French Collaborative Group and 1,176 of their first-degree relatives, Martinez et al. (1998) found that familial clustering of Alzheimer disease was largely due to factors other than APOE status.

Silverman et al. (1999) hypothesized that elderly individuals who lived beyond the age of 90 years without dementia had a concentration of genetic protective factors against Alzheimer disease. Although they recognized that testing this hypothesis was complicated, probands carrying genetic protective factors should have relatives with lower illness rates not only for early-onset disease, in which genetic risk factors are a strong contributing factor to the incidence of AD, but also for later-onset disease, when the role of these factors appears to be markedly diminished. AD dementia was assessed through family informants in 6,660 first-degree relatives of 1,049 nondemented probands aged 60 to 102 years. Cumulative survival without AD was significantly greater in the relatives of the oldest proband group (aged 90 to 102 years) than it was in the 2 younger groups. In addition, the reduction in the rate of illness for this group was relatively constant across the entire late life span. The results suggested that genetic factors conferring