Pathogenesis (disease development)
The cause of Alzheimer’s disease is unknown. Genetic and metabolic disorders are discussed, as well as slow virus infections (infection of the central nervous system (CNS), which is associated with an extremely long incubation period (time between the entry of a pathogen into the body and the appearance of the first symptoms)). Toxic, infectious and immunological factors are also considered as possible causes.In the brain of affected patients, deposits of certain protein molecules – amyloid plaques (beta-amyloid plaques) – can be detected after death by autopsy. These negatively affect the performance of the nerves and the transmission of excitation by means of transmitters. Furthermore, the cellular energy supply of the brain is impaired. The cause seems to be a small protein fragment called beta-amyloid. Mitochondria (power plants of the cells) consist of about 1,500 different proteins. These have to migrate into the mitochondria so that they can do their work there. This import takes place with the help of a so-called signal sequence, which are small protein fragments that smuggle the protein into the mitochondria. After import, i.e. after entry of the same, the signal sequence is normally removed. It has now been demonstrated that the protein fragment beta-amyloid prevents the mitochondria from removing these signal sequences. As a consequence, the mitochondria can only perform energy metabolism to a limited extent. Another important mechanism in the pathogenesis of Alzheimer’s disease is played by the neurotransmitter glutamate, which is produced in excess when large amounts of beta-amyloid accumulate in the brain. Glutamate controls about 70% of all nerve cells and ensures that learning and memory processes can take place. In Alzheimer’s patients, the glutamate concentration between the nerves is permanently increased, i.e. the nerve cells are permanently excited and lose their ability to function. It is known that hyperinsulinism (increased concentration of the hormone insulin in the blood above the normal level) – found in diabetes mellitus (diabetes), type 2 – leads to an increase in beta-amyloid in the blood plasma. In Alzheimer’s disease, deposits of amyloid are found in the brain. Therefore, a link between hyperinsulinism and the later onset of Alzheimer’s disease is hypothesized. Amyloid pathology only seems to accelerate the process of neurodegeneration. Other neurodegenerative processes, which can be detected with neurodegeneration markers, are probably decisive.Patients with amyloid pathology and conspicuous neurodegeneration markers showed a marked progression in cognitive decline. However, patients without amyloid pathology with AD could also be detected, all of whom had pathological neurodegeneration markers.A quarter of all patients who have moderate to severe dementia do not have extensive amyloid deposits in the brain at all. In the presence of the genetic risk factor ApoE-ε4 allele on chromosome 19, the proportion was as low as one-third. New research results show that the long filaments consisting of many hundreds of ß-amyloid molecules and the plaques themselves are less harmful to the brain. In contrast, ß-amyloid molecules stably stored together as oligomers appear to be critical: These oligomers cause far greater functional disruption of neurons as they form smaller deposits in the neurons themselves. Another important role in the development of Alzheimer’s disease may have the peptide aeta-amyloid (synonym: amyloid-η; pronounced: A(myloid)-Aeta) that slows neuronal stimulation. This discovery is significant because drug suppression of beta-secretase leads to a reduction of beta-amyloid, but at the same time to a massive overproduction of aeta-amyloid. This would then lead to a disturbance of neuronal activity and thus brain function. Meanwhile, a direct toxic effect of ß-amyloid has been demonstrated: The activating neurotransmitter (messenger) glutamate is not transported away from the synaptic cleft fast enough; so that the pathological excitation of neurons is increased. Tau proteins, which spread along interconnected brain regions in the course of the disease, appear to be decisive for the progression of dementia.A tau PET study demonstrated that the more severe the tau pathology, the more pronounced the clinical symptoms of the patients.
Etiology (Causes)
Biographical causes
Genetic burden-first-degree relatives; however, it is still influenced by second- and third-degree relatives as well
- Genetic risk dependent on gene polymorphisms:
- Genes/SNPs (single nucleotide polymorphism; English : single nucleotide polymorphism):
- Genes: APOE, CLU, GRN, OTC, PSEN1.
- SNP: rs429358 in the gene APOE
- Allele constellation: CT (One ApoE4 allele) (3-fold).
- Allele constellation: CC (Two ApoE4 alleles).
- SNP: rs7412 in the gene APOE
- Allele constellation: CT (One ApoE2 allele).
- Allele constellation: CC (Two ApoE2 alleles)
- SNP: rs11136000 in the CLU gene.
- Allele constellation: AG (0.84-fold decreased risk of Alzheimer’s disease in European populations).
- Allele constellation: AA (0.84-fold decreased risk of Alzheimer’s disease in European populations).
- SNP: rs10519262 in an intergenic region.
- Allele constellation: AG (1.9-fold).
- Allele constellation: AA (> 1.9-fold)
- SNP: rs5848 in the gene GRN
- Allele constellation: TT (1.36-fold).
- SNP: rs5963409 in the gene OTC
- Allele constellation: AG (1.19-fold).
- Allele constellation: AA (1.19-fold)
- SNP: rs3025786 in the gene PSEN1
- Allele constellation: CT (slightly decreases Alzheimer’s risk if ApoE4 is present).
- Allele constellation: CC (slightly decreases Alzheimer’s risk when Apoe4 is present).
- SNP: rs597668 in an intergenic region.
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- Allele constellation: CT (1.18-fold).
- Allele constellation: CC (1.39-fold)
- SNP: rs744373 in an intergenic region.
- Allele constellation: CT (1.13-fold).
- Allele constellation: CC (1.28-fold)
- Genetic disease
- Early-Onset or Late-Onset Alzheimer’s disease: in the genes PSEN1, PSEN2 and APP are found a total of more than 100 SNPs, whose risk alleles bring a more than 90% risk to develop early-onset or late-onset Alzheimer’s disease – in the context of an autosomal dominant inheritance.
- Genes/SNPs (single nucleotide polymorphism; English : single nucleotide polymorphism):
- Higher age of the mother at birth (> 32 years).
- Age of life – increasing age (> 65 years of age; exponential increase).
- Low level of education
- Hormonal factors
- Estrogen deficiency in the brain
- Multiparity (“multiple births”): Women with ≥ 5 children were 68% more likely to develop the disease than the comparison group with fewer children (odds ratio [OR] = 1.68, 95% confidence interval [CI] 1.04-2.72); women who had more than one miscarriage had about half the risk of women who never had an abortion (OR = 0.43, 95% CI 0.24-0.76 for 1 miscarriage; OR 0.56, 95% CI 0.34-0.92 for ≥ 2 miscarriages). CONCLUSION: Moderately elevated estrogen levels in the first trimester of pregnancy are within the optimal range; thereafter, increases during pregnancy up to 40 times the normal maximum.
- Occupations – footballers (professional footballers: 5-fold increased risk due toheaders for Alzheimer’s disease), rugby players (Alzheimer’s disease, dementia or chronic traumatic encephalopathy (CTE)).
Behavioral causes
- Nutrition
- Intake of saturated or trans-saturated fats (the fats are found in margarine, for example).
- Low consumption of fruits, vegetables, fish, and omega-3-rich oils leads to an increased risk of dementia and Alzheimer’s disease, especially in ApoE-ε4 non-carriers.
- Micronutrient deficiency (vital substances) – see Prevention with micronutrients.
- Consumption of stimulants
- Physical activity
- Low or lack of physical activity (has the highest impact on Alzheimer’s prevalence at 21%).
- Psycho-social situation
- Psychosocial stressors leading to cognitive overload.
- Overweight (BMI ≥ 25; obesity) (in middle age).
Disease-related causes
- Apoplexy (stroke)
- Depression?
- Depression is associated with twice the risk of developing Alzheimer’s dementia
- Depression could be a prodromal symptom (symptom indicative of disease) for Alzheimer’s disease rather than a cause of it
- Diabetes mellitus type 2 (insulin resistance).
- HSV-1 infection (herpes simplex virus) – doubles the risk of Alzheimer’s disease.
- Hypertension (high blood pressure)
- Hypothyroidism (hypothyroidism)
- Metabolic syndrome
Laboratory diagnoses – laboratory parameters that are considered independent risk factors.
- ApoE-ε4 allele on chromosome 19 – approximately ten- to twelvefold increased risk of dementia among individuals with two alleles for apolipoprotein E4 (ApoE4).
- Hypercholesterolemia: LDL cholesterol elevation.
- Prospective studies show that high serum cholesterol levels in middle age and ApoE4 together increase the risk of Alzheimer’s disease
- Genetically-related elevated cholesterol levels appear to contribute significantly to early-onset autosomal dominant Alzheimer disease (EOAD) ); in addition to ApoE genes, the gene encoding apolipoprotein B (ApoB) appears to be relevant. Note: ApoB is an essential component of LDL cholesterol.
- Hyperhomocysteinemia
Medication
- Benzodiazepines – are associated with a 51% increased rate of Alzheimer’s disease when prescribed at > 91 daily doses.In a cohort study of over 4700 participants, medication use in the 10 years prior to study entry was reliably determined from prescription data, and participants’ cognitive performance was assessed every 2 years. Study participants were on average 74 years old at baseline. The study design suggests that dementia is driving benzodiazepine use, rather than the other way around.
- Diuretics, antiepileptic drugs, or ACE inhibitors – these can lead to drug-induced hyponatremia (sodium deficiency), resulting in secondary dementia
- Hormone ablative therapy (HAT; synonyms: Hormone ablation; English androgen deprivation therapy, ADT; hormone therapy that withholds the male sex hormone testosterone); multivariate analysis: risk increased by 66%.
- Proton pump inhibitors (PPIs; acid blockers) in elderly patients.
Environmental exposure – intoxications (poisonings).
- Aluminum? ; contra
- Air pollutants: particulate matter (PM2.5) – 13% increased risk of disease per 5 µg/m3 increase in particulate matter at residence (hazard ratio 1.13; 1.12 to 1.14); association was dose-dependent up to a PM2.5 concentration of 16 µg/m3.
- Copper.
- Manganese
