Dementia: Causes

Pathogenesis (development of disease)

Dementia is usually preceded by a mild “cognitive impairment” (“MCI”), which presents as an anamnestic (affecting memory) form, a precursor of Alzheimer’s dementia. In about 10-20% of all patients with MCI, the mild impairment progresses to manifest dementia within a year. Vascular cognitive impairment (VCI) is probably present in approximately 20% of all forms of dementia. Histopathologically, the following diagnoses have been shown to be likely associated: large infarcts, lacunar infarcts, microinfarcts, meningeal and cerebral amyloid angiopathy, atherosclerosis (arteriosclerosis, hardening of the arteries), perivascular lacunae, and a loss of myelin. The pathogenesis of dementia is not yet fully understood. The most important factors in the development of dementia are age and cardiovascular (heart disease) risks. However, genetic factors also play a role. In addition, there are a variety of other triggers of dementia (see below).

Etiology (causes)

Biographic causes

  • Genetic burden from parents, grandparents
    • Genetic risk dependent on gene polymorphisms, related to frontotemporal dementia (FTD; rare form of dementia in which there is loss of neurons in the frontal lobe (frontal lobes) and temporal lobe (temporal lobes); major symptoms are changes in behavior as well as personality):
      • Genes/SNPs (single nucleotide polymorphism):
        • Genes: GRN
        • SNP: rs5848 in the gene GRN
          • Allele constellation: TT (3.2-fold)
    • Genetic diseases
      • Hallervorden-Spatz syndrome – genetic disorder with autosomal recessive inheritance leading to neurodegeneration with iron deposition in the brain, resulting in mental retardation and early death; onset of symptoms before the age of 10.
      • Wilson’s disease (copper storage disease) – autosomal recessive inherited disease in which copper metabolism in the liver is disturbed by one or more gene mutations.
      • Porphyria or acute intermittent porphyria (AIP); genetic disease with autosomal-dominant inheritance; patients with this disease have a 50 percent reduction in the activity of the enzyme porphobilinogen deaminase (PBG-D), which is sufficient for porphyrin synthesis. Triggers of a porphyria attack, which can last a few days but also months, are infections, drugs or alcohol. The clinical picture of these attacks presents as acute abdomen or neurological deficits, which can take a lethal course. The leading symptoms of acute porphyria are intermittent neurologic and psychiatric disturbances. Autonomic neuropathy is often in the foreground, causing abdominal colic (acute abdomen), nausea (nausea), vomiting or constipation (constipation), as well as tachycardia (heartbeat too fast: > 100 beats per minute) and labile hypertension (high blood pressure).
      • Trisomy 21 (Down syndrome) – special genomic mutation in humans in which the entire 21st chromosome or parts of it are present in triplicate (trisomy). In addition to physical characteristics considered typical for this syndrome, the cognitive abilities of the affected person are usually impaired; furthermore, there is an increased risk of leukemia (blood cancer).
  • Ethnicity – African American (36% more likely to have dementia than white).
  • Age – increasing age; in persons > 85 years of age, the prevalence for vascular dementia is circa 14%; for Alzheimer’s dementia, it is 20-40% in this age group
  • Height – men who were six centimeters taller than average at the transition to adulthood had a lower risk of dementia (also significant when education level was taken into account)
  • Educational level – low educational level
  • Marital status – lifelong singles: married people had a 42% lower risk of developing dementia than lifelong singles
  • Occupations – Footballers (professional footballers: 5-fold increased risk of Alzheimer’s disease), rugby players (Alzheimer’s disease, dementia or chronic traumatic encephalopathy (CTE)).

Behavioral causes

  • Nutrition
    • High intake of sweet drinks, especially if they contain artificial sweeteners
    • Micronutrient deficiency (vital substances) – see Prevention with micronutrients.
  • Consumption of stimulants
    • Alcohol (woman: > 20 g/day; man: > 30 g/day)
      • > 24 grams daily: 20% increased risk of dementia.
      • People with high alcohol consumption (men > 60 g/day; women 40/day) are more than 3 times more likely than others to develop dementia; onset often at younger ages
    • Tobacco (smoking)
      • Smoking over the age of 65: 60% increased risk.
  • Physical activity
    • Low physical activity and exercise; according to the results of a meta-analysis, the physical inactivity factor has been overestimated because of mostly too short study duration. However, in patients in whom no metabolic disease preceded dementia, physical inactivity (measured more than 10 years ago) represents some risk of dementia (HR 1.3) statistical significance was missed, however.
    • Physical inactivity: 40% increased risk.
    • Professional soccer players (5-fold more likely to require dementia medication than non-athletes; including fewer goalkeepers than field players due to chronic traumatic brain injury (“concussion”) caused by repetitive headers or collisions)
  • Psycho-social situation
    • Psychological stress
    • Social isolation
  • Sleep duration (long sleep: > 9 hours; ratio of dementia mortality in long sleepers to 1.63 (p = 0.03)).
  • Overweight (BMI (body mass index) > 25; obesity).
    • 60% increased risk of dementia
    • In middle years of life
    • Women who are obese in their mid-50s; after age 70, these women have been shown to have an increased risk of dementia
  • Underweight
    • Women with a body mass index (BMI) of less than 20 kg/m2 were 2.93 times more likely to develop dementia than normal-weight women [time of onset of dementia: 5 years after recruitment of women who were approximately 55 years old at the time of enrollment in the study].
  • Android body fat distribution, that is, abdominal/visceral truncal central body fat (apple type) – high waist circumference or waist-to-hip ratio (THQ; waist-to-hip ratio (WHR)) is presentWhen waist circumference is measured according to the International Diabetes Federation (IDF, 2005) guideline, the following standard values apply:
    • Men < 94 cm
    • Women < 80 cm

    The German Obesity Society published somewhat more moderate figures for waist circumference in 2006: < 102 cm for men and < 88 cm for women.

Disease-related causes

Respiratory system (J00-J99)

Blood, blood-forming organs – immune system (D50-D90).

Endocrine, nutritional and metabolic diseases (E00-E90).

  • Diabetes mellitus (hypoglycemia and hyperglycemia/ hypoglycemia and hyperglycemia) (77% higher rate of dementia)
    • Adult-onset diabetes: 50% increased risk
  • Electrolyte disorders such as.
    • Hyponatremia (sodium deficiency)
    • Hypernatremia (excess sodium)
  • Hyperlipidemia / hyperlipoproteinemia (lipid metabolism disorders).
  • Hyperparathyroidism (parathyroid hyperfunction).
  • Pituitary insufficiency (hypofunction of the pituitary gland).
  • Hyperthyroidism (hyperthyroidism)
  • Hypoglycemia (hypoglycemia), severe (especially in old age).
  • Hypothyroidism
  • Hypoparathyroidism (hypothyroidism of the parathyroid gland).
  • Hypothyroidism (hypothyroidism)
  • Malnutrition (veganism)
  • Addison’s disease (primary adrenocortical insufficiency; NNR insufficiency) – disease caused by the underactivity of the adrenal cortex with decreased hormone production.
  • Cushing’s disease – disease in which too much ACTH is produced by the pituitary gland, resulting in increased stimulation of the adrenal cortex and, as a consequence, excessive production of cortisol
  • Vitamin deficiency:
  • Wernicke’s encephalopathy (synonyms: Wernicke-Korsakow syndrome; Wernicke’s encephalopathy) – degenerative encephaloneuropathic disease of the brain in adulthood; clinical picture: brain-organic psychosyndrome (HOPS) with memory loss, psychosis, confusion, apathy, and gait and stance unsteadiness (cerebellar ataxia) and eye movement disorders / eye muscle paralysis (horizontal nystagmus, anisocoria, diplopia)); vitamin B1 deficiency (thiamine deficiency).

Skin and subcutaneous (L00-L99).

Cardiovascular system (I00-I99)

  • Apoplexy (stroke)
  • Atherosclerosis (arteriosclerosis; hardening of the arteries)
  • Chronic heart failure (cardiac insufficiency) – in the very old (85+), chronic heart failure combined with low systolic blood pressure (< 147 mmHg) leads to significantly faster cognitive decline than compared with those with high systolic pressure (> 162 mmHg)
  • Cardiac arrhythmias (esp. atrial fibrillation (VHF))
    • VHF increased the risk of dementia by 2.9-fold even without the occurrence of an apoplexy compared with study participants without AF; thus, this group was not at all different from a group with AF who had a stroke at baseline or during the course of the study; subgroup analysis showed that the risk of dementia was significantly increased only in men (HR: 4.6; p < 0.001 versus HR: 0.6; p = 0.59).
  • Hypertension (high blood pressure; risk factor for subcortical white matter lesions).
    • High-normal systolic values of 130 mmHg and above already increase the risk of dementia; participants who exceeded this threshold developed dementia at a rate of 6.3%, compared with only 3.7% at low pressures
    • Above 140 mmHg systolic in middle age increases the risk of dementia by 60%.
    • Women who continued to have elevated blood pressure in their mid-30s and at age 40 were 65% more likely to later develop dementia (HR 1.65; 1.25-2.18)
    • Occurrence of hypertension after the age of 80 lowers the risk of dementia
  • Coronary artery disease (CAD; coronary artery disease).
  • Orthostatic hypotension (with postural change (orthostasis = upright standing) show a systolic pressure drop of at least 20 mmHg or a diastolic of at least 10 mmHg) (15% increased risk).
  • Subacute sclerosing panencephalitis (inflammatory disease of the brain; usually caused by measles infection)
  • Vasculitides (vascular inflammations), unspecified.

Infectious and parasitic diseases (A00-B99).

  • AIDS (Acquired Immunodeficiency Syndrome).
  • Creutzfeldt-Jakob disease
  • Cytomegaly
  • Gerstmann-Sträussler-Scheinker disease – disease affecting the brain, which is associated with BSE.
  • HIV infection
  • Syphilis (Lues)
  • Tuberculosis

Liver, gallbladder and bile ducts – Pancreas (pancreas) (K70-K77; K80-K87).

Mouth, esophagus (esophagus), stomach, and intestines (K00-K67; K90-K93).

  • Ulcerative colitis – chronic inflammatory disease of the mucosa of the colon (large intestine) or rectum (rectum) (people with CED have 2.54 times the risk as people without the disease)
  • Crohn’s disease – chronic inflammatory bowel disease; it usually progresses in relapses and can affect the entire digestive tract; characteristic is the segmental affection of the intestinal mucosa (intestinal mucosa), that is, several intestinal sections may be affected, which are separated by healthy sections (people with CED have a 2.54-fold risk as people without the disease)
  • Whipple’s disease – rare systemic infectious disease; caused by the gram-positive rod bacterium Tropheryma whippelii (from the actinomycete group), which can affect several other organ systems in addition to the obligately affected intestinal system and is a chronic relapsing disease; symptoms: Fever, arthralgia (joint pain), brain dysfunction, weight loss, diarrhea (diarrhea), abdominal pain (abdominal pain), and more. → Malabsorption syndrome
  • Celiac disease (gluten-induced enteropathy) – chronic disease of the mucosa of the small intestine (small intestinal mucosa) due to hypersensitivity to the cereal protein gluten → malabsorption syndrome.

Neoplasms – tumor diseases (C00-D48).

  • Brain tumors (ventricle III or in the hypothalamus).
  • Brain tumors, unspecified
  • Brain metastases
  • Insulinoma – in the majority of cases benign neoplasm in the area of the pancreas (pancreas) → hypoglycemia (low blood sugar)
  • Metastases (daughter tumors).
  • Plasmocytoma (multiple myeloma) – malignant (malignant) systemic disease. It belongs to the non-Hodgkin’s lymphomas of B lymphocytes.
  • Polycythaemia vera – pathological multiplication of blood cells (particularly affected are: especially erythrocytes / red blood cells, to a lesser extent also platelets (blood platelets) and leukocytes / white blood cells); stinging itch after contact with water (aquagenic pruritus).

Ears – mastoid process (H60-H95).

Psyche – nervous system (F00-F99; G00-G99).

  • Alcohol dependence
  • ALS (amyotrophic lateral sclerosis)-Parkinson’s dementia complex.
  • Anxiety disorders
  • Alzheimer’s dementia
  • Chorea-Huntington – genetic neurological disease with increasing degradation of brain mass.
  • Delir (acute state of confusion).
  • Dementia pugilistica – dementia caused by repeated traumatic brain injury.
  • Depression?
    • Patients with depressive symptoms whose depression increased from examination to examination had a 42% increased risk of dementia
    • The Whitehall II cohort study, with 28 years of follow-up and data on more than 10,000 middle-aged individuals, concluded the following:
      • Participants who complained of depression in middle age did not have a significantly increased risk of developing dementia later in follow-up.
      • Participants who had symptoms of depression from 11 years prior to a dementia diagnosis had a 70% increased risk of developing dementia.

      CONCLUSION: Depression symptoms are a feature of the prodromal stage of dementia. Depression and dementia must share a common cause.

  • Dialysis Dementia
  • Encephalitis (inflammation of the brain)
  • Encephalopathy (brain disease).
    • Hepatic (liver-related)
    • Pancreatic (pancreas-related)
    • Uremic (uremic-related)
  • Epilepsy
  • Frontotemporal dementia (FTD) (synonym: formerly also Pick’s disease) – a neurodegenerative disease usually occurring before the age of 60 in the frontal or Temporal lobe of the brain; progressive dementia characterized by early, slowly progressive personality change and loss of social skills; disease is followed by impairment of intellect, memory and language functions with apathy, euphoria and occasionally extrapyramidal phenomena; dementia progresses in FTD usually much faster than in Alzheimer-type dementia.
  • GAD antibody encephalitis (GAD encephalitis; GAD = glutamate decarboxylase).
  • Gerstmann-Sträussler-Scheinker syndrome (GSSS) – transmissible spongiform encephalopathy caused by prions; it resembles Creutzfeldt-Jakob disease; disease with ataxia (gait disorder) and increasing dementia.
  • Brain abscess – encapsulated collection of pus in the brain.
  • Hydrocephalus (hydrocephalus; pathological enlargement of the liquid-filled fluid spaces (cerebral ventricles) of the brain).
  • Corticobasal (or corticobasal) degeneration (CBD).
  • Leigh encephalomyelopathy – genetic neurological disorder of early infancy.
  • Leukodystrophy – disease of the central nervous system characterized by metabolic disorders.
  • Lewy body dementia – dementia with special histological picture.
  • Limbic-predominant age-related TDP-43 encephalopathy (LATE) – deposition of the protein TDP-43 in the memory centers of the brain (amygdalae (stage 1) and the hippocampi (stage 2) and later (stage 3) also in the frontalis medius gyrus); Occurs in a quarter of all people over the age of 85; 5 risk alleles (on the GRN, TMEM106B, ABCC9, KCNMB2 and APOE genes) have been found so far – thus there is overlap with Alzheimer’s disease and frontotemporal dementia.
  • Meningoencephalitis – combined inflammation of the brain (encephalitis) and meninges (meningitis).
  • Parkinson’s disease
  • Multi-infarct dementia (dementia due to brain damage after multiple strokes) – begins gradually with transient ischemic attacks (TIA; sudden disturbance of blood flow to the brain, resulting in neurological dysfunction that resolves within 24 hours)
  • Multiple sclerosis (MS)
  • Multisystem atrophy – neurological disease associated with parkinsonism.
  • Neuroses
  • Normal pressure hydrocephalus brain changes due to a decrease in brain matter and simultaneous increase in cerebrospinal fluid (nervous fluid).
  • Neuroacanthocytosis – syndrome with many different neurological and psychiatric signs of disease.
  • Progressive multifocal encephalopathy – brain changes caused by papovavirus.
  • Progressive supranuclear palsy – neurological disease associated with dementia.
  • Psychosis
  • Schizophrenia
  • Sleep apnea
  • Social isolation (60% increased risk of dementia).
  • Subcortical arteriosclerotic encephalopathy (SAE) – dementia due to vascular changes with arteriosclerosis in the brain.
  • Subacute sclerosing panencephalitis – panencephalitis usually caused by measles infection.
  • Vasculitis in the area of the brain
  • Cerebral vasculitis

Pregnancy, childbirth and puerperium (O00-O99).

Symptoms and abnormal clinical and laboratory findings not classified elsewhere (R00-R99)

  • Weight loss in old age – people over 70 years of age who lose weight may be at increased risk for cognitive impairment (= risk factor for dementia)
  • Subclinical inflammation (English “silent inflammation”) – permanent systemic inflammation (inflammation that affects the whole organism), which runs without clinical symptoms.
  • Uremia (occurrence of urinary substances in the blood above normal values) → uremic encephalopathy.

Genitourinary system (kidneys, urinary tract – reproductive organs) (N00-N99).

Causes (external) of morbidity and mortality (V01-Y84).

Injuries, poisonings, and other consequences of external causes (S00-T98).

  • Mild traumatic brain injury; risk for dementia.
    • Mild TBI without loss of consciousness: 2.36-fold higher risk.
    • Mild TBI with loss of consciousness: 2.51-fold higher risk
    • Moderate to severe TBI: 3.77-fold higher risk.
  • Traumatic brain injury (TBI) (moderate to severe TBI in middle age).
  • Heavy metal poisoning

Laboratory diagnoses – laboratory parameters that are considered independent risk factors.

  • Albuminuria (albumin in the urine).
  • Anemia (anemia) – 34% more likely to have dementia (hazard ratio 1.34; 95 percent confidence interval 1.11 to 1.62); risk of Alzheimer’s disease was 41% higher than among seniors without anemia (hazard ratio 1.41; 1.15 to 1.74); however, the fifth with the highest hemoglobin levels also had a 20 percent increased risk (hazard ratio 1.20; 1.00 to 1.44)
  • High LDL variability in older individuals (70 to 82 years): significant cognitive deficits.
  • Hyperhomocysteinemia – increased concentration of the amino acid homocysteine in the blood (vascular dementia/vascular dementia).
  • Carriers of the ApoE-ε4 allele (developed dementia twice as often as those without).
  • Fasting glucose? (> 6.1 mmol/L; > 110 mg/dL → 6-10% hippocampal and amygdala volume reduction).

Medications

  • Antiandrogens in prostate cancer patients (androgen deprivation: 2.2-fold increased risk).
  • Anticholinergics; in particular, use of multiple anticholinergics; associations were sometimes still detectable after 15 to 20 years; Conclusion: reduction of anticholinergics from middle age.
  • Antiepileptic drugs
  • Antihypertensive
  • Hormones
    • Systemic hormone therapy – study results:
      • No significant differences between estradiol-only and combined estrogen-progestin preparations.
      • Women had to have taken the preparations for at least ten years before age 60; shorter duration of use was not associated with increased risk of dementia.
      • Women who were 60 years old when treatment began showed a higher likelihood of dementia after only three years of use.
  • Proton pump inhibitors (PPI; acid blockers) in elderly patients; another study showed that MCI (mild cognitive impairment; mild cognitive impairment) and dementia, were significantly lower with PPI than withoutConclusion: randomized trials are lacking.
  • Psychotropic drugs
  • Tamsulosin (α1-adrenoceptor antagonist).

Environmental stress – intoxications

  • Anoxia, for example, due to anesthesia incident.
  • Lead
  • Carbon monoxide
  • Solvent encephalopathy
  • Air pollutants: particulate matter (PM2.5) and nitrogen oxides; seniors at greatest risk were those with heart failure or ischemic heart disease
  • Drug-induced hyponatremia such as from diuretics, antiepileptic drugs, or occasionally ACE inhibitors – this can lead to secondary dementia
  • Perchloroethylene
  • Mercury
  • Heavy metal poisoning (arsenic, lead, mercury, thallium).

Other causes

  • Blood pressure fluctuations, daily severe; participants in the top quarter with the highest daily blood pressure fluctuations were 2.27 times more likely to develop dementia; for vascular dementias, the hazard ratio was 2.79 (1.04-7.51) and for Alzheimer’s disease, 2.22 (1.31-3.75); the absolute risk of developing dementia within the next 5 years was approximately 4 percent
  • Cardiovascular arrest
  • Altitude sickness
  • Polypharmacotherapy (regular daily use of five or more medications).
  • Diver’s disease