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etiology/risk of Alzheimer's disease

Etiology: 1) genetic links with Alzheimer's disease 2) hypotheses a) cholinergic hypothesis (see CNS cholinergic system) - cholinergic neurons in the nucleus basalis of Meynert & in the septum are selectively vulnerable in AD - choline acetyltransferase & acetylcholine are decreased with moderate stage dementia - degree of cognitive impairment may correlate with loss of cholinergic neurons & fibers - chronic anticholinergic use may increase risk of AD [24,69] b) Free radical/oxidative stress hypothesis 3) chronic psychosocial stress a) midlife psychosocial stress increases risk of dementia 25 years later [116] b) chronic stress exacerbates cognitive impairment in a rat model of Alzheimer's disease [19] c) chronic stress also impairs long-term potentiation 4) toxins: a) aluminum: cerebral plaques seen in autopsy of dialysis patients using tap water for dialysis & reproducible in rabbits by infusion of aluminum are morphologically distinct from amyloid plaques seen in Alzheimer's disease & Down's syndrome b) dichlorodiphenyldichloroethylene (DDE), metabolite of pesticide dichlorodiphenyltrichloroethane (DDT) associated with increased risk of Alzheimer's disease [33[ c) gingipains produced by Porphyromonas gingivalis identified in the brains of patients with Alzheimer's disease [65] - COR388, an oral agent that inhibits gingipain proteases secreted by P gingivalis in a clinical trial [70] - gingivitis may be a risk factor for AD [84] d) trans fats, elaidic acid 5) infection: - viral encephalitis with strongest association [122] - Chlamydia pneumoniae & Herpes simplex type 1 found in brain tissue of patients with Alzheimer's disease [11] - analysis by 16S rRNA Next Generation Sequencing reveals - more bacteria found in postmortem brain of patients with Alzheimer's disease (7-fold more) [55] - 10-fold higher ratio of Actinobacteria to Proteobacteria in postmortem brain of patients with Alzheimer's disease [55] - most Actinobacteria identified as Propionibacterium acnes - HHV6A & HHV7 may affect metabolism of APP in brain [60] - HSV1 & Herpes zoster may increase risk of AD [60] - reactivation of quiescent Herpes Simplex Virus Type 1 in brain may result in release of pro-inflammatory cytokines & beta-amyloid & phosphorylated tau accumulation [110] - HHV6A, HHV6B, HHV7 & HSV1 found in postmortem brains of AD patients [70] - HSV1 may be a risk factor [78] 6) rare cases of transmissible Alzheimer's disease - five children treated with human growth hormone from pituitary glands obtained from cadavers developed early dementia or biomarkers consistent with Alzheimer's disease by age 38-55 years [128] === risk factors === - aging is greatest risk factor for dementia - for risk factors specific to Alzheimer's disease, see predictors of Alzheimer's disease - 2 apolipoprotein E4 alleles (2nd greatest risk factor) (see genetics) - previous head trauma - traumatic brain injury controversial [104] - family history of dementia in a 1st degree relative - greater risk than head trauma without loss of consciousness - low level of education - illiteracy associated with risk for dementia, but literacy status does not affect rate of cognitive decline [74] - a higher level of education associated with a delayed diagnosis [18] - family history of Down's syndrome - olfactory impairment is an independent risk factor - olfactory bulb & olfactory tract are effected early in Alzheimer's disease - see olfaction & Alzheimer's disease - hypercholesterolemia - serum cholesterol > 250 mg/dL, in midlife [6] - serum cholesterol, LDL cholesterol, HDL cholesterol NOT risk factors [5] - low LDL cholesterol levels due to PCSK9 & HMGCR variants not linked to Alzheimer's disease, vascular dementia, any dementia, or Parkinson's disease [43] - low LDL cholesterol level may diminish risk of vascular dementia - higher apoE levels in HDL linked to lower dementia risk, but only when HDL did not contain apoC3 [82] - low plasma apoE is associated with higher risk of dementia & Alzheimer's disease independent of apoE genotype [82] - blood pressure & cardiovascular risk factors - hypertension (systolic BP > 160 mm Hg, in midlife) [5] - low diastolic blood pressure in the elderly (< 70 mm Hg) associated with increased risk of AD (RR=1.92) [10] - antihypertensive agents confer reduced risk [14,23,131] - lowest hazzard ratio for K+ sparing diuretics (0.26) - orthostatic hypotension [83] - no convincing evidence that lowering blood pressure prevents the development of dementia or cognitive impairment in hypertensive elderly with no apparent prior cerebrovascular disease - Cochrane Database Syst Rev 2006 [15] - attenuation of the decline in blood pressure during sleep is associated with increased amyloid burden in the posterior cingulate gyrus & altered cerebral blood flow (see blood pressure) [37] - vascular risk factors in middle age are associated with elevated brain amyloid deposition in later life [39] - coronary artery disease before age 45 years [127] - midlife hypertension associated with risk for later dementia only in women [51] - resting heart rate > 80/min vs 60-69/min associated with increased risk for dementia (RR=1.55) [94] - systolic blood pressure variability (RR=1.02-1.10) [121] - calcium channel blockers may lower risk - the same risk factors that cause atherosclerosis, are also major risk factors for late-life cognitive impairment & Alzheimer's disease [48] - 25 g of processed-meat daily (2 strips of bacon) associated with increased risk of dementia over 8 years, independent of the APOE-4 status [88] - multimorbidity - multimorbidity during midlife increases risk for dementia [96] - multimorbidity associated with 63% increased risk of dementia within 15 years [111] - risk highest in patients with cardiovascular disease [111] - higher plasma neurofilament associated with a 54% greater risk for all-cause dementia & a 49% greater risk for Alzheimer's dementia [77]. - hyperhomocysteinemia may be risk factor [8,9] - diabetes mellitus 65% increased risk [4] - hyperinsulinemia provokes increases in brain inflammation & beta amyloid [3] - hyperglycemia is a risk factor for dementia, even at levels of plasma glucose = 115 mg/dl (HR = 1.18) [32] - diabetes mellitus type 2 for >10 years doubles risk of dementia at age 70 [90] - peripheral neuropathy linked to higher risk of dementia (RR=1.9) [99] - J-shaped association between plasma estradiol & dementia [34] - 2.4-fold risk for women with high levels - 2.2-fold risk for women with high levels - diabetic women with high estradiol with 14-fold risk - anemia is a risk factor for dementia in older adults (RR=1.5) [31] - sleep disturbance in middle age may be a risk factor [36] - diminished REM sleep may be a risk factor [47] - disruption of slow-wave activity leads to higher CSF A-beta & CSF tau [50] may be due to diminished glymphatic clearance - sleep duration < 5 hours (RR=2.6) or > 10 hours (RR=1.7) per night associated with increased risk for dementia [59] - sleep duration < 7 hours per night [91] - similar U-shaped associations for Alzheimer's disease & vascular dementia [59] - use of sleeping pills in later life increases risk (RR=1.5) [100] - nightmares in middle-age or older adults [113] - disruption of circadian rhythyms may be associated with amyloid plaque pathology prior to emergence of cognitive impairment [56] - higher outdoor nighttime light exposure is associated with higher prevalence of Alzheimer's disease [133] - obesity is risk factor for dementia [13] - weight loss may preceed the onset of dementia [115] - low body mass index is not a risk factor for AD [42] - possibly oophorectomy prior to menopause [17] - active smoking & heavy smoking in midlife [25,26] - not a risk factor according to [30] - quitting smoking reduces risk, but cutting back may be of no benefit [120] - air pollution (RR=1.4) risk stronger for Alzheimer's disease than vascular dementia [63] - particulate matter < 2.5 microns,including air pollution alters brain structure & increases risk for preclinical AD [75] - long-term exposure to air pollution increases risk of dementia [76] - heart failure & ischemic heart disease may enhance this risk - stroke may be intermediate condition between exposure to air pollution & dementia [76] - living without a partner at midlife [22] - hospitalization &/or delirium increase risk of AD [28] - an intensive care unit (ICU) stay double risk of AD [108] - psychologic stress greatest risk factor according to [30] - anxiety [21] - late-life depression [27] may interact with beta-amyloid - chronic pain [44] - repetitive negative thinking [80] - repeated rumination or worry [80] - AD may start sooner for people with anxiety, depression [87] - greater risk of dementia when spouse has dementia? [108] - widows & lifelong singles tend to be underdiagnosed [53] - loneliness 45-64 years of age persisting after age 65 (RR=1.9) [89] - loneliness triples risk of dementia & is associated with worse neurocognitive markers of Alzheimer's disease & related dementia vulnerability [97] - marriage confers lower risk for dementia [53] - social isolation increases risk of dementia (RR=1.3) [119] - apathy is a risk factor [61] - benzodiazepine use in the elderly - new benzodiazepine use in the elderly [29] - > 180 days of use RR=1.7 [29] - antidepressant use [41] (RR=3.3-4.9) - anticonvulsant use [58] (RR=1.15-1.3) - androgen deprivation therapy may be associated with increased risk for AD [38] - menopausal hormone replacement therapy increases risk of AD (RR=1.2) [124] - chronic anticholinergic use may increase risk of AD [24,69] - hypermagnesemia & hypomagnesemia appear to be risk factors [49] - diminished retinal nerve fiber layer thickness on retinal optical coherence tomography linked to cognitive decline & dementia [64] - autoimmunity may be a modifiable component in diseases associated with dementia [98] - inflammatory disorders appear to increase risk & TNF-alpha inhibitors appear to mitigate that risk - inflammatory bowel disease is a risk factor (RR > 2) [81] - breakdown of the blood-brain barrier may provide entry for components of autoimmune processes [98] - intestinal microbiota proinflammatory genus Collinsella, identified as a risk factor for AD positively correlating with the APOE rs429358 risk allele [129] - hospitalization with infection associated with increased risk for dementia [118] - gout is associated with a diminished risk of AD (RR=0.73-0.76) - uric acid may be neuroprotective [35] - gout increases risk for vascular dementia (RR=2.3) - vitiligo (RR=12.2) [85] & alopecia areata (RR=3)[95] - frailty is a risk factor for mild cognitive impairment & dementia [86] - sensory impairment - visual impairment is a potentially modifiable risk factor [101] - hearing impairment is a potentially modifiable risk factor (see hearing loss) - link between ADHD & Alzheimer's disease [93] - nonalcoholic fatty liver disease (RR=1.4) [106] - hypothyroidism requiring levothyroxine replacement therapy (RR=3) [107] - common vaccinations (especially influenza virus vaccine & pneumococcal vaccine) may increase risk of dementia in elderly after a 2-year lag period (RR=1.4) [123] - most consistent associations at all time points over a 15-year span include - depression, erectile dysfunction, gait abnormalities, hearing loss, & nervous & musculoskeletal symptoms [117] - nose picking associated with increased risk [12] === modifiable risk factors === 1) midlife obesity [102] 2) midlife hypertension 3) physical inactivity 4) depression - social isolation [105,119] 5) smoking 6) low education 7) diabetes mellitus 8) hearing loss [102] 9) visual impairment [101] 10) diet - ultraprocessed foods associated with increased risk for dementia [112] === protective factors === - genetically proxied lean mass is associated with a reduced risk of Alzheimer's disease [125] - multiple sclerosis is associated with reduced plasma amyloid-beta & reduced Alzheimer disease risk [134] === risk factors for amyloid & tau deposition === - risk factors for amyloid deposition & neurodegeneration appear to be distinct [40] - maternal history (at any age) & paternal history of early-onset memory impairment are associated with beta-amyloid burden among asymptomatic elderly [130] - midlife dyslipidemia is associated with amyloid deposition - midlife obesity, smoking, diabetes, hypertension, cardiovascular disease & metabolic disease associated with neurodegeneration [40] - intellectual activity does not predict of amyloid deposition or neurodegeneration [40] - elevation in baseline brain amyloid in cognitively normal persons associated with higher likelihood of later cognitive decline, although of uncertain clinical significance (median follow-up = 3.1 years) [45] - higher plasma amyloid-beta42 associated with 40% decreased risk for AD [77] - repetitive negative thinking linked to amyloid deposisition & entorhinal cortex tau deposits [80] - greater depressive symptoms over time are associated with amyloid accumulation in regions associated with emotional control (medial orbitofrontal cortex, isthmus cingulate cortex & middle frontal cortex) independent of cognitive function [132] - service in the U.S. military - associated with post mortem neuritic amyloid plaque & tau pathology [126] === plasma proteins linked to increased risk of cognitive impairment === - proteins that inhibit central nervous system axonogenesis & synaptogenesis - SLIT2, CHST12, PAM [92] === not risk factors === - proton pump inhibitors not a risk factor [46,52] - controversial, some data suggests a link [103] - alcohol consumption 1-7 drinks weekly not associated with risk of dementia (lowest risk) - abstinence or more associated with higher risk [62] - midlife diet does not appear to be a risk factor [67] - physical inactivity [68] (controversial [102] Radiology: - cerebral abnormalities on neuroimaging in older adults & in midlife are associated with an increased risk for dementia [66] - MRI brain perivascular spaces may be proxy measure of cerebral small vessel disease, glymphatic dysfunction & risk of dementia [114] Comparative biology: - in a triple transgenic mouse model of Alzheimer's disease canola oil increased in body weight, impaired working memory, decreased post-synaptic density protein-95 (marker of synaptic integrity), & increased the ratio of insoluble Abeta42/Abeta40 [54] - pericyte dysfunction may initiate leukoaraiosis prior to neuronal loss [57] - in 3xTg-AD mice, Klebsiella pneumoniae can translocate from the gut to the bloodstream by penetrating the gut epithelial barrier & susequently infiltrate the brain by penetrating the blood-brain barrier [135] Notes: Also see: 1) prevention of Alzheimer's disease 2) investigational therapies for AD 3) causes of dementia 4) risk factors for dementia * risk factors for Alzheimer's disease vs dementia in general are not well differentiated, largely because the literature does not always distinguish the two

Related

Alzheimer's disease (AD) olfaction & Alzheimer's disease predictors of Alzheimer's disease prevention of Alzheimer's disease/dementia risk factors & protective factors for vascular dementia

General

causes of dementia risk factors for dementia

References

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