|Year : 2016 | Volume
| Issue : 2 | Page : 100-107
Etiologies and risk factors for dementia
Sandeep Grover, Aditya Somani
Department of Psychiatry, Postgraduate Institute of Medical Education and Research, Chandigarh, India
|Date of Web Publication||13-Dec-2016|
Department of Psychiatry, Postgraduate Institute of Medical Education and Research, Chandigarh
Source of Support: None, Conflict of Interest: None
Dementia is understood as a clinical syndrome characterized by impairment in memory impairment along with cognitive deficits in other domains. Over the years, understanding about the causes of dementias has improved. Broadly, dementias can be classified as irreversible degenerative dementias and reversible dementias. Alzheimer's disease is the prototype of degenerative dementias and is characterized by the accumulation of beta-amyloid protein (called as amyloid plaques) outside the neurons and accumulation of tau protein (called tau tangles) inside the neurons. Vascular dementias are characterized by cerebrovascular insults which lead to pathological brain changes that impair cognition. The pathological hallmark of Lewy body dementia is the presence of α-synuclein neuronal inclusions, also known as Lewy bodies, accompanied by neuronal loss. Frontotemporal dementias are characterized by abnormal deposits of the microtubule-associated protein tau, the trans-activation response TAR DNA-binding protein with molecular weight 43 kDa (TDP-43), and the fused in sarcoma protein. Reversible dementias are characterized by the primary illness and may not present with characteristic brain deposits as seen with many degenerative dementias.
Keywords: Dementia, etiology, risk factors
|How to cite this article:|
Grover S, Somani A. Etiologies and risk factors for dementia. J Geriatr Ment Health 2016;3:100-7
| Introduction|| |
According to the Diagnostic and Statistical Manual of Mental Disorders IV (DSM-IV),  dementia is understood as a clinical syndrome caused or characterized by impairment in memory impairment along with cognitive deficits in one more domain in the form of aphasia, apraxia, agnosia, or disturbance in executive functioning.  Further, it is understood that the cognitive deficits occur in clear sensorium to distinguish it from delirium and are associated with social and occupational dysfunction.  According to International Classification of Diseases - 10 th revision (ICD-10),  dementia is understood as a syndrome due to disease of the brain, which is usually chronic or progressive in nature, manifests in the form of disturbance of multiple higher cortical functions, including memory, thinking, orientation, comprehension, calculation, learning capability, language, and judgments. The cognitive disturbances are seen without alteration in the level of consciousness. Further, ICD-10 considers that the impairments of cognitive function in dementia are commonly accompanied by and occasionally preceded by deterioration in emotional control, social behavior, or motivation. 
DSM-5,  renamed dementia as a major neurocognitive disorder (NCD) and it further recognizes a less severe form of cognitive impairment, i.e. minor NCD, which is equivalent to mild cognitive impairment (MCI) and prodromal dementia. However, the threshold between mild NCD and major NCD is inherently arbitrary. DSM-5 preferred to use the term "neurocognitive" for these disorders to emphasize that these disorders are caused by brain diseases and disrupted brain function which leads to cognitive symptoms (DSM-5).  DSM-5 has also provided the list of six cognitive domains which may be affected in both mild and major NCD, which are complex attention (which includes sustained attention, divided attention, selective attention, and information processing speed), executive function (which involves planning, decision-making, working memory, responding to feedback, inhibition, and mental flexibility), learning and memory (free recall, cued recall, recognition memory, semantic and autobiographical long-term memory, and implicit learning), language (which includes object naming, word finding, fluency, grammar and syntax, and receptive language), perceptual-motor function (which includes visual perception, visuo-constructional reasoning, and perceptual-motor coordination), and social cognition (which includes recognition of emotions, theory of mind, and insight). Based on the cause of cognitive deficits, DSM-5 categorizes minor and major NCD due to Alzheimer's disease (AD), frontotemporal NCD, NCD with Lewy bodies, vascular NCD, NCD due to traumatic brain injury, substance/medication-induced NCD, NCD due to HIV infection, NCD due to Prion disease, NCD due to Parkinson's disease, NCD due to Huntington's disease, NCD due to another medical condition, NCD due to multiple etiologies, and unspecified NCD (DSM-5). 
However, traditionally, different types of dementias are understood as irreversible and reversible dementia. The prototype of irreversible dementia is Alzheimer's dementia. The various irreversible and reversible causes of dementia are shown in [Table 1]. ,,,,, AD is considered as a prototype of irreversible dementia and accounts for 60-80% of all cases of dementia.  Despite the ever extending list of causes of irreversible dementia, various clinic-based studies suggest that irreversible dementias account for 0-23% of all cases of dementia. ,,, Among the various causes of reversible dementia, studies vary regarding most common causes, with some studies reporting depression to be the most common cause,  whereas others suggest that neurosurgical causes in the form of benign tumors, normal pressure hydrocephalus, and subdural hematoma form the most common causes of reversible dementias.  A clinic-based study from India suggests that reversible dementias account for 18% of all dementias, with neuroinfections and Vitamin B12 deficiency account for most of the cases of reversible dementias. 
However, it is important to understand that many a time, patients may have risk factors and clinical manifestations of more than one type of dementia.
| Alzheimer's Disease|| |
AD is characterized by insidious onset, progressive memory loss in the initial phase of the illness. Memory loss may be accompanied by or followed by disturbances in the other cognitive functions such as language, executive functions, and visuospatial functions.  As the severity of the illness increases, cognitive disturbances may be accompanied by behavioral symptoms and in the most advanced stage patients require assistance for basic activities of daily living, i.e. bathing, toileting, and dressing, and patients may not be able to communicate, recognize their family members, and become bed-bound. 
Many modifiable and nonmodifiable factors have been shown to increase the risk of AD. Among the various risk factors, increasing age is considered to be the most important risk factor. A recent meta-analysis evaluated the modifiable risk factors for AD and reported that presence of hyperhomocysteinemia, depression, frailty, carotid atherosclerosis, hypertension, low-diastolic blood pressure, type 2 diabetes mellitus (Asian population), low education, high-body mass index (BMI) in mid-life, and low BMI were associated with increased risk of AD. 
Factors which were found to be protective for AD included medical exposures to estrogen, statin, antihypertensive medications and nonsteroidal anti-inflammatory drugs therapy and dietary exposure to folic acid, Vitamin E, Vitamin C, and coffee. Factors which were associated with decreased risk of AD were a history of arthritis, heart disease, metabolic syndrome, cancer, cognitive activity, current smoking (Western population), light-to-moderate drinking, stress, high-BMI in late-life.  The unmodifiable risk factors for AD include increasing age, family history of AD, presence of apolipoprotein E å4 allele, multiple sclerosis, and Parkinson's disease. It is suggested that after the age of 65 years, the risk of AD, doubles approximately every 5 years.  It is suggested that those with a parent or sibling with AD, are 2-3 times more likely to develop AD, with further increase in the risk with an additional family member with AD. Studies suggest that 40-65% of patient with AD have one or two copies of the APOE-å4 gene.  Studies have also evaluated the role of MCI in developing AD, and these suggest that compared to people without MCI, patients with MCI, especially those with memory problems are at increased risk of developing AD. 
Pathogenesis of AD is better understood than other degenerative dementias. The primary culprits for AD are the accumulation of beta amyloid protein (called as amyloid plaques) outside the neurons and accumulation of tau protein (called tau tangles) inside the neurons. Physiologically, Aβ peptides are considered to play an important role in metal chelation, cholesterol transport, repair of blood vessels, and have an anti-oxidant property. In normal states, amyloid precursor protein (APP) is the first cleaved by α-secretase to an 83-amino acid peptide which is further cleaved by g-secretase into two smaller fragments viz., p7 and p3.  However, in subjects with AD, APP is first cleaved by β-secretase into a 91 amino acid peptide which is then cleaved by g-secretase into smaller Aβ40, Aβ42, or Aβ43 amino acid peptides. Among these, Aβ42 is specifically involved in the production of amyloid plaques. These Aβ42 peptides form oligomers that interfere with synaptic functioning and action of neurotransmitters, particularly acetylcholine. Later, these oligomers further aggregate to form plaques. Formation of plaques leads to a series of inflammatory and biochemical reactions that result in hyperphosphorylation of tau proteins of microtubules. These tau proteins then aggregate to form neurofibrillary tangles. Accumulations of beta amyloid proteins disrupt the communication at the synapse between different neurons, whereas accumulation of tau proteins disrupts the inflow of nutrients and other essential molecules into the neurons. Together these plaques and tangles lead to neuronal death and gradual loss of cognitive functions. ,,
Although the majority of cases of AD are sporadic in nature, certain genes have been identified that are involved in the pathogenesis of AD. The genes aberrations lead to either faulty production or processing of APP. Mutation of APP gene, located on chromosome 21, lead to a fault in APP itself and have been shown to cause AD in subjects of Down's syndrome who survive beyond the age of 40 years. Mutation of PSEN1 gene, located on chromosome 14, which codes for the production of presenilin-1, a component of g-secretase enzyme complex has also been implicated in the pathogenesis of AD. Another gene, PSEN2, located on chromosome 1 which codes for presenilin-2, which is a component of a different form of g-secretase has been found to be of importance in the pathogenesis of AD. , ApoE protein, which normally removes β amyloid plaques, if faulty could lead to accumulation of these plaques. Among various alleles of this protein, the gene that codes for ApoE å4 is of importance, because people with two alleles of ApoE å4 are at much higher risk for AD. 
Considering the importance of amyloid accumulation, different amyloid proteins have been evaluated as biomarkers of AD. Amyloid accumulation can be detected with the help of low levels of Aβ42 amyloid in cerebrospinal fluid and by radioactive tracer retention on amyloid positron emission tomography (PET) scan. Neurodegeneration can be detected with the help of levels of tau protein in cerebrospinal fluid, decreased fludeoxyglucose uptake on PET scan and by structural imaging with the help of magnetic resonance imaging (MRI). ,,
Considering the importance of amyloid proteins in AD, new treatment modalities are being developed to target the amyloid plaques. The vaccine against Aβ peptide (AN1792) has been tried, but it led to meningoencephalitis in 6% subjects in phase II trial, which lead to discontinuation of the trial. Monoclonal antibodies against different segments of Aβ peptide namely, bapineuzumab, solanezumab, and crenezumab have also been tried, but results so far are not promising. Trials of intravenous immunoglobulins are underway. , Production of APP can be halted by inhibiting g-secretase. Semagacestat is one of the medications considered to have potential to inhibit g-secretase and studies shown that it led to reduced the production of Aβ plaques; however, it caused further impairment of cognition, which led to discontinuation of the study. 
| Vascular dementia|| |
Vascular dementia (VaD) is the second most common type of dementia seen worldwide. It was earlier known as multi-infract dementia or Binswanger's disease. The clinical manifestations of VaD are determined by the extent of blood vessel affected. The cognitive deficits in this condition largely depend on the site of the brain involved and memory may not be necessarily impaired.  In contrast to other degenerative dementias, VaD is characterized by abrupt onset and a step ladder deterioration. The patient often presents after a stroke with symptoms of confusion, disorientation, difficulty in speaking or understanding speech, and vision loss. The cognitive symptoms may be accompanied by focal neurological signs and symptoms.  Researchers have described many subtypes of VaD and these include multi-infarct dementia (cortical VaD), small vessel dementia (subcortical VaD), strategic infarct, hypoperfusion dementia, hemorrhagic dementia, hereditary VaD cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, and AD with cardiovascular disease.  Some researchers subtype VaD as poststroke dementia, subcortical VaD, and combined AD and VaD (AD + VaD). 
As the name suggests, cerebrovascular insult leads to pathological brain changes in patients with VaD that impairs cognition. However, the exact contribution of these changes is difficult to ascertain. There are large vessel atherosclerotic changes, small vessel infarcts, and microinfarcts. Furthermore, these changes overlap with those seen in patients with AD. Therefore, cases of pure VaD can be described perhaps only with large infarcts. With increasing age, vascular changes in the brain are increasingly common. , Risk factors for VaD include transient ischemic attacks (TIAs) and stroke. Accordingly, all those factors which increase the risk of atherosclerosis are considered to be risk factors for VaD. These include the presence of hypertension, diabetes mellitus, dyslipidemia, metabolic syndrome, smoking, and use of estrogen in postmenopausal women. Other risk factors for VaD include increasing age, male gender, history of stroke, TIAs, presence of cardiovascular disease, history of sleep apnea, history of depression, and family history of cardiovascular disease.  Studies suggest that compared to those without a history of stroke, those with a history of stroke have 9 fold increased risk of VaD.  Follow-up studies suggest that about 30% of patients who develop stroke develop dementia in subsequent 6-12 months.  Considering the importance of cardio-metabolic risk factors management of VaD involves the control of risk factors for vascular diseases. 
Lewy body dementia (LBD) is considered to be the third most common cause of dementia after AD and VaD, and it accounts for 0-30.5% of all cases of dementia. Further, depending on the definition of case, the prevalence of LBD in the general population ranges from 0% to 5%. , LBD is an umbrella term use to describe two related forms of dementia, i.e., dementia with Lewy bodies and Parkinson's disease dementia. When dementia starts after 1 year or more after, the onset of motoric symptoms of Parkinson's disease, it is known as Parkinson's disease dementia, and if dementia occurs concurrently or within 1 year of onset of motoric symptoms of Parkinson's disease, it is known as dementia with Lewy bodies.  Clinical features of LBD are categorized as central features, core features, suggestive features, and supportive features. The central feature includes the presence of cognitive deficits, which typically involves attention and executive functions. Memory impairment may not be seen in the early stages however these emerge with the progression of dementia. The core features of LBD include the presence of fluctuating attention and concentration, recurrent well-formed visual hallucinations, and the presence of parkinsonian motor signs. The clinical features which are considered as suggestive of LBD include the presence of rapid eye movement sleep behavior disorder, severe neuroleptic sensitivity, and low dopamine transporter uptake in basal ganglia demonstrated by single-photon emission computed tomography or positron emission technique imaging. The supportive features of LBD include repeated falls and syncope (fainting), transient, unexplained loss of consciousness, presence of autonomic dysfunction, hallucinations in other modalities, visuospatial abnormalities and other psychiatric disturbances such as systematized delusions, aggression, and depression. Based on the different combination of core and suggestive symptoms the diagnosis of LBD is considered as probable or possible. A probable diagnosis is made when the patient has dementia along with two or more core features or when the patient has dementia along with one core feature and one or more suggestive feature. A possible diagnosis is considered when the patient has dementia along with one core feature or when the patient has dementia along with one or more suggestive features. 
The pathological hallmark of LBD is the presence of α-synuclein neuronal inclusions, also known as Lewy bodies, accompanied by neuronal loss. However, it is believed that pathogenesis of LBD is multifactorial as there have been postmortem cases with severe α-synuclein pathology and yet without symptoms of the disease. , The majority of cases of LBD are sporadic. However, familial cases have associated with SNCA and LRRK2 genes. The mutations of these genes can lead to Parkinson's disease, Parkinson's disease dementia, or dementia with Lewy bodies. The gene APOE å4 closely associated with AD has also been found in higher frequencies in patients LBD. , The risk factors for LBD include increasing age and male gender. When compared to healthy controls, other studies suggest that the presence of a history of depression, anxiety, stroke, adult attention deficit hyperkinetic disorder, family history of Parkinson's disease are associated with increased risk of LBD. In addition, the risk is higher among those who carry APOE å4 alleles. ,
| Frontotemporal dementia|| |
Frontotemporal dementia (FTD) also known as Pick's disease is a neurodegenerative disorder characterized by deficits in behavior, language and executive functions that precede the development of memory deficits. It is also characterized by selective atrophy of frontal and temporal lobes and only in late stage, the structural and functional changes are diffuse.  FTD is characterized by loss of neurons, gliosis and microvascular changes in frontal lobes, anterior temporal lobes, anterior cingulate cortex, and insular cortex. 
Clinically, two different variants of FTD are described; these include behavior variant FTD (bvFTD) and primary progressive aphasia (PPA), both of which could be associated with motor neuron disease. The bvFTD is characterized by personality change which often leads to interpersonal problems. This subtype is characterized by atrophy of areas of the brain involved in conduct, judgment, empathy, and foresight. PPA subtype of FTD is characterized by problems of language, speaking, writing, and comprehension. It usually starts before the age of 65 years, but can start on a later date too. PPA is further subdivided into semantic variant (i.e., characterized by difficulty in formulating spoken sentences), progressive nonfluent aphasia variant (i.e., hesitant, labored or ungrammatical speech), and logopenic progressive aphasia (characterized by difficulty in naming and retrieval of single words). ,,
There are three proteins whose abnormal deposits are responsible for FTD, namely, microtubule-associated protein tau (MAPT), the TAR DNA-binding protein with molecular weight 43 kDa (TDP-43), or the fused in sarcoma (FUS) protein. The three pathological variants of FTD have been named after these proteins. , Nearly, 40% patients of FTD have a positive family history of dementia. The genes that are most commonly implicated in the pathogenesis of FTD are C9orf72, MAPT, and GRN. Together, these account for 60% of all familial cases of FTD. Mutations of gene C9orf72, located on chromosome 9, alone are responsible for up to 25% cases of FTD. Other important genes for FTD are the ones that code for TDP-43 and FUS. ,, Studies have also linked FTS with mutations of chromatin-modifying protein 2B gene on chromosome 3 and mutations involving ubiquitin inclusions. , Patients with FTD associated with motor neuron disease have ubiquitin-immunoreactive inclusions which have been included to genetic defects on chromosome number 9 and 3. ,
| Prion related dementia|| |
Prion diseases are a group of fatal neurodegenerative conditions, which include Creutzfeldt-Jakob disease More Details (CJD) and Gerstmann-Strδussler-Scheinker (GSS) in humans. There different variants of CJD, based on the possible etiologies have been described, i.e., sporadic, genetic, and acquired. The sporadic variant accounts for 85% of case load and occurs due to posttranslational modification of native cellular prion protein into pathologic scrapie prion protein.  The sporadic variant of CJD usually occurs at 60-65 years of age. The familial variant of CJD accounts for 10-15% of cases and results from genetic mutations of the prion protein gene (PRNP). Most of the cases of familial CJD are caused by Autosomal dominant point mutations.  The third variant acquired CJD, which contributes to 1% of CJD cases, occurs due to exposure to an external source of abnormal PRNP.  GSS occurs due to PRNP mutations and is characterized by the long duration of illness, in contrast to the short duration of illness in CJD.  CJD as an illness affects the gray matter and leads to neuronal loss, gliosis, and characteristic spongiform change. 
All prion diseases are characterized by cognitive impairment as the most common neuropsychiatric manifestation, followed by behavioral/personality changes seen in 20% of subjects, affective symptoms seen in 14% of cases, and psychotic symptoms and agitation seen in 14% of cases.  The cognitive symptoms include executive dysfunction, progressive loss of speech, visual symptoms, memory problems, parietal dysfunction, a largely expressive dysphasia, with reduced motor speed.  Patients with young onset sporadic CJD often present with affective symptoms. Electroencephalogram, cerebrospinal fluid analysis, and MRI of the brain show characteristic findings for CJD. 
| Reversible dementias|| |
Compared to degenerative dementias, reversible dementia is characterized by reversal in the cognitive symptoms, with appropriate management of the primary cause. However, it is important to remember that the reversibility of cognitive symptoms depends on the time of diagnosis and severity of concomitant medical illness.  The list of etiological causes of reversible dementia is increasing. Diagnosis of reversible dementia often depends on careful clinical history, examination, and appropriate investigations to delineate the cause of dementia.  It is very important to look for the classical symptoms of particular disorders to clench the diagnosis. For example, patients with normal pressure hydrocephalus may present with gait disturbances, memory deficits, and urinary incontinence. It is also important to remember that certain reversible causes such as heavy metal intoxication must always be considered while evaluating patients of dementia. Similarly, history taking should focus on the intake of specific medications, for example, certain antihypertensives, may lead to cognitive deficits. If these are not considered, the patient may be misdiagnosed as having VaD in view of the underlying illness. 
| Conclusion|| |
Dementias are a heterogeneous group of disorders, which are characterized by cognitive symptoms. However, regarding etiology, many different causes of dementia have been documents. Although AD remains the most common cause of dementia, it is important to remember that about one-fifth of the dementias may arise due to reversible causes. Hence, a proper evaluation of a patient with dementia should involve through history taking, physical examination, and required investigations to delineate the cause of dementia.
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