History and exam

Key diagnostic factors

common

memory loss

The hallmark feature of AD is memory decline, with loss of recent memory first. Symptoms progress, with new information rapidly lost, and later, only fragments of memory remaining.

disorientation

Disorientation to time and place. Subtle at first; may manifest behaviorally as misplacing items or getting lost.

nominal dysphasia

Difficulties naming objects/people. Assessed in the Mini-Mental State Examination. Proper names and low-frequency words decline first.

misplacing items/getting lost

May be initial presenting symptom and may be due to memory disorientation or visuospatial dysfunction.

apathy

May become passive, sleep more than usual, or not want to perform usual activities.

decline in activities of daily living and instrumental activities of daily living (IADLs)

Some people are able to remain physically functional long into the disease process. The earliest deficits are in performing IADLs, such as cooking and shopping. This may be due to memory and/or executive function difficulties. Later in AD, continence, ability to dress and groom, and eventually, ambulation and verbalization may be lost.

personality change

Subtle changes develop in personality, and diminished interest in usual activities may be evident.

unremarkable initial physical exam

Physical exam is mostly unremarkable in early stages. In advanced disease patients tend to appear sloppily dressed, confused, apathetic, and disorientated with a slow, shuffling gait and stooped posture. Terminal disease is marked by rigidity and inability to walk and speak.

Other diagnostic factors

common

mood changes

Some people with AD may become depressed, apathetic, agitated, and/or irritable.

poor abstract thinking

Complex tasks requiring organization and planning become difficult.

constructional dyspraxia

Parietal lobe deficits may lead to difficulties completing the clock-drawing test or intersecting pentagons in the Mini-Mental State Examination.

uncommon

prosopagnosia

Failure to recognize familiar faces.

autoprosopagnosia

Failure to recognize oneself in the mirror. More common late in the illness.

Risk factors

strong

advanced age

Numerous studies have shown that the risk of AD increases with advancing age. Age is considered the major risk factor in incidence of AD.

Above the age of 65 years, AD incidence doubles every 5 years.[33]

family history

The estimated lifetime risk of AD in first-degree relatives without a defined underlying genetic risk factor for AD is 25% to 50%.[34][35]

genetics

Mutations in three genes - presenilin 1 (PSEN1), presenilin 2 (PSEN2), and amyloid precursor protein (APP) - are associated with early onset familial cases of AD.[15] Around 70% of AD risk is thought to be due to genetic factors.[15]

The ApoE-4 allele contributes to sporadic cases of late-onset AD, whereas the ApoE-2 isoform is protective.[36] Although many polymorphisms have been explored in AD, none are used predictively.[37][38]

Down syndrome

Trisomy 21 resulting in Down syndrome is associated with the development of amyloid plaques in the brain. Rate of deposition increases markedly between 35 and 45 years of age.

Clinical signs and symptoms of AD develop in some people with Down syndrome from around age 50 years, and are observed in around 75% of people with Down syndrome over age 60 years.[39]

cerebrovascular disease

Cerebrovascular disease is a strong risk factor for vascular dementia, which sometimes coexists with AD (mixed dementia).

Incident atrial fibrillation has been shown to be a risk factor for dementia in older people, even in the absence of stroke.[40]

lifestyle factors and medications

Smoking, midlife obesity, a diet high in saturated fats, abstinence from alcohol in midlife, and consumption of more than 14 units of alcohol/per week have been associated with an increased risk for the development of AD.[21][22][23][24] Moderate alcohol consumption (1-14 units/week) may protect against dementia.[21][24]

Modifiable risk factors associated with the greatest increased risk for dementia include smoking in midlife, hypertension and prehypertension, and diabetes (although one study suggested that type 2 diabetes is associated with an increased risk of vascular dementia, but not of AD).[23][41][42]

Some medications (e.g., anticholinergic drugs; long-term use of postmenopausal systemic estrogen in women; androgen deprivation therapy in men with prostate cancer) have been associated with increased risk of AD, but it is unclear whether this is the direct effect of the medications themselves or is related to the underlying medical conditions and/or related lifestyle factors.[43][44][45]

less than high school education

Less than high school education has been associated with a greater risk of developing dementia.[23][42][46]

weak

traumatic brain injury

Even mild injury without loss of consciousness increases the risk of developing dementia. The more severe the traumatic brain injury, the higher the risk.[23][25] 

depression

Increases the risk of developing AD.[23][47][48]

It is unclear whether depression represents a true risk factor or a prodrome of AD. One meta-analysis found that late-life depression was associated with a twofold increased risk of AD.[49]

hearing loss

Age-related hearing loss is associated with cognitive decline and dementia.[23][26]

hyperlipidemia

Hyperlipidemia is a weak risk factor for vascular dementia (which sometimes coexists with AD [mixed dementia]).

female sex

AD is more common in women than in men.[5][11]

elevated plasma homocysteine level

It is not clear whether homocysteine is a proxy marker for an underlying metabolic process or an etiologic factor in its own right.[50]

artificially sweetened soft drink consumption

Daily intake of artificially sweetened soft drinks has been associated with an increased risk of dementia.[51]

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