Alzheimer Disease (AD)

Description:
- Progressive, irreversible neurodegenerative disease causing neuron death.
- Accounts for 60-80% of dementia cases.
- Sixth leading cause of death in the US.
- Average survival after diagnosis (≥65 years): 4 to 8 years.
- Underdiagnosed: ~50% unaware of diagnosis.
- Economic burden (2023): ~$245 billion, projected $1.1 trillion by 2050 (1).

Distinctions:
- Age-related cognitive decline: normal lifelong changes.
- Mild cognitive impairment (MCI): greater impairment than normal aging; patients remain largely independent; affects 17-22% ≥65 years, with 32-38% progressing to dementia within 5 years (1).

AD Diagnostic Classification:
- Preclinical AD: no symptoms but biomarkers present.
- MCI due to AD: very mild impairment.
- Dementia due to AD:
- Mild: impairment in some activities.
- Moderate: impairment in many activities.
- Severe: impairment in most activities.

Epidemiology

Age: predominantly >65 years.
Incidence equal in females and males; prevalence higher in females.
New US cases annually: 484,000.
Incidence rates increase with age:
65-75 yrs: 2/1000
75-84 yrs: 11/1000
≥85 yrs: 37/1000
Prevalence: ~6.7 million US; ~50 million worldwide (1).
Projected US prevalence by 2050: 13.8 million.
1 in 9 ≥65 yrs have AD dementia; 33.3% ≥85 yrs have AD dementia.
Early-onset AD (<65 yrs): ~200,000 cases in US.

Etiology and Pathophysiology

Progressive cognitive decline due to β-amyloid plaques (extracellular) and tau protein tangles (intracellular) causing neuronal loss.
Influenced by age, genetics, systemic diseases, lifestyle factors.

Genetics

Autosomal dominant <5% (usually early onset).
Familial (non-dominant): 15-25%.

Risk Factors

Nonmodifiable:
- Age, gender (female longevity).
- Family history, genetic mutations (APOE-e4 variant increases risk 2-3x heterozygous, 8x homozygous).
- Racial and ethnic disparities.

Cardiovascular:
- Hypertension (esp. midlife), hyperlipidemia.
- Obesity, diabetes, impaired glucose metabolism.
- Tobacco use, poor diet, physical inactivity.
- Cerebrovascular disease/stroke.

Other Modifiable:
- Low education (<8th grade).
- Lack of cognitive stimulation.
- Traumatic brain injury.
- Social isolation.
- Late-life depression.
- Poor sleep quality.
- Hearing/vision deficits.
- High alcohol use.
- Environmental toxins (air pollution).

General Prevention

Manage hypertension, increase physical activity, cognitive training (3)[B].
NSAIDs, estrogen, vitamin E not effective; statins and PPIs insufficient evidence (3)[B].
Healthy lifestyle may delay/prevent AD (3)[B].
Treat psychiatric conditions; prevent delirium in hospital.

Commonly Associated Conditions

Down syndrome
Depression

Diagnosis

Medicare wellness visits require cognitive screening.
Dementia diagnosis requires ruling out delirium; thorough H&P, cognitive, and diagnostic tests.
DSM-IV-TR (2000): impairment in ≥2 cognitive domains with significant functional interference.
DSM-5 (2013): "Neurocognitive disorder"; impairment in ≥1 domain disrupting independence.

History

Obtain informant info (family/caregiver).
Alzheimer’s Association 10 signs: memory loss, difficulty tasks, planning issues, word problems, spatial difficulties, mood/personality changes, misplacing items, poor judgment, social withdrawal, confusion.

Physical Exam

Evaluate for other dementia/delirium causes.
Neuro: speech, language, vision, hearing, gait, reflexes, tremor, abnormal movements.
Late stage: assess skin, nutrition, hydration.
Cognitive screening: Mini-Cog, MoCA, MMSE.
Depression screening: PHQ-9, GDS.
Functional assessment: IADLs, Functional Activities Questionnaire.

Differential Diagnosis

Vascular dementia, mixed dementia
Frontotemporal lobar degeneration
Lewy body dementia
Parkinson disease
Normal pressure hydrocephalus
Creutzfeldt-Jakob disease, Huntington disease, Wernicke-Korsakoff syndrome
Metabolic (thyroid, vitamin deficiencies, uremia, hepatic, hyponatremia)
Autoimmune (vasculitis, MS)
Infectious (HIV, syphilis, Lyme, VZV, prions)
Depression, brain tumors, subdural hematoma
Medication or substance-related

Diagnostic Tests & Interpretation

Neuropsych testing for atypical, young onset, unclear cases.
Labs: CBC, homocysteine, chemistry panel, thyroid function, syphilis, lipid, vitamin B12, ESR, HIV, folate, CRP, HbA1c.
Imaging: MRI preferred; CT if MRI contraindicated or urgent.
Functional/biomarker imaging (SPECT, PET) rarely indicated.
Consider genetic testing for familial AD.
CSF biomarkers not routinely indicated.

Treatment

General Measures

Optimize risk factor and comorbidity management (e.g., hearing).
Advance care planning early.
Assess caregiver support and burnout.
ALERT: American Geriatrics Society advises against cholinesterase inhibitors without periodic cognitive and GI side effect assessment.

Medication

First Line:
- Acetylcholinesterase inhibitors (ChEIs):
- Best in mild-moderate AD; also for Lewy body dementia.
- Donepezil, rivastigmine, galantamine (equally effective).
- Side effects: GI, bradycardia, syncope.
- Benefits mild cognition and behavior after ≥6 months.
- Titrate doses per guidelines; caution with digoxin and beta-blockers.

Memantine:
NMDA receptor antagonist for moderate-severe AD.
Used alone or with ChEIs.
Aducanumab:
Anti-β-amyloid monoclonal antibody with limited benefit and side effects.
Not recommended routinely; specialist evaluation advised.

Second Line:
- SSRIs for moderate-severe depression.
- Insomnia meds have limited efficacy; avoid antihistamines.
- Low-dose risperidone or SSRIs for agitation/anxiety/restlessness; caution for severe psychosis.

Precautions:
- Avoid anticholinergics if possible.
- Benzodiazepines may cause paradoxical excitation/drowsiness.
- Triazolam may cause confusion and psychosis.

Issues for Referral

Geriatric psychiatry for behavioral symptoms needing psychotropics.

Additional Therapies

Exercise for restlessness.
Cognitive stimulation therapy.
Occupational, music, aroma, pet therapy.

Ongoing Care

Follow-Up

Medication reconciliation including OTCs at each visit.
Encourage healthy lifestyle: exercise, nutrition, sleep, social and cognitive engagement.
Educate about unproven products marketed for brain health.
Monitor ChEI and memantine side effects and efficacy.
Late AD may require skilled nursing care.
Advance care planning is Medicare reimbursable.
Driving safety resources: https://www.nhtsa.gov/older-drivers/driving-safely-while-aging-gracefully

Diet

Trial ketogenic diet may improve cognition.

Patient Education

Alzheimer's Association: https://www.alz.org/
Emphasize early advance care planning, caregiver support.

Prognosis

Average survival 4-8 years post diagnosis; often diagnosed late.

Complications

Behavioral: hostility, agitation, wandering, sundowning, depression, suicide.
Medical: infections, malnutrition, drug toxicity.

References

Alzheimer's Association. 2023 Alzheimer's disease facts and figures. Alzheimers Dement. 2023;19(4):1598-1695.
Atri A. Alzheimer's disease clinical spectrum: diagnosis and management. Med Clin North Am. 2019;103(2):263-293.
Livingston G, Huntley J, Sommerlad A, et al. Dementia prevention, intervention, and care: Lancet Commission report. Lancet. 2020;396(10248):413-446.

Additional Reading

Gerontological Society of America. GSA KAER Toolkit for Primary Care Teams. 2020. https://www.geron.org/publications/kaer-toolkit

ICD10 Codes

G30 Alzheimer's disease
G30.1 Alzheimer's disease with late onset
G30.9 Alzheimer's disease, unspecified

Clinical Pearls

AD common: >33% prevalence in ≥85 years; greatly underdiagnosed.
Typical AD diagnosis usually clinical; imaging not required.
Early diagnosis facilitates advance care planning and caregiver support.
Atypical antipsychotics increase mortality risk.