The Alzheimer’s disease spectrum: biomarkers and treatment pipeline

Dementia due to Alzheimer’s disease

As life expectancies increase across the globe, the pandemic of dementia in older individuals accelerates, most of which is due to Alzheimer’s disease (AD). In the US alone, AD afflicts approximately 7 million older individuals and thus approximately 7 million caregivers and families. Mild cognitive impairment (MCI) due to AD – the precursor to dementia – affects many more (approximately 15–20% of those over age 65). The major risk factors for MCI and AD are aging and family history/genetics, both considered nonmodifiable. African American and Hispanic individuals have a higher risk than Asians and Caucasians. Women have a slightly higher risk than men. Potentially modifiable risk factors include quantity and quality of education, diabetes mellitus, obesity, hypertension, hypercholesterolemia, metabolic syndrome (particularly in midlife), smoking, traumatic brain injury, and exposure to air pollution. Dementia is not a true diagnosis but requires elaboration regarding etiology. Other than AD, the most common causes of dementia in older adults include dementia with Lewy bodies (DLB), Parkinson’s disease with dementia, frontotemporal dementia (FTD)/Pick’s disease, vascular dementia (multiple strokes), and mixed dementias (AD plus vascular dementia or AD plus DLB).

AD presents with gradual and progressive cognitive and functional decline, as well as behavioral disturbance. Cognitive symptoms include a loss of:

  • Memory (amnesia)
  • Gnosis (agnosias)
  • Praxis (apraxias)
  • Language (anomia, aphasia)
  • Visuospatial skills
  • Executive function (intellect, reasoning, insight, foresight).

Functional decline in mild dementia is reflected by requiring assistance with complex activities of daily living (ADLs) – household finances, daily medications, and driving. As dementia advances, assistance is also required with basic ADLs – dressing, grooming, bathing, toileting, walking, transfers, and eating/drinking.

Similar to schizophrenia, symptoms of AD may be “negative” (a loss) or “positive” (a gain). Negative symptoms include a loss of empathy, mood (depression), motivation (apathy, social withdrawal), navigation (wandering, getting lost), responsibility (dependency), circadian rhythm (insomnia), hunger (weight loss), thirst (dehydration), and continence (incontinence). Positive symptoms include irritability, anxiety (agitation, pacing), separation anxiety (shadowing), auditory or visual hallucinations/delusions/paranoia (psychosis), obsessive-compulsive behaviors (rummaging, picking), violence (hitting), and catastrophic reactions. While typical AD presents with a loss of episodic memory, less common variants present with language dysfunction (the logopenic variant, also a primary progressive aphasia), visuospatial agnosias and apraxias (posterior cortical atrophy), or frontal/executive dysfunction.1 Myoclonus and seizures are more common in late stages. The terminal stage, often in hospice care, is characterized by inanition and a vegetative state. The individual usually succumbs to infection (pneumonia) and sepsis, approximately 7–10 years after dementia onset (but with wide variation).