NCD due to Alzheimer’s disease, impairments increase over time, and functional status gradually declines until symptoms reach the threshold for the diagnosis of major NCD.
The onset of symptoms is usually in the eighth and ninth decades; early-onset forms seen in the fifth and sixth decades are often related to known causative mutations. Symp- toms and pathology do not differ markedly at different onset ages. However, younger in- dividuals are more likely to survive the full course of the disease, while older individuals are more likely to have numerous medical comorbidities that affect the course and man- agement of the illness. Diagnostic complexity is higher in older adults because of the in- creased likelihood of comorbid medical illness and mixed pathology.
Environmental. Traumatic brain injury increases risk for major or mild NCD due to Alz- heimer’s disease.
Genetic and physiological. Age is the strongest risk factor for Alzheimer’s disease. The at onset, particularly in homozygous individuals. There are also extremely rare causative
Alzheimer’s disease genes. Individuals with Down’s syndrome (trisomy 21) develop Alz- heimer’s disease if they survive to midlife. Multiple vascular risk factors influence risk for direct effects on Alzheimer pathology.
Detection of an NCD may be more difficult in cultural and socioeconomic settings where memory loss is considered normal in old age, where older adults face fewer cognitive de- mands in everyday life, or where very low educational levels pose greater challenges to objective cognitive assessment.
Cortical atrophy, amyloid-predominant neuritic plaques, and tau-predominant neurofibril— lary tangles are hallmarks of the pathological diagnosis of Alzheimer’s disease and may be continued via postmortem histopathological examination. For early-onset cases with auto- somal dominant inheritance, a mutation in one of the known causative Alzheimer’s disease genes—amyloid precursor protein (APP), presenilin 1 (PSENl), or presenilin 2 (PSEN2)— may be involved, and genetic testing for such mutations is commercially available, at least for PSEN1. Apolipoprotein E4 cannot serve as a diagnostic marker because it is only a risk factor and neither necessary nor sufficient for disease occurrence.
Since amyloid beta-42 deposition in the brain occurs early in the pathophysiological cascade, amyloid-based diagnostic tests such as amyloid imaging on brain positron emis- sion tomography (PET) scans and reduced levels of amyloid beta—42 in the cerebrospinal ﬂuid (CSF) may have diagnostic value. Signs of neuronal injury, such as hippocampal and temporoparietal cortical atrophy on a magnetic resonance image scan, temporoparietal hypometabolism on a ﬂuorodeoxyglucose PET scan, and evidence for elevated total tau and phospho—tau levels in CSF, provide evidence of neuronal damage but are less specific for Alzheimer’s disease. At present, these biomarkers are not fully validated, and many are available only in tertiary care settings. However, some of them, along with novel bio- markers, will likely move into wider clinical practice in the coming years.
Functional Consequences of Major or Mild
Neurocognitive Disorder Due to Alzheimer’s Disease
The prominence of memory loss can cause significant difficulties relatively early in the course. Social cognition (and thus social functioning) and procedural memory (e.g., danc- ing, playing musical instruments) may be relatively preserved for extended periods.