Memory loss

Linda A Hershey MD PhD (Dr. Hershey of the University of Oklahoma Health Sciences Center has no relevant financial relationships to disclose.)
Ferenc Deak MD PhD (Dr. Deak of the University of Oklahoma Health Sciences Center has no relevant financial relationships to disclose.)
Calin I Prodan MD (Dr. Prodan of the University of Oklahoma Health Sciences Center has no relevant financial relationships to disclose.)
Sergio Ramirez-Salazar MD (

Dr. Ramirez Salazar of the University of Oklahoma Health Sciences Center has no relevant financial relationships to disclose.

Martin R Farlow MD, editor. (

Dr. Farlow of Indiana University received research grant support from AbbVie, Biogen, Boehringer Ingelheim, Eisai, Eli Lilly, Genentech, Roche, Novartis, Suven Life Sciences Ltd, and vTv Therapeutics; fees from Cerecin/Accera, Allergan, Avanir, AZ Therapies, Eli Lilly, Kyowa Kirin Pharma, Longeveron, Medavante, Merck, Neurotrope Biosciences, Proclara, Takeda, and vTv Therapeutics for consultancy, or advisory board/DSMB membership; licensing fees from Elan; and consulting fees from Cortexyme, Green Valley, Regenera, Samumed, Zhejiang Hisun Pharmaceuticals, Cognition Therapeutics, Danone, Eisai, and Otsuka.

Originally released November 24, 1997; last updated June 25, 2019; expires June 25, 2022

This article includes discussion of memory loss, amnesia, amnestic disorder, cognitive impairment, dementia, anterograde amnesia, retrograde amnesia, short-term memory loss, mild cognitive impairment, chronic traumatic encephalopathy, Alzheimer disease, Wernicke-Korsakoff syndrome, frontotemporal dementia, vascular dementia, dementia with Lewy bodies, and subjective cognitive impairment. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.


In this article, the authors provide an overview of memory loss and its most common presentations in the clinical setting (mild cognitive impairment, Alzheimer disease, vascular dementia, dementia with Lewy bodies, Wernicke-Korsakoff syndrome, and chronic traumatic encephalopathy). Risk factors for mild cognitive impairment are reviewed, along with lifestyle changes that have been suggested to slow progression from mild cognitive impairment to dementia.

Key points


• Early-onset Alzheimer disease patients are more likely to have atrophy in both parietal lobes, rather than in medial temporal lobes, or diffusely over the cortex, as is commonly seen in late-onset Alzheimer disease. They also have more problems with language, attention, visuospatial function, and executive tasks, compared to the memory loss seen in their late-onset peers.


• Chronic traumatic encephalopathy causes early memory loss in boxers, football players, and war veterans. The neurofibrillary tangles and extracellular plaques in the brains of these patients at autopsy are similar to those seen in the brains of Alzheimer disease patients, but chronic traumatic encephalopathy is defined pathologically by an abnormal accumulation of tau protein that is different from the pattern seen in Alzheimer disease.


• There has been a recent cluster of young people (mean age = 35 years) who developed anterograde amnesia after waking up after acute episodes of substance abuse (62% involving heroin or other opiates). MRI in several of these patients showed ischemic changes in both hippocampi.


• Longitudinal studies in older adults have demonstrated that a higher level of total daily physical activity is associated with reduced risk of cognitive decline and Alzheimer disease. Recent animal studies have shown that both exercise and sleep accelerate glymphatic clearance of beta amyloid from the brain and reduce the accumulation of amyloid plaques.


• Several longitudinal cohort studies have followed biomarker profiles of brain amyloid, brain tau, and neurodegeneration in cognitively normal older adults over a mean of seven years and have found that abnormal markers of both amyloid and tau are necessary for the occurrence of the accelerated neurodegeneration and memory loss that precedes Alzheimer disease.

Historical note and terminology

Wernicke-Korsakoff syndrome. In 1881, Carl Wernicke described two male alcoholics and one female with persistent vomiting who presented with acute confusion and ataxia (all three died by the end of two weeks). In 1887, Sergei Korsakoff reported 20 patients with either alcoholism or vomiting who developed chronic memory loss and polyneuropathy. We now use the term “Wernicke-Korsakoff syndrome” to describe this biphasic illness, where the acute phase is called Wernicke encephalopathy, and the chronic disorder is known as Korsakoff syndrome (Sechi and Serra 2007). MRI signs of Wernicke-Korsakoff syndrome include the chronic signs of shrunken mammillary bodies and acute signs of hyperintense T2 signal in thalami and periaqueductal grey (Sullivan and Pfefferbaum 2009).

Vascular dementia. In 1894, Otto Binswanger wrote about eight patients who were middle-aged when they developed acute confusion, then chronic memory loss, focal neurologic signs, gait disorder, and functional impairment. Their memory disorder fluctuated over time, but at autopsy all of them showed evidence of diffuse subcortical demyelination with sparing of cortical neurons. Hypertension and diabetes are the most important risk factors for vascular dementia, especially the subtype known as Binswanger disease (Hershey 2008; Moorhouse and Rockwood 2008).

Alzheimer disease. In 1906, Alois Alzheimer described two women who experienced the insidious onset of memory problems in their 50s. Their memory disorders steadily progressed, and when they died several years later, Dr. Alzheimer found microscopic changes (tangles and plaques) in and around cortical neurons. Genetic analysis from one of these first patients identified a point mutation in the presenilin 1 gene, leading to a Phe176Leu amino acid substitution (Muller et al 2013). This could explain the early memory loss in this first case.

In the 1950s, we learned the pivotal importance of the hippocampus to memory function (Williams and Pennybacker 1954; Scoville and Milner 1957). More recently, transient hippocampal hypoperfusion was shown to be the cause of transient global amnesia (Tanabe et al 1991), and hippocampal atrophy was recognized as the first MRI sign of Alzheimer disease (Jack et al 1992).

Frontotemporal dementia. In the late 19th century, Arnold Pick described the first cases of frontotemporal dementia (Warren et al 2013). Now, frontotemporal dementia refers to a diverse group of disorders that involve atrophy of specific areas of the frontal or temporal lobes, or both (brain MRI and neuropsychological testing are both needed for an accurate diagnosis). The presenting features are behavioral changes (behavioral variant), language problems (progressive nonfluent aphasia, semantic dementia), or behavioral changes associated with motor neuron disease rather than memory loss.

Dementia with Lewy bodies. Lennox and others described diffuse Lewy body disease as being different from Alzheimer disease in that it has a more fluctuating clinical course, extrapyramidal signs, well-formed visual hallucinations, and increased sensitivity to neuroleptic drugs (Lennox et al 1989). An autopsy study from one large dementia clinic in North America showed that dementia with Lewy bodies accounted for at least 20% of the total number of brains, although many of these brains showed features of Lewy body disease and Alzheimer pathology (Bowler et al 1998). The diagnostic accuracy for this disease varies widely from one study to another. Visual hallucinations, for example, are not required for the diagnosis and were recorded in only 42% of those in an autopsy study (Merdes et al 2003). Besides dementia, patients must have at least two of these four clinical features for a probable diagnosis: (a) visual hallucinations, (b) fluctuating levels of alertness, (c) signs of parkinsonism, or (d) REM sleep disorder (McKeith et al 2017).

Mild cognitive impairment. In 1999, Petersen and others described mild cognitive impairment as being a transitional state between normal aging and dementia (Petersen et al 1999). A large epidemiologic study in 2002 showed that cognitive impairment without dementia affected approximately five million elderly people in the United States, more people than are affected by Alzheimer disease (Plassman et al 2008). Symptoms of mild cognitive impairment can vary depending on whether they are preclinical manifestations of Alzheimer disease (memory complaints), vascular dementia (executive dysfunction), dementia with Lewy bodies (fluctuations in cognition), or other dementias (Ingles et al 2007; Molano et al 2010). Duff and others showed that nearly 40% of those genetically at risk for Huntington disease meet criteria for mild cognitive impairment (Duff et al 2010), just as about 40% of Parkinson patients have mild cognitive impairment (Kim et al 2009).

Chronic traumatic encephalopathy. In 2009, McKee and others described a condition in football players and war veterans that is now known as chronic traumatic encephalopathy (McKee et al 2009). In these brains, there are deposits of neurofibrillary tangles of tau protein and extracellular amyloid plaques that are similar to those seen in Alzheimer disease. These brains also look similar to those of boxers (dementia pugilistica). Jordon and others earlier showed that the risk of dementia was higher in victims of sports injuries if they had one or two of the apolipoprotein E epsilon 4 alleles (Jordan et al 1997).

Subjective cognitive decline. When patients complain of memory loss, but have unimpaired performance on cognitive tests, we say that they have subjective cognitive decline (Scheef et al 2012). The newest criteria for subjective cognitive decline have been reported by the Subjective Cognitive Decline Working Group (Jessen et al 2014). Stage 3 of preclinical Alzheimer disease, for example, is defined by biomarker evidence for Alzheimer disease plus subjective cognitive decline without the objective cognitive impairment that is seen with mild cognitive impairment.

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